Hoffmann | Rockstroh

Hoffmann | Rockstroh

HIV 2023/24
Hoffmann | Rockstroh HIV 2023/2024
HIV 2023/2024 [Link]

[Link]
What to start with? When to switch? How can a failing antiretroviral
drug combination be improved? How to treat pregnant women and
children, patients with tuberculosis or other AIDS events, with
hepatitis coinfections or with HIV-2? What about STDs, Mpox and
COVID-19? How should PrEP be taken and monitored?

To answer these and many more questions, HIV physicians need to

be constantly updating themselves. This textbook, also available at
[Link], will help them – with clear-cut recommendations
for everyday practice.

Medizin Fokus Verlag

ISBN 978-3-941727-30-4 Medizin Fokus Verlag

This project has been supported
with unrestricted grants from
Gilead Sciences
Janssen-Cilag
MSD
ViiV Healthcare
With texts and illustrations by

Georg Behrens – Hannover

Dirk Berzow – Hamburg
Jan Boergel – Hamm
Christoph Boesecke – Bonn
Patrick Braun – Aachen
Rob Camp – Barcelona (Spain)
Christian Eggers – Linz (Austria)
Stefan Esser – Essen
Gerd Fätkenheuer – Cologne
Sarah Fischer – Ahlen
Henning Gruell – Cologne
Gunar Günther – Bern (Switzerland)
Annette Haberl – Frankfurt
Georg Haerter – Ulm
Thomas Harrer – Erlangen
Marcus Hentrich – Munich
Christian Herzmann – Bad Segeberg
Andreas Hintz – Hamburg
Christian Hoffmann – Hamburg
Heinz-August Horst – Kiel
Martin Hower – Dortmund
Florian Klein – Cologne
Christoph Königs – Frankfurt
Tim Niehues – Krefeld
Christian Noah – Hamburg
Sebastian Noe – Munich
Christian Perro – Hamburg
Anke Reitter – Zurich (Switzerland)
Ansgar Rieke – Koblenz
Jürgen K. Rockstroh – Bonn
Thorsten Rosenkranz – Hamburg
Bernhard Schaaf – Dortmund
Guido Schäfer – Hamburg
Philipp Schommers – Cologne
Christoph D. Spinner – Munich
Thomas Splettstößer – Berlin
Hendrik Streeck – Bonn
Tim Umland – Hamburg
Markus Unnewehr – Hamm
Kathrin van Bremen – Bonn
Martin Viehweger – Berlin
Kathrin van Bremen – Bonn
Mechthild Vocks-Hauck – Berlin
Eva Wolf – Munich
HIV 2023/2024
[Link]

Edited by

Christian Hoffmann
and
Jürgen K. Rockstroh

Medizin Fokus Verlag

IV

Christian Hoffmann, MD, PhD

Infektionsmedizinisches Centrum Hamburg (ICH)
ICH Stadtmitte
Glockengiesserwall 1
20095 Hamburg, Germany
[Link]
email: hoffmann@[Link]

Jürgen K. Rockstroh, MD, PhD

Department of Medicine I
University of Bonn
Sigmund-Freud-Strasse 25
53105 Bonn, Germany
email: [Link]@[Link]

Important note for readers:

Information on dosage and application forms has been checked carefully to the best
of our knowledge. However, neither the editors nor Medizin Fokus Verlag can
guarantee the accuracy of the information. Each reader is advised to check the
package inserts of the drugs. Any dosage or application is at the user's own risk. The
contributors disclaim responsibility for any errors, omissions, or results obtained
from the information contained herein. However, the authors would be grateful for
any comments and suggestions.
The work as a whole and in parts is protected by copyright. Reproductions,
translations, microfilming and storage, and further processing in electronic systems
are prohibited within the narrow limits of copyright law and are subject to criminal
prosecution.

Pharmaceutical industry support in 2020–2022 was 3,333 euros per year, each from
Gilead Sciences and Janssen-Cilag and 2,500 euros from ViiV Healthcare and MSD.
Notably, no influence was exerted on the contents of the book. No person or
employees from the pharmaceutical industry was involved in the production or had
seen the book before publication.

© 2023 by Hoffmann & Rockstroh

Medizin Fokus Verlag
Zöllnerstrasse 17, 22761 Hamburg, Germany
Printed in Germany
ISBN-13: 978-3-941727-30-4

Cover and Print-Production: SchrödersAgentur Berlin | [Link]

Graphic-Design: Tobias Emskoetter, Hamburg
V

Preface 2023/2024
The goal of this book has not changed: To make a textbook that is easily readable
and can be used in the daily practice of HIV treatment. A book that, despite
(unrestricted) support from the pharmaceutical industry, remains independent and
is freely available and accessible via a website.
As in previous years, all chapters of HIV 2023/24 have been thoroughly revised.
A new book was urgently needed almost eight years after the last edition. A lot has
happened. Not only have COVID-19 and monkeypox (Mpox) been added, but also
many new drugs such as bictegravir, doravirine, lenacapavir, or fostemsavir, and long-
acting and dual therapies. New chapters on parenteral and other routes of ART
administration have been created, as well as chapters on prevention (PrEP!), HIV-2,
rheumatology, psychiatry, and trans*medicine.
New editions are also planned for the future. As in the past, the editors and authors
of this book may agree to remove the copyright on HIV 2023/2024 for all languages
except English and German. Therefore, after an official inquiry, you may translate
this book's content into any language and publish it without paying a license fee.
HIV 2023/2024 is also free and available online ([Link]). We firmly
believe this is how medical textbooks should be handled in the 21st century. Research,
knowledge, and expertise in the field of HIV should be shared and accessible to those
dedicated to the treatment and care of people living with HIV.

Christian Hoffmann, Jürgen K. Rockstroh

Hamburg, Bonn – April 2023

Acknowledgements
We want to express our sincere thanks to all those who sent us important suggesti-
ons, comments, and corrections. Thanks also to the companies involved, without
whose unconditional and unrestricted support the production of this work (see
above) would not have been possible. Christian Hoffmann (CH) and Jürgen
Rockstroh (JR) would also like to thank for the clinical images at:
Christian Eggers, Linz (Austria) (CE)
Stefan Esser, Essen (SE)
Stefan Fenske, Hamburg (SF)
Christoph Gerigk, Hamburg (CG)
Georg Haerter, Ulm (GH)
Stefan Hansen, Hamburg (SH)
Johannes Jongen, Kiel (JJ)
A. Rainer Jordan, Cologne (RJ)
Christoph Lange, Borstel (CL)
Marc Oette, Cologne (MO)
Carl-Knud Schewe, Hamburg (KS)
Michael Sabranski, Hamburg (MS)
Guido Schäfer, Hamburg (GS)
Hans-Jürgen Stellbrink, Hamburg (HJS)
Jan Thoden, Freiburg (JT)
Image credits page 686
VI

Contributors

Georg Behrens, MD, PhD Gerd Fätkenheuer, MD, PhD

Department of Clinical Immunology Department of Internal Medicine
Hannover Medical School University of Cologne
Carl-Neuberg-Str. 1 Joseph-Stelzmann-Str. 9
30625 Hannover 50924 Cologne
Phone: +49 511 532-5713
Sarah Fischer, Pharmacist
Dirk Berzow, MD medicalORDER®pharma
Schäferkampsallee 56-58 Krankenhausapotheke St. Franziskus
20357 Hamburg Hospital GmbH, Münster
Phone: +49 40 404711 Kruppstr. 37
dirkberzow@[Link] 59227 Ahlen
Phone: +49 2382 9686 343
Jan Börgel, MD, PhD [Link]@[Link]
Cardio/Nephrology, Intensive Care Medicine Henning Gruell, MD
St. Barbara-Clinic Hamm Institute for Virology
Am Heessener Wald 1 University of Cologne
59073 Hamm Fürst-Pückler-Str. 56
Phone: +49 2381 681 0 50935 Cologne
Jboergel@[Link] Phone: +49 221 478 85801
[Link]@[Link]
Christoph Boesecke, MD
Department of Medicine I Gunar Günther, MD, MPH, DTM&H
University of Bonn Department for Pulmonology and
Sigmund-Freud-Str. 25 Allergology
53105 Bonn Inselspital, Bern University Hospital
Phone: +49 228 287-16558 Freiburgstr. 10
[Link]@[Link] 3010 Bern, Switzerland

Patrick Braun Annette Haberl, MD

PZB Aachen, Blondelstr. 9 HIVCENTER
52062 Aachen JW Goethe University of Frankfurt
Phone: +49 241 470970 Theodor-Stern-Kai 7
pab@[Link] 60590 Frankfurt/Main
Phone: +49 69 6301-7680
Christian Eggers, MD, PhD [Link]@[Link]
Neurology, MCIII
Georg Härter, MD
Kepler University Hospital
MVZ Medicover Ulm
Krankenhausstr. 9
Münsterplatz 6
4021 Linz, Austria
89073 Ulm
Phone: +43 57680 83 -73019
Phone: +49 731 14063-0 (Fax: -110)
[Link]@[Link]
[Link]@[Link]
Stefan Esser, MD, PhD Thomas Harrer, MD, PhD
Department of Dermatology and Venereology Institute for Clinical Immunology
University of Essen University of Erlangen
Hufelandstr. 55 Krankenhausstraße 12
45122 Essen 91054 Erlangen
Phone: +49 201 723-3878 (Fax: -3845) Phone: +49 9131 854-3004
[Link]@[Link] [Link]@[Link]
Contributors VII

Marcus Hentrich, MD, PhD Tim Niehues, MD, PhD

Internal Medicine III – Immunodeficiency and Pediatric
Hematology and Oncology Rheumatology Centre
Red Cross Hospital Munich Helios Klinikum Krefeld
Rotkreuzplatz 8 Lutherplatz 40
80634 Munich 47805 Krefeld
Phone: +49 89 1303-0 Phone: +49 2151 322301 (Fax: 322334)
[Link]@[Link] [Link]@[Link]
Christian Herzmann, MD
Kreis Stormarn Christian Noah, MD
Public Health Dept. Labor Lademannbogen
Reimer-Hansen-Str. 3 Lademannbogen 61-63
23843 Bad Oldesloe 22339 Hamburg
[Link]@[Link] Phone: +49 40 53805-706 (Fax: -879)
[Link]@[Link]
Andreas Hintz, Pharmacist
Alexander Apotheke
Steindamm 81 Sebastian Noe, MD, PhD
20099 Hamburg MVZ München am Goetheplatz
Phone: +49 40 28009922 Waltherstr. 32
team@[Link] 80337 Munich
Phone: +49 89 5503941
Heinz-August Horst, MD, PhD
sno@[Link]
University Hospital of Schleswig-Holstein,
Campus Kiel
II. Department of Medicine Christian Perro, MD
Arnold-Heller-Str. 3, Haus L Eppendorfer Landstr. 37
24105 Kiel 20249 Hamburg
Phone: +49 431 5000 Phone: +49 40 464554
[Link]@[Link]
Martin Hower Anke Reitter, MD, PhD
Medizinische Klinik Nord Spital Zollikerberg
Klinikum Dortmund, ID-Ambulanz Trichtenhauserstr. 20
Beuerhausstr. 26 8125 Zollikerberg (Zurich), Switzerland
44137 Dortmund
Phone: +49 231 95320-700 (Fax: -702)
Ansgar Rieke, MD
[Link]@[Link]
Klinikum Kemperhof Koblenz
Florian Klein, MD, PhD II. Med. Klinik
Institute for Virology Immunologische Ambulanz
University of Cologne Koblenzer Str. 115-155
Fürst-Pückler-Str. 56 56065 Koblenz
50935 Cologne Phone: +49 261 499-2691 (Fax: -2690)
Phone: +49 221 478 85801 [Link]@[Link]
Christoph Königs, MD
Department of Pediatrics and Adolescent Thorsten Rosenkranz, MD
Medicine Department of Neurology
JW Goethe University of Frankfurt Asklepios Clinic St. Georg
Theodor-Stern-Kai 7 Lohmühlenstr. 5
60596 Frankfurt am Main 20099 Hamburg
Phone: +49 69 6301 83030 Phone: +49 40 181885-2241 (Fax: -2971)
ckoenigs@[Link] [Link]@[Link]
VIII Contributors

Bernhard Schaaf, MD, PhD Markus Unnewehr, MD

Medizinische Klinik (Pneumologie/ St. Barbara-Clinic Hamm GmbH
Infektiologie) Am Heessener Wald 1
Klinikum Dortmund GmbH 59073 Hamm
Münsterstr. 240 Phone: +49 2381 681 0
44145 Dortmund munnewehr@[Link]
Phone: +49 231 95318-100 (Fax: -199)
[Link]@[Link] Kathrin van Bremen, MD
Department of Medicine I
Guido Schäfer, MD University of Bonn
ICH Grindel Sigmund-Freud-Str. 25
Grindelallee 35 53105 Bonn
20146 Hamburg Phone: +49 228 287 16558
Phone: +49 40 41 32 42-0 [Link]@[Link]
schaefer@[Link]
Martin Viehweger, MD
Philipp Schommers, MD ViRo Praxis im Schillerkiez
Institute for Virology Okerstr. 11
University of Cologne 12049 Berlin
Fürst-Pückler-Str. 56 mv@[Link]
50935 Cologne
Phone: +49 221 478 85801 Mechthild Vocks-Hauck, MD
KIK Berlin
Christoph D. Spinner, MD, PhD Friedbergstr. 29
Department of Medicine II 14057 Berlin
Technical University of Munich Phone and Fax: +49 30 3247421
Ismaninger Str. 22 kik@[Link]
81675 Munich
Phone: +49 89 4140-0 Eva Wolf, Dipl. Phys. Univ., MPH
[Link]@[Link] MUC Research GmbH
Karlsplatz 8
Hendrik Streeck, MD, PhD 80335 Munich
Institute for Virology Phone: +49 89 558 70 30
University of Bonn Fax: +49 89 550 39 41
Venusberg-Campus 1, B. 63 [Link]@[Link]
53127 Bonn
hstreeck@[Link]

Tim Umland, Pharmacist

Alexander Apotheke
Assistant Editor
Steindamm 81 Rob Camp
20099 Hamburg Barcelona (Spain)
Phone: +49 40 28009922 Phone: +34 600 207 455
team@[Link] camporama@[Link]
IX

Contents
Preface 2023/2024 ................................................................................................. V
Acknowledgements ............................................................................................... V
Contributors .......................................................................................................... VI
Abbreviations......................................................................................................... XV

SECTION 1 The Basics

1. Introduction................................................................................................. 2
The HIV epidemic ................................................................................................. 2
Transmission routes............................................................................................... 3
The natural course of HIV infection ..................................................................... 6
Staging of HIV infection ....................................................................................... 8
Epidemiology......................................................................................................... 9
Summary ............................................................................................................... 10

2. HIV testing ................................................................................................... 13

Diagnostics basics.................................................................................................. 13
Diagnostics for occupational exposure ................................................................. 17
Practical hints ........................................................................................................ 18

3. Pathophysiology of HIV infection............................................................. 20

4. Acute HIV infection .................................................................................... 31

SECTION 2 Antiretroviral Therapy (ART)

5. ART 2023 ...................................................................................................... 40
5.1. Perspective..................................................................................................... 40
5.2. Overview – Classes of antiretrovirals and specific drugs ............................. 43
5.3. ART 2024+: Beyond the horizon .................................................................. 94
5.4. Goals and principles of therapy.................................................................... 121
5.5. When to start with ART? .............................................................................. 145
5.6. The optimal first-line therapy....................................................................... 157
5.7. Management of side effects .......................................................................... 183
5.8. Simplification, de-escalation......................................................................... 199
5.9. Virological failure .......................................................................................... 209
[Link] therapy ............................................................................................. 215
[Link] interruptions................................................................................ 226
[Link] ART ............................................................................................ 234
[Link] Access to HIV Treatment................................................................... 245

6. Viral Resistance and Tropism ..................................................................... 253

Methods of resistance testing................................................................................ 253
Interpretation of genotypic resistance profiles..................................................... 263
Summary ............................................................................................................... 274
X Contents

SECTION 3 AIDS
7. Opportunistic infections (OI)..................................................................... 286
Pneumocystis pneumonia (PCP)........................................................................... 288
Cerebral toxoplasmosis ......................................................................................... 294
CMV retinitis ......................................................................................................... 298
Candidiasis ............................................................................................................ 302
Tuberculosis ........................................................................................................... 305
Atypical mycobacteriosis (MAC)........................................................................... 316
Herpes simplex ...................................................................................................... 319
Herpes zoster ......................................................................................................... 322
Progressive multifocal leukoencephalopathy ....................................................... 324
Bacterial pneumonia ............................................................................................. 328
Cryptosporidiosis................................................................................................... 331
Cryptococcosis....................................................................................................... 333
Salmonella septicemia ........................................................................................... 337
Immune Reconstitution Syndrome (IRIS)............................................................. 338
Wasting Syndrome ................................................................................................ 342
Rare opportunistic infections (OIs)....................................................................... 344

8. Kaposi’s sarcoma.......................................................................................... 354

9. Malignant lymphomas................................................................................ 361

Systemic non-Hodgkin’s lymphoma (NHL).......................................................... 362
Primary CNS lymphoma ....................................................................................... 371
Hodgkin’s lymphoma (HL) ................................................................................... 373
Multicentric Castleman disease (MCD) ................................................................ 375

10. Non-AIDS-defining malignancies .............................................................. 381

Anal carcinoma ..................................................................................................... 383
Testicular tumors ................................................................................................... 386
Lung cancer .......................................................................................................... 386

SECTION 4 Other Infections

11. HIV and HBV/HCV co-infections .............................................................. 392
HCV co-infection .................................................................................................. 392
HBV co-infection ................................................................................................... 398

12. HIV and COVID-19...................................................................................... 403

13. HIV and sexually transmitted diseases ..................................................... 409

Epidemiology......................................................................................................... 409
Syphilis (Lues) ....................................................................................................... 411
Gonorrhea (gonorrhea) ......................................................................................... 416
Chlamydia, lymphogranuloma venereum (LGV)................................................. 418
Genitoanal mycoplasma infections ...................................................................... 420
Chancroid.............................................................................................................. 421
Granuloma inguinale (donovanosis, granuloma venereum) ............................... 422
Condylomata acuminata (genital warts) .............................................................. 422
Shigellosis .............................................................................................................. 428
Mpox...................................................................................................................... 431
Contents XI

14. Vaccinations ................................................................................................. 435

Practical procedures............................................................................................... 435
Vaccinations in detail (selected vaccinations) ...................................................... 436

15. HIV and travel medicine ............................................................................ 445

Specific risks .......................................................................................................... 450

16. HIV-2 infection ............................................................................................ 455

Antiretroviral therapy for HIV-2 infection ........................................................... 457

SECTION 5 Women and Children

17. HIV and women .......................................................................................... 466

18. HIV and gynecology.................................................................................... 470

Gynecological screening ....................................................................................... 470
Cycle and menopause ........................................................................................... 473
Other infections .................................................................................................... 474

19. Pregnancy and HIV ..................................................................................... 477

ART before and during pregnancy........................................................................ 477
HIV drugs during pregnancy................................................................................. 480
Risk of perinatal HIV infection ............................................................................. 483
Treatment of the newborn .................................................................................... 487

20. Antiretroviral therapy in children ............................................................ 493

Therapy requirements and practical procedures .................................................. 496

SECTION 6 Organs · Interdisciplinary Medicine

21. Checklist: the new patient ........................................................................... 508
Laboratory tests ..................................................................................................... 509
Further investigations ........................................................................................... 510

22. HIV and cardiopulmonary disease .............................................................. 511

Lung diseases ......................................................................................................... 511
Medical history...................................................................................................... 512
Pulmonary complications and co-morbidities ..................................................... 513
Cardiovascular diseases ......................................................................................... 516

23. HIV and nephrology ..................................................................................... 519

The clinic and diagnosis of nephropathy............................................................. 519
Routine tests for kidney damage........................................................................... 521
HIV-associated nephropathy (HIVAN) .................................................................. 521
Other glomerulonephritides (GN) in HIV ............................................................ 522
Therapeutic principles in glomerulonephritis ...................................................... 523
Renal toxicity of drugs .......................................................................................... 524
Renal function and PrEP ....................................................................................... 527
Dosage of ART in renal failure .............................................................................. 528
OIs and renal insufficiency ................................................................................... 530
XII Contents

24. Organ transplantation in HIV infection................................................... 535

25. HIV-associated thrombocytopenia ............................................................ 538

26. HIV-associated skin diseases....................................................................... 543

27. HIV-1-associated neurocognitive disorder (HAND) and HIV-associated

myelopathy .................................................................................................. 552
HAND .................................................................................................................... 552
HIV myelopathy .................................................................................................... 558

28. Neuromuscular diseases ................................................................................ 562

Polyneuropathies and polyradiculitis ................................................................... 562
Myopathies ............................................................................................................ 569

29. HIV and psychiatric diseases........................................................................ 571

Depression and other affective disorders.............................................................. 571
Psychotic disorders ................................................................................................ 573
Addictive disorders ................................................................................................ 575
Personality disorders ............................................................................................. 576
Legal aspects and psychiatric emergencies ........................................................... 576

30. HIV and rheumatology................................................................................. 578

Prevalence.............................................................................................................. 578
Special features ...................................................................................................... 578

31. Sexuality ....................................................................................................... 583

Male sexual dysfunction ....................................................................................... 583
Chemsex ................................................................................................................ 587
Trans*Medicine...................................................................................................... 593

SECTION 7 Prevention
32. Prevention of HIV infection....................................................................... 600
Treatment as Prevention (TasP)............................................................................. 600
Pre-exposure Prophylaxis (PrEP) ........................................................................... 603
Medical prevention, in addition to TasP and PrEP............................................... 607

33. Preventive HIV-1 vaccination: current status........................................... 614

34. Post-exposure prophylaxis (PEP) ............................................................... 621

SECTION 8 Drugs
35. Drug Profiles ................................................................................................ 628
3TC (lamivudine) .................................................................................................. 628
Abacavir ................................................................................................................. 628
Acyclovir................................................................................................................ 629
Amphotericin B ..................................................................................................... 630
Atazanavir.............................................................................................................. 630
Contents XIII

Atovaquone ........................................................................................................... 631

Atripla® .................................................................................................................. 632
Azithromycin......................................................................................................... 632
AZT (zidovudine)................................................................................................... 633
Bictegravir.............................................................................................................. 633
Cabotegravir .......................................................................................................... 634
Cidofovir................................................................................................................ 634
Clarithromycin ...................................................................................................... 635
Clindamycin.......................................................................................................... 635
Cobicistat............................................................................................................... 636
Combivir® .............................................................................................................. 637
Cotrimoxazole ....................................................................................................... 637
Dapsone ................................................................................................................. 638
Darunavir............................................................................................................... 638
Daunorubicin (liposomal) ..................................................................................... 639
Delstrigo® ............................................................................................................... 639
Descovy® ................................................................................................................ 640
Dolutegravir........................................................................................................... 640
Doravirine.............................................................................................................. 641
Dovato®.................................................................................................................. 641
Doxorubicin (liposomal) ....................................................................................... 642
Efavirenz ................................................................................................................ 642
Elvitegravir............................................................................................................. 643
Emtricitabine (FTC) ............................................................................................... 643
Epclusa® ................................................................................................................. 644
Ethambutol............................................................................................................ 645
Etravirine ............................................................................................................... 645
Eviplera® (USA: Complera®) .................................................................................. 646
Fluconazole............................................................................................................ 646
Fosamprenavir ....................................................................................................... 647
Foscarnet................................................................................................................ 647
Fostemsavir ............................................................................................................ 647
Ganciclovir ............................................................................................................ 648
Genvoya® ............................................................................................................... 648
Harvoni® ................................................................................................................ 649
Ibalizumab ............................................................................................................. 649
Interferon alpha 2a/2b .......................................................................................... 650
Isoniazid ................................................................................................................ 650
Itraconazole ........................................................................................................... 651
Juluca® ................................................................................................................... 651
Kivexa® (USA: Epzicom®)....................................................................................... 652
Lenacapavir............................................................................................................ 652
Lopinavir ............................................................................................................... 653
Maraviroc............................................................................................................... 653
Maviret® ................................................................................................................. 654
Nelfinavir............................................................................................................... 655
Nevirapine ............................................................................................................. 655
Odefsey® ................................................................................................................ 655
Pentamidine .......................................................................................................... 656
Pyrimethamine ...................................................................................................... 656
Raltegravir.............................................................................................................. 657
Rekambys® (US: Cabenuva®) ................................................................................. 657
XIV Contents

Ribavirin ................................................................................................................ 658

Rifabutin ................................................................................................................ 659
Rifampicin ............................................................................................................. 659
Rilpivirine .............................................................................................................. 660
Ritonavir ................................................................................................................ 661
Saquinavir.............................................................................................................. 662
Sofosbuvir .............................................................................................................. 662
Stribild® .................................................................................................................. 663
Sulfadiazine ........................................................................................................... 663
Symtuza® ................................................................................................................ 664
T-20 (enfuvirtide)................................................................................................... 664
Tenofovir-DF (TDF) and Tenofovir-AF (TAF)......................................................... 665
Tipranavir .............................................................................................................. 666
Triumeq® ................................................................................................................ 666
Trizivir® .................................................................................................................. 667
Truvada® ................................................................................................................ 667
Valganciclovir ........................................................................................................ 667
Vosevi® ................................................................................................................... 668
Zepatier® ................................................................................................................ 669

36. Drug interactions......................................................................................... 670

Combinations of ART + ART................................................................................. 671
ART + concomitant medications .......................................................................... 671
Gastrointestinally active substances ..................................................................... 671
Antiarrhythmics .................................................................................................... 671
Antibiotics/tuberculostatics................................................................................... 672
Antidepressants ..................................................................................................... 673
Antidiabetics (oral) ................................................................................................ 673
Antihelmintics....................................................................................................... 673
Antihistamines ...................................................................................................... 674
Anticoagulants/antiplatelet agents ....................................................................... 674
Anticonvulsants..................................................................................................... 674
Antifungals ............................................................................................................ 675
Calcium antagonists (CCB) ................................................................................... 675
Immunosuppressants/cytostatics .......................................................................... 676
Contraceptives....................................................................................................... 676
Malaria/Protozoan Therapy................................................................................... 677
Phosphodiesterase type 5 inhibitors ..................................................................... 677
Statins/lipid-lowering agents ................................................................................ 677
Substitution ........................................................................................................... 678
Virustatics/antivirals.............................................................................................. 678
Other...................................................................................................................... 679

37. ART – alternative administrations............................................................. 680

Clinical Images .................................................................................................... 685

Index ..................................................................................................................... 705

XV

Abbreviations
AIDS Acquired Immunodeficiency Syndrome
AIN Anal Intraepithelial Neoplasia
ART Antiretroviral Therapy
AUC Area under the curve
BAL Bronchoalevolar Lavage
BGA Blood Gas Analysis
BMI Body Mass Index
CDC Centers for Disease Control and Prevention
CHD Coronary Heart Disease
CMV Cytomegalovirus
CNS Central Nervous System
CROI Conference on Retroviruses and Opportunistic Infections
CT Computed Topography
CTL Cytotoxic T Cells
CVC Central Venous Catheter
DD Differential diagnosis
DEXA Dual Energy X-ray Absorptiometry
DNA Deoxyribonucleic Acid
DOT Directly Observed Therapy
EAP Expanded Access Program
EBV Epstein-Barr Virus
ED Erectile Dysfunction
ELISA Enzyme-Linked Immunosorbent Assay
ELISPOT Enzyme-Linked Immunosorbent Spot Assay
EMEA European Medicines Agency
FDA US Food and Drug Administration
FDC Follicular Dendritic Cells
G-CSF Granulocyte Colony-Stimulating Factor
GFR Glomerular Filtration Rate
HAART Highly Active AntiRetroviral Therapy
HbsAG Hepatitis B Surface Antigen
HBV Hepatitis B Virus
HCC Hepatocellular Carcinoma
HCV Hepatitis C Virus
HDL High-density Lipoprotein
HHV-8 Human Herpesvirus 8
HIV Human Immunodeficiency Virus
HIVAN HIV-Associated Nephropathy
HIVE HIV-Encephalopathy
HLA Human Leukocyte Antigen
HPV Human Papillomavirus
HSR Hypersensitivity Reaction
HSV Herpes Simplex Virus
IC50 50% Inhibitory Concentration
INSTI Integrase Strand Transfer Inhibitor
XVI Abbreviations

IRIS Immune Reconstitution Inflammatory Syndrome

ITP Idiopathic Thrombocytopenic Purpura
ITT Analysis Intention-to-Treat Analysis
IU International Unit
CHD Coronary Heart Disease
KS Kaposi’s sarcoma
LDH Lactate Dehydrogenase
LDL Low-Density Lipoprotein
LGV Lymphogranuloma venereum
LIP Lymphocytic Interstitial Pneumonia
LTNP Long-Term Non-Progressor
MAC Mycobacterium Avium Complex
MCD Multicentric Castleman's Disease
MDR Multi-Drug Resistant
MHC Major Histocompatibility Complex
MRT Magnet Resonance Tomography
MSM Men who have sex with men
NASBA Nucleic Acid Sequence Based Amplification
NHL Non-Hodgkin’s Lymphoma
NK-Cells Natural Killer Cells
NNRTI Non-nucleoside Reverse Transcriptase Inhibitor
NRTI Nucleoside Reverse Transcriptase Inhibitor
OHL Oral Hairy Leukoplakia
OI Opportunistic Infection
PBMC Peripheral Mononuclear Cell
PCNSL Primary Central Nervous System Lymphoma
PCP Pneumocystis Pneumonia
PCR Polymerase Chain Reaction
PEL Primary Effusion Lymphoma
PEP Post-Exposure Prophylaxis
PI Protease Inhibitor
PML Progressive Multifocal Leukoencephalopathy
PNP Polyneuropathy
PrEP Pre-Exposure Prophylaxis
RNA Ribonucleic Acid
SD Sexual Dysfunction
SIV Simian Immunodeficiency Virus
STD Sexually Transmitted Diseases
STI Structured Treatment Interruption
TAM Thymidine Analogue Mutation
TCR T-cell Receptor
TDM Therapeutic Drug Monitoring
TSH Thyroid-stimulating Hormone
VL Viral Load
VZV Varicella Zoster Virus

For abbreviations of antiretroviral agents, see ART chapter.

SECTION 1

The Basics
2

1. Introduction
J Ü RGEN KU RT ROC KSTROH

Acquired immunodeficiency syndrome (AIDS) was first described as a clinical entity

in 1981. The initial reports were based on an unusual clustering of previously rare
conditions such as Kaposi sarcoma (KS) and Pneumocystis pneumonia (PCP).
Although these syndromes occasionally occur in various populations (such as KS in
older Mediterranean men or PCP in leukemia patients after intensive chemotherapy),
the occurrence of these indicator diseases of immunodeficiency had never been
observed in previously healthy young people. Given the initially affected patient
group, men who have sex with men (MSM), the disease and those affected were
strongly stigmatized. After the cause had initially been suspected to be specific
lifestyles, the human immunodeficiency virus (HIV) was finally identified as the
causative agent of AIDS in 1983.
The first antiretroviral agent, AZT (zidovudine, Retrovir®), was introduced in 1987.
Although this – as monotherapy – inadequately suppressed HIV replication, it at
least succeeded in improving symptoms of HIV infection in the short term and some-
what delaying the onset of AIDS. What followed remains unique in medicine: Within
a decade of its discovery, an inevitably fatal disease became one that could be treated
chronically and effectively. The rapid introduction of further classes of drugs and
the so-called highly active antiretroviral therapy (HAART, a term that is replaced by
ART in this book) succeeded and continues to this day in permanently suppressing
viral replication and preventing progression of the disease – as long as the drugs are
taken regularly and tolerated. Long-term toxicities and resistance necessitated search-
ing for and identifying further promising substances with a different mechanism of
action or a more favorable resistance profile. Incremental improvements have
happened in the administration, use, and eventual tolerability of HIV drugs over the
years. Today, in 2023, several HIV therapies are available via one tablet daily, a
possibility via fixed-dose combinations, as well as once-monthly or bi-monthly injec-
tions of various agents.
However, all this should not hide the fact that lifelong drug treatment can cause
considerable problems – in terms of both short-term and long-term toxicities and
adherence to therapy (so far, limited long-term experience even after almost more
than a quarter-century of effective use). Infection with HIV should continue to be
avoided at all costs. Therefore, in addition to further improvement of ART and new
concepts such as eradication, our efforts must focus on prevention to prevent further
spread.

The HIV epidemic

In 1981, the first three clinical descriptions of AIDS appeared in the Morbidity and
Mortality Weekly Report and later in the New England Journal of Medicine. They included
an epidemic of community-acquired Pneumocystis pneumonia in previously healthy
MSM and chronic ulcerative perianal herpes infections (Gottlieb 1981a, Gottlieb
1981b, Masur 1981, Siegal 1981).
A little later, in June 1982, a Centers for Disease Control (CDC) note was published
on three cases of PCP in hemophiliacs (CDC 1982a). That same year, a clinical case
of cryptosporidiosis in a Pennsylvania hemophiliac (Eyster 1982) and an AIDS case
in a young child following a blood transfusion were also published (CDC 1982b).
The occurrence of AIDS in hemophiliacs triggered a debate about whether AIDS might
Introduction 3

be a virus-related disease (Marx 1982). In particular, the similarity of the risk popu-
lations for AIDS and hepatitis B suggested a viral genesis of AIDS.
Studies of AIDS cases from different patient collectives quickly revealed common
features: for example, CD4-positive T lymphocytes were decreased in all of them
compared with healthy control subjects. In contrast, there was a relative and absolute
increase in CD8-positive T lymphocytes (Gottlieb 1981, Masur 1981, Siegal 1981,
Mildvan 1982, Stahl 1982). It soon became apparent, however, that manifest disease
was not a condition of immunodeficiency. A defect in cellular immunity associated
with lymphadenopathy was described very early in otherwise asymptomatic MSM
(Kornfeld 1982, Stahl 1982). In January 1983, a description of two hemophiliacs with
lymphadenopathy syndrome appeared, both of whom had significant disturbances
of cellular immunity (Ragni 1983). It suggested that the lymphadenopathy and cel-
lular immunity disturbance were preliminary stages of AIDS and that transmission
of the AIDS agent by blood products was likely. Subsequently, various papers reported
alterations in cellular immunity in hemophiliacs. Only in individuals who were
treated with small amounts of factor VIII or whose factor VIII consisted of small
donor pools were regular lymphocyte subpopulations found (Luban 1983, Rasi 1984).
The immunologic findings in hemophiliacs were initially controversial and were
partly explained by a chronic antigen load due to factor VIII administration. Other
groups considered this explanation unlikely since hemophiliacs had not shown an
increased risk of infection than other populations (except for viral infections, espe-
cially hepatitis B and non-A non-B hepatitis via administration of blood products)
until the arrival of AIDS. Overall, no reason was seen at this time that would ques-
tion the concept of factor treatment in hemophiliacs (Anonymous 1983, Goldsmith
1983). Co-infection with human cytomegalovirus, drug use, inhalation of amyl
nitrate (poppers), and exposure to foreign proteins (spermatozoa) were discussed as
possible alternative explanations for AIDS within the MSM risk group (Essex 1997).
In 1983, several research groups suggested that the possible trigger of AIDS might be
a variant of the T-lymphotropic retrovirus (HTLV-I) discovered by Gallo and col-
leagues in 1980 (Essex 1983, Gallo 1983). Several arguments supported this hypoth-
esis. For example, at that time, HTLV-I was the only known human virus with the
potential to infect CD4 T lymphocytes (Poiesz 1980). In addition, HTLV-I was trans-
mitted via the same transmission routes as the possible causative agent of AIDS,
namely via sexual contact, blood, and perinatally (Essex 1982).
Initial attempts to isolate a virus related to HTLV-I or -II were only partially success-
ful. Although cross-reacting antibodies with HTLV-related genome sequences could
be found in a few AIDS patients, the overall reactivity was weak, suggesting only
HTLV co-infection. Instead, these observations suggested the etiological role of a
more distant, weakly reactive virus. Indeed, a little later, the isolation of HTLV-III,
later renamed human immunodeficiency virus type 1 (HIV-1), was identified as the
causative agent of AIDS (Barré-Sinoussi 1983, Popovic 1984). In 2008, the French
research group led by Luc Montagnier and Françoise Barré-Sinoussi was awarded the
Nobel Prize in Medicine for this work.

Transmission routes
HIV is transmitted by
1. Unprotected sexual contact with an HIV-positive partner (who has a detectable
HIV viral load).
2. Shared use of syringe paraphernalia, primarily for drug use.
3. In the context of transmission from an HIV-positive mother to the newborn (before
birth, during birth or through breastfeeding).
4 The Basics

There is still transmission in the context of transfusions of blood or blood products

in countries where blood donations are not regularly tested for HIV. All other
described types of infection transmission are very rare.
Absolute rarities are contact of infected blood with open wounds, mucous
membranes, or HIV transmission via a bite wound (Bartholomew 2008). A few cases
have also been published in which mothers infected their newborns, presumably
through pre-chewed food (Gaur 2008). However, these are all rather casuistic
communications. Extensive aggregate statistics, especially from the CDC, that have
looked at other possible transmission routes clearly show that regular daily inter-
action, including using a shared toilet or drinking from the same glass, does not lead
to transmission. Similarly, in health care settings, a composite statistic of saliva con-
tacts, contacts with urine, or infectious blood in contact with skin failed to detect a
single contagion (Henderson 1990). Below, the different transmission routes will be
briefly presented and discussed about favorable factors and risks.

Sex
The most important route of infection for HIV remains sexual contact. The pre-
requisite for this is direct contact with infected body secretions or fluids. Here, the
highest virus concentrations are found in blood and seminal fluid. It should be noted
that it is impossible to calculate the transmission risk for individual risk exposure
since this is also determined by many accompanying circumstances, such as sexual
practices, other sexually transmitted diseases, skin lesions, circumcision, and mucosal
injury. The average transmission risk for HIV transmission during unprotected sex
with an HIV-positive partner not on antiretroviral therapy is summarized in Table 1.

Table 1: Risk probabilities of HIV transmission during unprotected sex (without condom, without
PrEP) with an HIV-positive partner without antiretroviral therapy. It is calculated from seroincidence
and cohort studies (Patel 2014).
Type of contact Risk per 10,000 exposures 95% confidence interval
Receptive anal intercourse 138 102–186
Insertive anal intercourse 11 4–28
Receptive vaginal intercourse 8 6–11
Insertive vaginal intercourse 4 1–14
Oral sex Individual cases described

The dependence of transmission risk on the amount of virus present has important
epidemiological consequences. Where body fluids such as blood and semen are
exchanged with many people within days and weeks, there is a significantly increased
risk of encountering people who have only been infected for a short time and are
highly infectious. The probability of infecting other people within the few weeks
between one’s new infection and the appearance of antibodies is also increased. The
stage when infection progresses without knowledge of the diagnosis and high viral
loads are again observed shortly before the onset of AIDS is particularly infectious.
STDs and inflammation open physiological skin and mucosal barriers, increasing the
risk of HIV infection. This is especially true in endemic areas with a high prevalence
of other STDs. For example, genital herpes infections, in particular, are a potential
co-factor in the spread of HIV in endemic areas (Mahiane 2009).
The observation that the level of viral load is decisive for the infectivity of an infected
person has triggered a discussion about the possibility of unprotected sexual contact.
Thus, for the first time, the Swiss Federal Commission for AIDS Issues (EKAF) pro-
Introduction 5

posed that HIV-positive persons whose viral load under ART is below the detection
limit and who have been receiving antiretroviral treatment for at least six months,
who consistently and reliably take medicine and regularly undergo medical check-
ups, and who do not have any infections with other sexually transmitted pathogens,
should be considered as persons who presumably do not pass on HIV via sexual con-
tacts and, accordingly, may also safely have unprotected sex (Vernazza 2008).
Additional data are now available from studies in discordant couples. They demon-
strate no longer a relevant transmission risk in people with undetectable viral loads
while on therapy (Cohen 2011). This was subsequently confirmed in discordant MSM
couples and unprotected anal intercourse (Rodger 2019).

Syringe exchange
Sharing syringes and needles is the most critical transmission route among intra-
venous drug users. Due to the usually quite large amount of blood that is transferred,
the risk is high. Aspiration to check needle position introduces blood into the syringe
and thus provides the reservoir for transmission. Fortunately, with needle exchange
programs, syringe vending machines, methadone substitution, and many other pre-
ventive and social measures, HIV transmission rates among intravenous drug users
in Western Europe have dropped dramatically. In Eastern European countries, where
drug use is prosecuted as a criminal act and clean injecting equipment is not provided,
HIV transmissions continue to increase unabated. It is hoped that the successes in
Western Europe will lead to more progressive handling and effective prevention
programs in Eastern Europe.

Mother-to-child transmission
Without intervention, up to 40% of children born to HIV-1-positive mothers will
become infected with HIV-1. The most critical risk factor is the viral load at birth.
Since 1995, the mother-to-child transmission rate among pregnant women with
known HIV-1 infection has been reduced to 1 to 2% in Germany. This has been
achieved by a combination of antiretroviral treatment or prophylaxis for the preg-
nant woman, elective cesarian section before the onset of labor (now no longer nec-
essary if the mother’s viral load before birth is below the limit of detection), anti-
retroviral post-exposure prophylaxis (PEP) for the newborn, and abstinence from
breastfeeding. For details, see chapter HIV and Pregnancy.

Blood
Transmission via blood and blood products remains a worldwide risk that has not
been completely eliminated. In Germany, blood and blood products are considered
safe. Since 1985, all blood donations have been tested for antibodies against HIV-1,
and since 1989 also for HIV-2. For some years, PCR collection has been carried out
to identify donors within the seroconversion period and for whom the HIV ELISA
is still negative. Furthermore, people with so-called risk behavior, i.e., active drug
users or “promiscuous” men and women (for example, people on oral PrEP must
wait three months after stopping PrEP before donating blood, people on injectable
PrEP must wait two years after stopping), and immigrants from endemic areas are
excluded from blood donations.

Occupationally acquired HIV infection

The overall risk of becoming infected after an HIV-infected needle stick injury is
0.3%. However, it is significantly higher with a hollow needle – e.g., for blood
collection – than with a surgical needle. For more information on transmission risks
in different situations, see chapter Post-exposure prophylaxis (PEP) in this book.
6 The Basics

Not suitable transmission routes: everyday contacts, insects

In general, HIV transmission through regular contact between family members is
unlikely. It is essential to avoid blood-to-blood contact. Therefore, razor blades or
toothbrushes should not be shared. If you use cannulas, used ones should go directly
into the discard container and not be put back into the plastic syringe.
All studies that have investigated possible transmission of HIV by insects have con-
cluded that this is not possible. This is also true for studies conducted in Africa with
high AIDS prevalence and large insect populations, such as mosquitoes (Castro 1988).

The natural course of HIV infection

The natural course – i.e., without antiretroviral therapy – is shown in Figure 1. Shortly
after the initial infection, a so-called acute retroviral syndrome is observed in some
patients, which rarely lasts longer than four weeks. Leading symptoms are lymph
node swelling, fever, a maculopapular exanthema, and myalgias (see also chapter
Acute HIV infection). Symptoms are non-specific and variable, so an HIV diagnosis is
rarely made without a specific suspicion. Several years follow, during which most
patients are clinically asymptomatic.
After that, symptoms or diseases assigned to clinical category B may occur accord-
ing to the CDC classification (see Table 2). In particular, oral thrush, oral hairy leuko-
plakia, and herpes zoster should be mentioned here, which should always lead to
the differential diagnosis of HIV infection. Although these diseases are not AIDS-
defining, they are causally related to HIV infection and indicate a disturbance of the
cellular immune defense.
AIDS-defining diseases occur later – a median of 8 to 10 years after the initial infec-
tion. Without highly active antiretroviral therapy, they eventually lead to death after
a period that varies from person to person.

Figure 1: The “natural” course of HIV infection without ART, CD4 T-cells and viral load.
Introduction 7

Table 2: Clinical categories of the CDC classification.

Category A
Asymptomatic HIV infection
• Acute, symptomatic (primary) HIV infection
Persistent generalized lymphadenopathy (LAS)
Category B
Symptoms of disease or illness that do not fall into category C but are causally attributable to
HIV infection or indicate a disturbance in cellular immune defenses. These include:
• Bacillary angiomatosis
• Pelvic inflammatory disease, especially with complications of a tubal -or ovarian- abscess
• Herpes zoster in case of infestation of several dermatomes or after recurrences in one dermatome
• Idiopathic thrombocytopenic purpura
• Constitutional symptoms such as fever over 38.5 degrees or diarrhea existing for > 1 month
• Listeriosis
• Oral hairy leukoplakia (OHL)
• Oropharyngeal candidiasis
• Vulvovaginal candidiasis that is either chronic (> one month) or poorly treatable
• Cervical dysplasia or carcinoma in situ
• Peripheral neuropathy
Category C
AIDS-defining diseases
• Candidiasis of bronchial tubes, trachea or lungs
• Candidiasis, esophageal
• CMV infections (except liver, spleen, lymph nodes)
• CMV retinitis (with loss of visual acuity)
• Encephalopathy, HIV-related
• Herpes simplex infections: chronic ulcers (existing > 1 month); or bronchitis, pneumonia,
esophagitis.
• Histoplasmosis, disseminated or extrapulmonary
• Isosporiasis, chronic, intestinal, > one month existing
• Kaposi Sarcoma
• Coccidioidomycosis, disseminated or extrapulmonary
• Cryptococcosis, extrapulmonary
• Cryptosporidiosis, chronic, intestinal, > one month existing
• Lymphoma, Burkitt
• Lymphoma, immunoblastic
• Lymphoma, primary cerebral
• Mycobacterium avium complex or M. kansasii infection, disseminated or extrapulmonary
• Mycobacterium infection, other or unidentified species, disseminated or extrapulmonary
• Pneumocystis pneumonia
• Pneumonias, bacterial recurrent (> 2 within one year)
• Progressive multifocal leukoencephalopathy
• Salmonella septicemia, recurrent
• Tuberculosis
• Toxoplasmosis, cerebral
• Wasting Syndrome
• Cervical carcinoma, invasive
8 The Basics

The HIV viral load, which reaches extremely high values shortly after primary infec-
tion, usually drops to less than 1% of the initial value simultaneously as HIV anti-
bodies appear and then initially remain relatively stable. This value is called the viral
“setpoint”. Its level decisively determines the speed of disease progression. While
individuals with less than 1,000 HIV RNA copies/mL have virtually no AIDS even
after 12 years, more than 80% of individuals with a viral load of more than 100,000
viral copies two years after seroconversion have already developed manifest AIDS
(O’Brien 1996). The higher the viral “set point”, the faster the drop in CD4 T-cells
occurs. These usually drop significantly during acute infection, initially returning to
above-average values after a few months, although rarely back to before infection.
The average values vary depending on the laboratory and are usually about “absolute”
435–1,600/µl or “relative” 31–60% of lymphocytes for adults. For children, other
standard values apply (see chapter Antiretroviral therapy in children).
In the further course of untreated HIV infection, there is a gradual decrease in CD4
T-cells. From a CD4 T-cell count below 200/µl, the occurrence of AIDS-defining
diseases must be increasingly expected.
To estimate the degree of immunodeficiency, the relative proportion of CD4 T-cells
should always be taken into account since, under certain circumstances (e.g., under
myelosuppressive interferon therapy), low absolute CD4 T-cells are observed in the
context of leukopenia and lymphopenia. However, an excellent immune status is
still present in percentage terms. In this context, 200 CD4 T-cells/µl correspond to
about 15% CD4-positive lymphocytes. Conversely, the absolute number may also
suggest falsely high values, for example, after splenectomy. Depending on the rate
of CD4 T-cell decline, a distinction is made (according to Stein 1997) between people
at high risk of disease progression (decline above 100/µl within six months), moderate
risk (decline 20–50/µl per year), and low risk (decline less than 20/µl per year).
While the overall AIDS risk increases significantly below 200 CD4 T-cells/µl, there
are considerable differences between the individual AIDS-defining diseases (see also
chapter AIDS). For example, opportunistic infections often occur at significantly
lower CD4 T-cell counts than AIDS-associated malignancies (Schwartländer 1992).
However, age is a significant risk factor in addition to CD4 T-cell count and viral
load level. For example, a 55-year-old person with 50 CD4 T-cells/µl and an HIV RNA
of 300,000 copies/mL has almost twice the risk of AIDS as a 25-year-old person.
In the “pre-HAART era,” the time between the first AIDS complication and death
was usually between two and four years. Without ART therapy, probably more than
90% of all people living with HIV (PLWH) die of AIDS. However, with the availabil-
ity of ART today, the progression of the disease to the AIDS stage can be prevented.
When maximum suppression of HIV RNA is achieved, CD4 T-cell counts usually
recover, and life expectancy is almost normal. The level of viral load or viral “set
point” is determined by several host-specific factors, such as chemokine receptor
mutations, HLA types, and other factors, some of which have not yet been identi-
fied. In addition, there are also virus-specific factors that are likely to be decisive for
progression. For more information, please refer to the chapter on Basic Principles. It
is important to note that the measurable viral activity is a balance between viruses
that emerge and viruses that are killed.

Staging of HIV infection

For staging, the CDC classification 1993 is still most broadly referenced, using the
individual CD4 T-cell count and clinical manifestations as criteria (see Table 3).
For both criteria, there are three stages each.
Introduction 9

In 2014, a revised CDC version of staging was presented (Selik 2014). This now applies
to all age groups, i.e., adults and adolescents over 13 years of age and children < 13
years of age. The goal of the revision was to provide a simplified staging for epi-
demiologic monitoring of all persons affected with HIV-1 and HIV-2 infection, which
would also reflect improved diagnostics and treatment options. In addition to the
three stages listed above, stage 0 was defined as early or recent HIV infection (with
a negative HIV test within the last six months). The category “stage unknown” was
introduced for patients without corresponding information. The basic rule is that a
person is reclassified if the disease progresses, but no downgrading is possible. For
example, a previously asymptomatic person with 530 CD4 T-cells/µl (category A1,
new classification: stage 1) will receive category B2 (new: stage 2) if oral thrush occurs
and CD4 T-cells drop to 320/µl. If the same person has a CD4 T-cell count of 550/µl
again after successful thrush therapy and initiation of ART, they will remain in
category B2 (new: stage 2).

Table 3: Classification of HIV infection according to the 1993 CDC classification.

CD4 T-cells Asymptomatic or Symptomatic AIDS disease*
acute HIV disease but not A or C
>500/μl A1 B1 C1
200–499/μl A2 B2 C2
<200/μl A3 B3 C3
* See Table 2 for AIDS disease or clinic.

The CDC classification provides a first orientation to the (so far worst) condition of
a person with HIV. It says nothing about the current situation. Unlike in Europe,
where the term AIDS is only applied when an AIDS-defining illness has occurred, in
the US, a drop in CD4 T-cells to below 200/µl is also considered AIDS. Old staging
systems, such as those according to Walter-Reed or the Frankfurt classification, are
no longer used.

Epidemiology
HIV probably originated in the 1920s-30s, when the Simian Immunodeficiency Virus
(SIV) spread from chimpanzees to humans in West Africa (Worobey 2008). The oldest
HIV-positive sample from a human was found in Kinshasa and dates back to 1959
(Zaire, Democratic Republic of Congo) (Zhu 1998). After the first description of AIDS
in 1981, there is now no country that is not affected.
In most cases, people at increased risk of HIV transmission (IV drug users, sex workers,
and MSM) contracted the disease first, with other groups of people subsequently
becoming infected through unprotected sex. In most industrialized nations, gay anal
sex is the most common mode of transmission; in the countries of the former Soviet
Union, it is intravenous drug use (via sharing of needles). In sub-Saharan Africa, most
people become infected through heterosexual intercourse. The prevalences in
different countries and their impact on societies thus differ significantly. More of a
marginal health problem in the industrialized countries of Western Europe, AIDS
became the leading cause of death in sub-Saharan Africa. One in five deaths in Africa
is now attributable to HIV/AIDS, and life expectancy in some countries has fallen
by more than 20 years. Well over 10 million children have been orphaned. The
economies of the affected countries have suffered and continue to suffer massive
declines. According to UNAIDS, 37.7 million people worldwide were living with
10 The Basics

HIV/AIDS at the end of 2020 (50% women). About 680,000 people died of AIDS in
2021 (see Table 4). There continues to be a significant decline in AIDS-associated
deaths, indicating broader access to ART. It is also encouraging to note that globally,
the number of new infections per year has declined from 2.1 million in 2010 to 1.5
million in 2020.
Table 4: The AIDS epidemic according to data from UNAIDS, 2021 ([Link]).
PLWH New infections Annual deaths
(adults and in 2020 from AIDS
children) in 2020
East and South Africa 20,600,000 670,000 310,000
West and Central Africa 4,700,000 200,000 150,000
Middle East and North Africa 230,000 16,000 7,900
Asia and Pacific 5,800,000 240,000 130,000
Latin America 2,100,000 100,000 31,000
Caribbean 330,000 13,000 6,000
Western and Central Europe and North America 2,200,000 67,000 13,000
Eastern Europe and Central Asia 1,600,000 140,000 35,000
Total 37,700,000 1,500,000 680,000

The region most severely affected is sub-Saharan Africa, with approximately

25 million PLWH. The greatest rate of spread is currently seen in the countries of
the former Soviet Union, especially Estonia, Latvia, Russia, and Ukraine, as well as
in South and Southeast Asia.
Pre-exposure prophylaxis (PrEP, see chapter Prevention of HIV infection), available in
Germany and other countries since 2017, is associated with the hope that new
infections can also be prevented among key populations at increased risk of HIV
transmission. In London, where PrEP has been given to HIV-negative MSM for some
time, reductions in new infection rates of over 50% have already been reported.

Summary
The first serological evidence of HIV antibodies is found in old sera from Zaire in
1959, Uganda in 1972, and Malawi in 1974 – evidence that HIV was already circu-
lating in Central Africa. The first AIDS cases were described in the United States in
1981. This was followed in 1983 by the discovery of HIV as the cause of AIDS. Since
then, there has been a worldwide epidemic that is still spreading 41 years later, with
1.5 million new infections in 2020, a slower rate than in previous years but still
significant. In particular, the unchanged high rates of new infections in Eastern
Europe and Central Asia point to the multiple challenges in prevention that need
to be overcome now and in the near future. Although the success of therapy to date
leads us to believe that the life expectancy of PWLH is near normal, knowledge of
the natural course of HIV infection remains essential to make the diagnosis before
the onset of AIDS, even in the case of early symptoms. With 40–50% of all infected
people in Europe unaware of their HIV infection, significant challenges remain. These
are currently being addressed collectively in Europe ([Link] to provide
patients with timely antiretroviral treatment and reduce the number of new infec-
tions.
Introduction 11

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13

2. HIV testing
C H R ISTIAN NOAH

Rapid diagnosis of HIV infection enables access to antiretroviral therapy and helps
prevent transmission. Despite widespread testing, many infections are still diagnosed
at a late stage. In many European countries, there is already an advanced immune
deficiency or even an AIDS-defining disease in about one-third of the cases. The
number of undiagnosed HIV infections is high.
The indications and reasons for testing may vary. For example, every pregnant
woman must be offered an HIV test. HIV diagnostics are also mandatory for blood
and organ donation. HIV tests are also performed in cases of clinical suspicion of
infection after exposure in a private or professional environment and to clarify the
infection status in a partnership.

Diagnostics basics
Laboratory diagnosis is based on a screening test, the result of which must be veri-
fied with an alternative test format (confirmatory test) in the reactive case (stepwise
diagnosis). Nowadays, a so-called 4th or 5th generation test is used as a screening
test due to its comparatively high sensitivity. In addition to HIV-specific antibodies,
these tests also detect a component of the virus, the p24 antigen. Because this antigen
is detectable earlier than the antibodies, the diagnostic window is smaller than earlier
test generations (Vallefuoco 2016). With a 5th generation test, in the case of a reac-
tive result, it is possible to differentiate further whether the measurement signal
results from detecting p24 antigen or HIV antibodies. Approved screening tests detect
all known types (HIV-1 and -2), groups, and subtypes.
The principle of all commercially available screening test systems is based on antigen-
antibody binding: the “prototype” is an ELISA (Enzyme-Linked Immunosorbent
Assay). The central element is a plastic plate with 96 wells (microtiter plate) serving
as reaction vessels (wells). On the surface of each well are coupled HIV antigens or
HIV p24 antibodies. When serum or plasma containing HIV antibody or p24 antigen
is added to a well, binding occurs. An enzyme-labeled second antibody is added that
recognizes and binds human antibodies. Finally, a substrate is added, which is con-
verted by the enzyme on the second antibody. This results in a color change, which
is measured photometrically. The optical density correlates with the concentration
of the antibodies or the p24 antigen. Modern test systems are mainly automated and
standardized; they provide a test result in less than one hour. In these systems, the
solid phase consists not of a plastic plate but microparticles to which viral antigens
and antibodies are coupled. Accordingly, the method is called “Microparticle Enzyme
Immunoassay” (MEIA).
The measured value is usually a dimension-free index calculated from the quotient
of the measured value of the sample and the negative control (Sample/Control, S/Co).
Values below one are judged to be negative, and values above are considered to be
reactive. It should always be referred to as a “reactive” result rather than a positive
result to document that this result must be confirmed using a second test format.
While maximum sensitivity is the top priority for the screening test (no infection
should be overlooked), the confirmation test focuses on high specificity. A specificity
of at least 99.5% is required for the screening tests approved in Germany. One in
200 HIV-negative samples may be falsely reactive on average. False-reactive results
can be caused by, among other things, stimulation of the immune system (viral infec-
tions, pregnancy, vaccinations, autoimmune diseases). Pregnant women or dialysis
14 The Basics

patients are more likely to have false-reactive screening tests. In our experience, at
least one in five initial reactive screening test results is non-specific. The HIV preva-
lence plays a decisive role in the probability that a reactive screening test indicates
an infection (positive predictive value): the lower the prevalence in a population
group, the lower the significance of the reactive screening test result. In principle,
an alternative test procedure must confirm every reactive result.
Immunoblot analysis (Western or line blot) is usually performed to confirm a reactive
screening test. In the Western blot, viral proteins (antigens) are electrophoretically
separated according to their molecular weight and transferred to a membrane, which
is then used as a test strip. A further development is the so-called line blot, in which
recombinant HIV antigens are sprayed onto a membrane. The test strip is incubated
with patient serum or plasma. If HIV-specific antibodies are present, they bind to
the antigen. The antigen-antibody complex is visualized analogous to ELISA (see
above) using an enzyme-labeled antibody and a test strip substrate. A corresponding
band spectrum appears on the test strip according to the antibody specificities
present.
Ideally, the laboratory uses an immunoblot that also detects antibodies against HIV-2.
If only a synthetic HIV-2 peptide is used for this purpose, any reaction must be
confirmed by an additional HIV-2-specific immunoblot. Usually, the immunoblot
discriminates between HIV-1 and HIV-2, but in some cases, cross-reactivities occur,
i.e., antibody reactions against both virus types. In these cases, differentiation can
be performed using a type-specific HIV PCR. The laboratory findings should always
indicate whether an HIV-1 or HIV-2 infection is present, as this influences the selection
of the therapy regimen.
HIV proteins are assigned to three functional groups. Here, “p” stands for protein,
“gp” for glycoprotein. The following number denotes the molecular weight in each
case (see Table 1). While antibodies against p24 and gp120 are detectable early, other
antibodies (e.g. against p31) usually appear later (Fiebig 2003).
The interpretation criteria for a positive test result are defined by the manufacturers
after appropriate validation and are binding as part of the approval of the test system.
As a rule, an immunoblot is considered positive if at least two bands are visible.
Further diagnostic clarification should be carried out if an antibody reaction is
detected but does not meet the conditions for a positive result in terms of number
and specificity. Since this constellation can occur in an acute infection, especially if
“early” antibodies (for example, against p24) are detectable, it makes sense to perform
an HIV PCR or at least a follow-up after 2–3 weeks.

Table 1: HIV proteins, three functional groups.

Antigens Function
HIV-1 HIV-2
Envelope proteins (env) gp160 gp140 Precursor of the envelope proteins
gp120 gp125 Outer layer protein
gp41 gp36 Transmembrane protein
Polymerase proteins (pol) p66 p68 Reverse transcriptase, RNase H
p51 p53 Reverse transcriptase
p32 p34 Endonuclease, integrase
Core proteins (gag) p55 p56 Precursors of the nuclear proteins
p24 p26 Inner core protein
p17 p16 Outer core protein
HIV testing 15

In contrast to a 4th or 5th generation screening test, the p24 antigen is not detected
by immunoblot. In the constellation “reactive screening test – negative immuno-
blot”, an acute infection in which no HIV-specific antibodies have yet been formed
but the p24 antigen is already detectable cannot be ruled out. At least such a result
should be checked after 2–3 weeks. If an acute infection is suspected (acute retrovi-
ral syndrome, risk contact), HIV PCR is useful. PCR is also recommended without a
risk history if the screening test is highly positive with a negative confirmatory test.
For 5th-generation tests, detection of p24 antigen usually indicates acute infection.
In contrast, a nonspecific reaction is more likely if only an antibody reaction is
detectable. In case of doubt, the further procedure (PCR vs. follow-up) should be
discussed with the laboratory.
To confirm a reactive screening test, HIV PCR can be used as an alternative to
immunoblot (see below). This procedure is particularly useful if only a p24 antigen
but no antibody response is detectable in the screening test. Other test formats (e.g.,
immunofluorescence tests) are less common.
A duplicate sample must confirm each positive initial result to exclude the possibil-
ity of sample mix-up, which is unlikely but possible. In particular, if HIV infection
is suspected, the viral load (see chapter Monitoring ART) can also be determined for
confirmation. A new serological test is then unnecessary. The earlier recommenda-
tion to inform patients about the test result only after this second blood sample has
been taken is obsolete.

HIV PCR
In addition to serological test systems, molecular methods (nucleic acid amplifica-
tion methods, NAT) are also available for detecting viral RNA. The most essential
method is PCR; other methods (bDNA, NASBA) are less common. Quantitative detec-
tion of HIV RNA (“viral load determination”) is an essential part of monitoring HIV
infection (Wittek 2007, Thompson 2010). HIV PCR is also mandatory for blood
donations. In contrast to individual serological testing, however, not every single
donation is examined by PCR, but as a rule, so-called “pools” consisting of several
individual samples. The maximum pool size depends on the sensitivity of the test
method used. In a single sample, an HIV concentration of at least 10,000 international
units/mL must be reliably detected. Although often not formally approved by the
manufacturers for this indication, HIV PCR is nowadays also an integral part of
primary HIV diagnostics beyond blood and organ donation. Indications include the
exclusion of infection in newborns of HIV-positive mothers (see below), unclear
serological constellations, and the suspicion of an acute HIV infection. HIV PCR can
also be used – as an alternative to immunoblot – to confirm a reactive screening test.
A reliable positive result in primary diagnostics can be assumed from a viral load of
1,000 copies/mL.
However, due to possible false-negative results, HIV PCR is of limited use for the
exclusion of HIV transmission – it should only be used in addition to, and not instead
of, serological testing procedures. Possible causes of false-negative results are:
1. Although HIV-2 is rare in most countries (the share of new diagnoses is 0.5% in
Germany), it should be noted that routine PCR only detects HIV-1. For the molec-
ular detection of HIV-2, an additional PCR is required.
2. HIV is characterized by high genetic diversity. In the case of new or previously
unknown variants, sensitivity can be impaired by mutations affecting the primer
and probe binding region. So-called “dual-target” PCR minimizes the risk of false-
negative results (Chudy 2012; see also chapter Monitoring ART). Dual-target PCR
has been mandatory in blood donation since 2015.
16 The Basics

3. In the rare “elite controllers”, no viral RNA is detectable in plasma by PCR despite
serologically confirmed infection (Okulicz 2011).
4. A false-negative diagnosis would result if screening under successful ART was based
on PCR alone.

HIV rapid and self-testing

Rapid tests correspond functionally to a screening test, i.e., an immunoblot must
confirm a reactive result. They are simple and can be used as so-called “point-of-
care” tests without equipment. Depending on the approval, whole or capillary blood
(from fingertip or earlobe) is suitable as test material in addition to plasma and serum
so that no centrifuge is required. For some tests, urine or oral fluid are also possible
– however, sensitivity decreases when materials other than serum or plasma are used
(Pavie 2010). The result is available in less than 30 minutes. The rapid test is usually
based on immunochromatographic methods, but particle agglutination or immuno-
filtration are used less frequently (Branson 2003, Greenwald 2006).
Rapid tests that carry a CE mark and meet the requirements of the European
Regulation for in vitro diagnostic medical devices are considered safe and show high
sensitivity and specificity. 4th generation rapid tests that detect the p24 antigen
component are superior to earlier tests (Chetty 2012, Fitzgerald 2017). However,
sensitivity remains poor in acute HIV infection before seroconversion (Kilembe 2012,
Brauer 2013, Lewis 2015, Tan 2016). Rapid tests should, therefore, only be used for
initial guidance. They seem unsuitable for ruling out acute infection. The result
should be confirmed in the routine laboratory with a conventional HIV test.
Rapid tests are helpful when the test result has an immediate consequence: in emer-
gency surgery, needlestick injuries, or pregnancies with unknown HIV status at delivery.
In such emergencies, the collaborating laboratory should be informed: even the result
of a conventional HIV test may be available within only one hour of sample receipt.
Rapid tests are also useful in countries lacking medical infrastructure and in the
context of low-threshold testing services.
The first rapid HIV test for self-use (self-test) was already approved in the US in 2012.
In Europe, self-tests have been available in pharmacies and drugstores since 2018.
Given many undiagnosed infections and positive experiences from other countries,
self-tests are a valuable addition to existing test offerings. Despite many concerns
(lack of possibility of immediate confirmation or counseling and possible applica-
tion errors with the risk of false-negative results), the willingness to test can be
increased among people whose previous counseling and testing offers have not been
reached.

The diagnostic window

The term “diagnostic window” refers to the period between the transmission of a
pathogen and the first appearance of laboratory-measurable infection markers such
as antibodies, antigens, or nucleic acids. In the case of HIV transmission, antibody
production begins at the earliest after two weeks. After four weeks, specific antibodies
are detectable in 60–65%, six weeks in 80%, eight weeks in 90% and twelve weeks
in 95%. A “seronegative” HIV infection is a rarity (Spivak 2010). The p24 antigen
can be detected about five days before seroconversion (the first appearance of specific
antibodies). The earliest laboratory marker is HIV RNA, which can be detected about
seven days before the p24 antigen and as early as two weeks after infection (Fiebig
2003). However, a negative PCR result at this time does not reliably exclude trans-
mission.
HIV testing 17

A negative result in the screening test indicates the absence of HIV antibodies and
p24 antigen at the time of testing. Accordingly, the person is considered HIV-nega-
tive. However, the certainty of this result depends in particular on the time interval
to the possible transmission event. This has significant consequences:
1. An HIV test immediately after exposure is not meaningful since no antibodies
have yet been formed. It is helpful in the 3rd week at the earliest unless it is to be
proven, e.g., after a needlestick injury, that there was no HIV infection at the time
of exposure.
2. According to guidelines (Gökengin 2014), HIV infection can be excluded with
sufficient certainty six weeks after exposure, provided that tests of at least the 4th
generation are used. In the case of post-exposure prophylaxis (PEP), the time
window starts only from the end of PEP. In the case of immunodeficiencies or the
presence of other sexually transmitted infections, a control test is recommended
after 12 weeks. For 3rd generation HIV tests or rapid tests, the diagnostic window
is always 12 weeks.
3. A negative test result is only sufficiently reliable if there was no re-exposure within
the diagnostic window.

Diagnostics in pregnant women and newborns

Timely diagnosis and therapy can almost always prevent mother-to-child transmis-
sion (Gingelmaier 2005). According to current guidelines (2022), an HIV test is rec-
ommended for every pregnant woman as early as possible in pregnancy. Repeated
testing is recommended in case of risk constellation (e.g., HIV-positive partner).
A medical consultation should precede the HIV test. Only the performance of the
test, but not the result, is documented in the maternity record.
In newborns of HIV-positive mothers, maternal antibodies may remain detectable
up to the age of 18 months. They are transmitted transplacentally from the 32nd
week of pregnancy but do not confer nest protection. A serological HIV test alone
is not sufficient for the detection or exclusion of vertical HIV transmission since a
positive result is to be expected in every case (Read 2007). According to the German-
Austrian guidelines (2020), at least two negative PCR results are required to exclude
transmission. The first HIV PCR should be performed after the first month of life
(sensitivity 96%, specificity 99%) and the second after the third month of life because
of the nearly one hundred percent sensitivity and specificity. However, laboratory
diagnostics can only rule out vertical transmission if there has not been a renewed
risk of infection through breastfeeding in the meantime. Even in the case of nega-
tive PCR results, the disappearance of maternal antibodies should be documented at
least once. In the positive case, the result must be confirmed by examination of a
second sample.

Diagnostics for occupational exposure

After needlestick injuries or other occupational exposure, hepatitis B and C and HIV
infection should be ruled out in the index person (consent of the index person!). In
the case of HIV infection, this is done using a screening test. Due to the possibly
necessary post-exposure prophylaxis (PEP), every needlestick injury is an emergency:
the earlier PEP is started, the higher the chances of success. According to the German-
Austrian PEP guidelines (2022), PEP should be started within 24 hours, ideally within
2 hours. If a short-term result of a screening test or a rapid test is not available, PEP
can also be started in case of doubt, which can be stopped at any time in case of a
negative result.
18 The Basics

If an index person does not exhibit symptoms compatible with an acute retroviral
syndrome, a negative screening test excludes an infection with a high degree of
certainty. HIV PCR is usually only considered if there is evidence of acute HIV infection
in the index person. If, on the other hand, the index person has an HIV infection
or if the status is unknown, an immediate screening test is advisable for the exposed
person. It documents that no HIV infection was present at the time of the accident.
Checks should be carried out after six weeks and three months. After six months,
only HCV and (in the absence of immunity) HBV diagnostics should be performed
(Stranzinger 2018).

Practical hints
• Legal situation: The HIV test retains a special status. Due to possible medical,
social, and legal consequences, a test without explicit consent is considered an
invasion of personal rights and can thus have legal implications for the ordering
physician. Written consent is not required; however, it should be documented. For
children or minors, parents or guardians must consent. In the US, CDC recommen-
dations now include an “opt-out” screening concept to increase willingness to test.
Although information is provided about a planned HIV test, it is always performed
if the person concerned does not explicitly refuse it (Branson 2006).
• Counseling: HIV testing should be accompanied by prior counseling and education.
This should include the test concept (step-by-step diagnostics) and its limitations,
including the value of (frequently requested) HIV PCR as part of primary diagnos-
tics (conditional suitability for rapid exclusion of HIV infection or transmission).
The high cost of PCR is rarely a deterrent if the patient suffers from the disease.
Attention should be drawn to the constellations of results, particularly the
“diagnostic window.” The desire for an HIV test can also be an occasion to discuss
transmission risks and other relevant sexually transmitted infections (syphilis,
gonorrhea, chlamydial infection).
• Notification of findings: If necessary, a negative test result can be communicated
by telephone if the person concerned has been informed beforehand. Ideally, the
diagnosis of “HIV” should be displayed in a personal conversation by a physician or
healthcare professional. The affected person’s reaction can only be poorly assessed
on the phones. HIV centers and counseling services should be mentioned. Similarly,
a negative confirmatory test with a reactive screening test should be discussed in
person to discuss the possibility of acute infection. A reactive screening test without
a confirmatory test should never be disclosed.

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20

3. Pathophysiology of HIV infection

H EN N I NG GRU ELL, PH I LI PP SCHOMMERS, FLORIAN KLEI N

Structure and design

The human immunodeficiency viruses (HIV) are members of the lentivirus genus
within the family of retroviruses. Two types of HIV (HIV-1 and HIV-2) need to be
distinguished. These have a similar structure and a nucleic acid identity of about
50% but differ in the typically observed disease courses. HIV-2 (see chapter HIV-2)
is endemic in West Africa but accounts for only a small proportion (<5%) of global
HIV infections. Therefore, this chapter focuses on HIV-1.

Morphology
HIV-1 particles are about 100 nm in diameter and have a lipid surface membrane in
which about 12–16 glycoprotein complexes (envelope, Env) are embedded. These
are the only proteins of viral origin (Zhu 2006) expressed on the viral surface and
form trimers composed of three heterodimers. These heterodimers are formed by
two non-covalently linked glycoproteins (gp), named gp120 and gp41, according to
their molecular mass (in kilodaltons). In addition to the Env protein, the lipid
membrane of the virus contains human proteins that are incorporated during the
budding of the virus from the virus-producing host cell. The inside of the viral
membrane is lined by the matrix protein (p17), which houses the conically shaped
capsid protein (p24) that encapsulates the viral genetic information and proteins.
Within the capsid, the viral genome is present as two copies of single-stranded RNA
bound in a protein-nucleic acid complex to nucleoprotein p7, reverse transcriptase
(p66/p51), and integrase (p32). The viral protease, which plays an essential role in
viral maturation after budding, is also found within the virion (Figure 1).

Figure 1: Structure of the HIV-1 virion.

Pathophysiology of HIV infection 21

Organization of the viral genome

Retroviruses have a similar genome structure characterized by partly overlapping
open reading frames, allowing many different proteins to be encoded by a single
nucleic acid strand (Figure 2). The three major components of the HIV-1 genome are
the genes gag (“group-specific antigen”), pol (“polymerase”), and env (“envelope”).
Each gene encodes different proteins that can be produced due to alternative splicing,
ribosomal frameshifts, and cleavage of precursor peptides. The LTR regions (“long
terminal repeats”) located at both the 5’ and 3’ ends of the genome are involved in
the regulation of transcription and integration into the host genome.

Viral proteins
While gag encodes for structural proteins (p24, p17, p7, and p6) and env encodes
for surface proteins (gp120 and gp41), pol encodes for enzymes essential for viral
replication (reverse transcriptase, protease, and integrase). These enzymes are targets
of several antiretroviral drug classes and are discussed in more detail in the follow-
ing section.
In addition, the HIV-1 genome has several genes encoding for proteins involved in
regulatory processes (tat, rev), as well as other so-called accessory genes (nef, vif,
vpr, vpu) that contribute to viral replication:
Tat is involved in the initiation of viral transcription.
Rev binds to the genome’s RRE (Rev Response Element) and is involved in the export
of viral mRNA from the nucleus to the cytoplasm.
Nef induces downregulation of CD4, CD8, CD28, CD3, SERINC3/5, tetherin, and
HLA class I antigens on the surface of HIV-1-infected cells. To this end, Nef inter-
feres with intracellular transport mechanisms, including clathrin-coated vesicles con-
taining cellular surface proteins. Lower expression of these surface markers reduces
the antiviral immune response, increases the infectivity of HIV, and leads to higher
viral replication rates (Buffalo 2019).
Vif inhibits the activity of APOBEC3G, a human enzyme that damages viral nucleic
acid through mutations (Mariani 2003; see below).
Among other things, Vpr is involved in transporting the viral genome into the cell
nucleus.
Vpu blocks the action of the antiviral tetherin protein that inhibits viral release from
the cell surface. In addition, Vpu is involved in the degradation of CD4-gp120 com-
plexes, increasing the levels of Env protein available for viral replication (Cullen
1998).

Figure 2: Gene map of HIV-1 showing encoded proteins. Individual gene regions overlap on the RNA
strand of the virus and are transcribed from different reading frames. The gag, pol, and env genes
encode different proteins: matrix protein (MA), capsid protein (CA), nucleocapsid (NC), protease (PR),
reverse transcriptase (RT), integrase (IN), glycoprotein 120 (gp120), glycoprotein 41 (gp41), and other
proteins such as p6 and p15. The regulatory proteins Tat and Rev are each composed of two exons
(connected with dashed lines). Nucleotide numbering (nt) is based on reference virus strain HXB2.
22 The Basics

The replication cycle of HIV-1

Entry of HIV-1 into the target cell
CD4 as primary HIV-1 receptor: In addition to the T cell receptor, the glycoprotein
CD4 interacts with CD4 T-cells with the MHC class II complex on the surface of
antigen-presenting cells. CD4 is, therefore, typically expressed on the surface of
T helper cells but also found on monocytes, macrophages, dendritic cells, and CNS
microglial cells. The viral Env surface protein binding to CD4 is the initial step of
the viral replication cycle (Dalgleish 1984) and determines the spectrum of cell types
infected by HIV-1 (Figure 3).
Chemokine receptors as HIV-1 co-receptors: While the binding of HIV-1 to CD4
is necessary, it is insufficient for cell infection. After the initial interaction of the
virus with CD4, additional binding to a cellular coreceptor (the human chemokine
receptor CCR5 or CXCR4) is required (Doranz 1996, Feng 1996). Different T cell
populations differ in the expression of these chemokine receptors. For example, CCR5
is primarily found on the surface of memory T cells whereas CXCR4 is expressed on
naive T cells. In addition, CCR5 can be detected on the surface of macrophages and
dendritic cells.
HIV-1 variants differ in their requirements for the coreceptor (tropism), which is
determined by sequences in the V3 loop of the envelope protein (Env). This results
in the differentiation of viruses only using CCR5 as a coreceptor (“R5-tropic”), viruses
that rely on CXCR4 (“X4-tropic”), and viruses that can use both coreceptors (“dual
tropism”).
Primary infection with HIV-1 is typically caused by R5-tropic variants that dominate
in the initial phase of infection. However, a tropism switch to X4-tropic viruses asso-
ciated with higher disease progression can occur in the course of infection.
The importance of the CCR5 coreceptor in the establishment of HIV-1 infection is
evident from people with a defective CCR5 gene: A deletion of 32 base pairs in the
CCR5 gene (CCR5 Δ32) leads to the formation of a non-functional CCR5 molecule.
Homozygous carriers of this mutation (approx. 1% prevalence in the Caucasian pop-

Figure 3: Life cycle of HIV. After binding to the surface receptors, the virus fuses with the cell mem-
brane. After the release of the capsid into the cytoplasm, reverse transcription of viral RNA into DNA
begins. DNA is transported into the cell nucleus (possibly still in the intact capsid) and incorporated
into the human genome by the viral enzyme integrase. Regulatory genes and structural proteins are
transcribed and translated from this so-called proviral DNA. New virus particles are assembled at the
cell surface and only mature completely after budding.
Pathophysiology of HIV infection 23

ulation) are largely resistant to infection with HIV-1 and only occasional infections
with X4-tropic viruses have been observed (Liu 1996, Naif 2002). CCR5 Δ32-medi-
ated resistance also forms part of the therapeutic approach in the small number of
HIV-1 patients reported cured to date (Hütter 2009, Gupta 2020, Hsu 2022, Jensen
2023). Due to severe hematologic disease, these individuals were dependent on
allogeneic stem cell transplantation for which stem cell donors with a homozygous
CCR5 Δ32 mutation could be identified. After discontinuation of antiretroviral
therapy, no evidence of persistent viral replication was found in these patients.
Heterozygous carriers of CCR5 Δ32 (approximately 10% in Europe) show reduced
CCR5 expression associated with reduced susceptibility to HIV-1 infection, lower
viral load, and slower disease progression (Dean 1996).
Fusion of HIV-1 with the cell membrane: CD4-binding of the gp120 unit induces
a change in the structural conformation of Env and enables additional binding to
the respective coreceptor. Through an incompletely understood mechanism medi-
ated by gp41, subsequent fusion occurs between the viral and cellular membranes
(Shaik 2019).

Processes after the virus entry

After membrane fusion, the viral capsid enters the cytosol and is transported along
microtubules towards the nucleus. After entering the cytosol and starting from the
LTR regions of the viral genome, the viral RNA is converted into double-stranded
DNA by the enzyme reverse transcriptase (RT). This highly error-prone process intro-
duces sequence mutations and often leads to defects in the viral genome, preclud-
ing the formation of new viral particles. However, the high mutation rate (approx-
imately five to ten errors per HIV-1 genome per round of replication) also explains
the large sequence variability of HIV-1. It leads to the development of closely related
but differing viral variants (“quasispecies”) within an infected individual (Preston
1988). Most critically, the incorporation of mutations during viral replication can
also result in the development of resistance to antiviral drugs or the host immune
response.
During uncoating, the capsid disintegrates and releases the viral genetic information
in the form of the pre-integration complex that supports the integration of the viral
DNA into the human genome. While earlier studies suggested uncoating to be ini-
tiated shortly after viral entry into the cytosol, more recent data indicate that it
occurs only upon reaching the nucleus or even within the nucleus (Zila 2021). This
may be necessary to prevent viral nucleic acid recognition by cellular “pattern recog-
nition receptors” (PRRs). In addition, the binding of cyclophilin a to the viral capsid
shortly after entry into the cell also serves this purpose (Campbell 2015).
Within the nucleus, the viral enzyme integrase mediates the stable integration of
the viral genetic information as double-stranded DNA into the human genome. This
integration does not appear to occur in specific chromosomal regions but is clus-
tered in regions of actively transcribed genes (Schröder 2002). After integration into
the human chromosome, the viral genome is also referred to as provirus. From the
proviral DNA, transcription of viral genes occurs by exploiting cellular replication
mechanisms that can be enhanced by cell activation (e.g., NF-κB-mediated in the
context of inflammatory immune responses).
Transcription of regulatory genes (tat, rev, nef) occurs early after infection, whereas
gag, pol, and env are transcribed at later stages of infection. The generation of struc-
tural proteins takes place in the cytoplasm using ribosomal translation, while the
Env precursor protein gp160 is formed in the rough endoplasmic reticulum, cleaved
into the gp120 and gp41 subunits by cellular proteases, and transported to the cell
surface via the Golgi apparatus.
24 The Basics

The interaction of gag-encoded structural precursor proteins, the cell membrane, and
cell membrane-integrated Env proteins results in the generation of new virus particles
(“assembly”) at the cell surface, which also includes the packaging of intermediately
generated complete HIV-1 genomes in single-stranded RNA form. After budding
from the cell surface, necessary maturation processes in the secreted virus particles
include protease-mediated cleavage of structural precursor proteins.

HIV-1 latency
Even after years of continuous suppression of viremia, discontinuation of antiretro-
viral therapy almost inevitably leads to a “viral rebound” and detectable viral plasma
RNA within a few weeks. As with other retroviruses, HIV-1 infection leads to stable
integration of viral genetic information into the human genome. Transcription of
proviral DNA and subsequent production of viral particles usually results in the rapid
death of infected cells. However, in a fashion somewhat similar to other viruses (e.g.,
herpes viruses), latent infection also develops. In this form of virologic quiescence,
no production of viral particles occurs, and the infected cell is unaffected by the viral
DNA. In addition, these cells are poorly recognized by the immune system because
they do not present viral antigens.
Since HIV-1 also infects very long-lived cells (e.g., memory T cells), a reservoir of
latently infected cells persists and can be the source of viral production (e.g., fol-
lowing cellular activation in the context of inflammatory reactions). Based on the
observed half-life of the reservoir of latently infected cells circulating in the blood
in ART-treated patients (44 months, Finzi 1999), it was calculated that continuous
and complete suppression of viral replication over several decades (about 50–60 years)
would be necessary to achieve (a highly speculative) elimination of this reservoir.
Thus, the reservoir of latently infected cells represents the critical hurdle for HIV-1
cure.

HIV-1 and the immune system

The human immune system plays a unique role in the context of HIV-1 infection.
The main clinical manifestations of HIV-1 infection result from direct and/or indirect
damage to the immune system, resulting in opportunistic infections and HIV-asso-
ciated diseases. While the number of CD4 T helper cells has high prognostic and
clinical relevance as a surrogate parameter for HIV-mediated immunodeficiency, HIV
also damages other immune system components. Although the immune response
fails to eliminate the virus once HIV-1 infection is established, immunologic antiviral
activity can significantly influence the course of the disease. In particular, sponta-
neous control of viral load in the blood is related to the immune response. For
example, Long-Term Non-Progressors (LTNPs, frequency approx. 10%) and Elite
Controllers (<1%) can be distinguished from other individuals. While LTNPs have
a detectable but low viral load of <2,000 HIV-1 RNA copies/mL without therapy, elite
controllers often have negative HIV-1 plasma RNA in the absence of antiretroviral
therapy.
Due to the high relevance of the immune system in HIV-1 infection, individual com-
ponents will be discussed in more detail below.

Innate immune system

While relatively non-specific, the innate immune system provides a first and very
rapidly active line of defense against pathogens. Although innate immunity does
not specifically adapt to a pathogen, it interacts with parts of the adaptive immune
system.
Pathophysiology of HIV infection 25

Dendritic cells
Dendritic cells (DCs) are a heterogeneous group of myeloid or lymphoid cells whose
essential function is HLA class II-mediated presentation of antigens to other immune
cells such as T helper cells (Wu 2006). Although DCs are relatively poorly infected
by HIV-1, they may play a role in transmission across DC-rich mucosae as part of
the processes establishing HIV-1 infection. They can transport HIV in vesicles without
becoming infected themselves. Migration into T-cell-rich lymphoid tissues and
shedding of the vesicles can subsequently infect CD4 T-cells (“trans-infection”)
(Wu 2006). It is also possible that DCs themselves become infected and produce viral
particles. Plasmacytoid DCs, a rare form of dendritic cells in the blood, can be strongly
activated by contact with HIV-1 and contribute to damaging immune activation via
the production of pro-inflammatory Interferon-α (Fonteneau 2004).
Follicular dendritic cells (FDCs) represent a cell type that can be distinguished from
other dendritic cells. Unlike other dendritic cells, FDCs are not derived from
hematopoietic stem cells and do not have HLA class II molecules. They accumulate
in lymphoid follicles and interact with B cells in the germinal centers. Importantly,
FDCs are considered to trap intact HIV-1 particles on their surface for long periods,
allowing subsequent infection or stimulation of other target cells (Smith 2001).

Restriction factors
In recent years, intracellular host mechanisms that serve to defend against HIV-1
have become increasingly known. These restriction factors are located on the cell
membrane, in vesicles, or the cytosol and can initiate antiviral mechanisms. However,
the accessory proteins of HIV have evolved to enable effective replication despite
many of the following restriction factors:
APOBEC3G (“Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like
3G”) leads to unspecific degradation of viral nucleic acid by deaminating cytosine
to uracil. This results in increased G-to-A mutations with stop codons. However, DNA
degradation often occurs beforehand, as uracil is modified by uracil DNA glycosidase,
and the viral genome then becomes a target of specific endonucleases (Sauter 2018).
CARD8 (“Caspase recruitment domain-containing protein 8”) can recognize the
activity of the HIV protease and subsequently induce cell death in infected cells.
However, since the HIV protease is usually inactive in the cytosol of infected cells
and only takes up its activity in the virion, HIV can bypass this recognition mech-
anism. Targeted intracellular activation of the HIV protease could make it possible
to exploit the effect of CARD8 therapeutically to eliminate infected cells (Wang 2021).
BST-2 (“bone marrow stromal antigen 2”, also called tetherin or CD137) is expressed
on the cell surface in response to interferon. It prevents the budding of newly pro-
duced immature virus particles. In addition, BST-2 can internalize newly formed
virions and deliver them to endosomes/lysosomes, which can destroy the viruses.
BST-2 itself acts as a PRR and can initiate cytokine release.
IFI16 (“Interferon-Gamma Induced Protein 16”) and cGAS (“Cyclic GMP-AMP
synthase”) recognize the DNA products of reverse transcriptase in the cytosol. cGAS
then forms cGAMP, which activates the cell’s interferon production via STING
(“stimulator of interferon genes”) and thus increases the formation of other
interferon-stimulated proteins (Altfeld 2015).
MX2 (“MX Dynamin Like GTPase 2”) interacts with the HIV capsid directly or via
CypA, preventing its uncoating or the correct import of viral DNA into the nucleus.
In addition, MX2 appears to be essential for SAMHD1 activity. However, the exact
interaction of both factors is still largely unclear (Kane 2013).
26 The Basics

RIG-I (“retinoic acid-inducible gene I”) is located in the cytosol and can recognize
viral RNA of the invading HI virus and newly produced viral mRNA. However, HIV
can escape this recognition through protease-mediated degradation of RIG-I
(Bergantz 2019).
SAMHD1 (“SAM domain and HD domain-containing protein 1”) inhibits HIV-1
replication, probably by depleting the intracellular pool of deoxynucleoside triphos-
phates. However, Vpx (present only in HIV-2) appears to reverse this effect by
promoting proteosomal degradation of SAMHD1 (Lahouassa 2012).
SERINC3 and SERINC5 (“serine incorporator 3/5”) are cell surface proteins that
become part of the membrane of newly emerging viruses and prevent the reinfec-
tion of further cells. However, the incorporation of SERINC3/5 into the viral mem-
brane is prevented by HIV through Nef, which guides the SERINC3/5 proteins to the
lysosomes. This resistance mechanism is thought to be one of the most critical func-
tions of Nef (Usami 2015).
TPIM5α (“tripartite motif-containing protein 5 α”) recognizes the HIV capsid and
leads to faster “uncoating”, allowing PRRs to recognize the viral RNA/DNA better.
Another recently discovered restriction factor that recognizes the capsid (especially
of HIV-2) is NONO (Lahaye 2018).
ZAP (“zinc finger antiviral protein”) recognizes newly formed viral mRNA in the
cytosol and destroys it (Zhu 2011).

Natural killer cells (NK cells)

NK cells are of lymphoid origin but do not use antigen-specific receptors to recognize
pathogens and are classified as components of innate immunity. They express various
activating receptors through which they can recognize, for example, cellular stress
signals. In addition, they exhibit inhibitory receptors such as KIRs (killer cell
immunoglobulin-like receptors) that interact with HLA class I molecules. The asso-
ciation of favorable disease outcomes with HLA alleles (see below) that act as NK cell
ligands underscores the importance of NK cells in HIV infection (Flores-Villanueva
2001).
Activated NK cells can lead to the elimination of HIV-1-infected cells via various
mechanisms. For example, the release of perforin and granzyme leads to apoptosis
of the targeted cell. This cytotoxic NK cell activity can also be mediated by anti-
bodies that label HIV-1-infected cells and interact with the activating Fc receptor on
the surface of NK cells via their Fc domains (see also section Humoral Immune
Response). In addition, NK cells can, among other things, modulate the antiviral
immune response by secreting cytokines such as Interferon-γ and inhibit the binding
of HIV-1 to co-receptors via the secretion of chemokines such as MIP-1β.

Adaptive immune response

Adaptive (or “acquired”) immunity enables an immune response that specifically
adapts to the pathogen. The enormous diversity of antigen receptors required for
this is made possible by the rearrangement of various gene segments and somatic
hypermutation.

The HLA system

The human leukocyte antigen (HLA, also known as MHC, major histocompatibility
complex) system comprises a group of surface receptors that present antigens to
T cell receptors and are encoded on chromosome 6. HLA classes I and II differ struc-
turally and functionally (Klein 2000). HLA class I molecules are found on almost all
Pathophysiology of HIV infection 27

nucleated cells and are essential for presenting antigens to cytotoxic T cells. Specific
HLA class I alleles, such as B*27 and B*57, are associated with enhanced control of
HIV-1 infection. In contrast, other alleles (e.g., B*07 and B*35) are typically associ-
ated with more rapid progression of HIV infection (O’Brien 2001, Pereyra 2010). HLA
class II molecules are found on specialized antigen-presenting cells (e.g., B cells,
macrophages, dendritic cells) and present antigens to CD4 T helper cells.

CD8 T-cells
CD8 T-cells recognize specific antigens (such as HIV-1 peptides) presented via HLA
class I molecules through their T cell receptors. Following HLA-mediated activation,
CD8 T-cells can secrete perforins and granzymes that can induce apoptosis and elim-
inate virally infected cells. CD8 T-cells are, therefore, also referred to as cytotoxic
T cells. In addition, they can secrete several other pro-inflammatory substances,
including, for example, MIP-1β, interferon-γ, TNF-α, and IL-2.
In the context of HIV-1 infection, a robust immune response by CD8 T-cells against
various epitopes is almost invariably induced (Addo 2003). However, viral variants
carrying resistance mutations against the CD8 T-cell response are subsequently
selected (Allen 2005). High CD8 T-cell activity can often still be detected in the late
stages of the disease. However, a lack of induction of novel escape mutations suggests
that this activity is not necessarily associated with substantial antiviral effects
(Draenert 2004).
The development of an HIV-1-specific CD8 T-cell response is associated with the
control of viral replication during the acute phase of HIV-1 infection and the devel-
opment of the so-called viral setpoint, i.e., the relatively stable early viral load after
acute infection (Streeck 2009, Collins 2020). Therefore, the CD8 T-cell-mediated
immune response plays a significant role in the extent of spontaneous HIV-1 control
and, thus, disease progression. As mentioned above, specific alleles of HLA class I
molecules interacting with the T cell receptor on CD8 T-cells are associated with
favorable or adverse disease outcomes. Compared with CD8 T-cells from individu-
als with typical disease courses, CD8 T-cells from long-term non-progressors often
have a higher proliferative capacity (Migueles 2002). A possible cause for the lower
activity of CD8 T-cells in typical progressive disease might be PD1-mediated immune
exhaustion (Day 2006).

CD4 T-cells ("Helper T-cells")

Different types of CD4 helper T-cells can be phenotypically distinguished. These
include Th1 (type 1), Th2 (type 2), Th17 (type 17), and (follicular) Tfh cells. The CD4
surface protein plays a role as a co-receptor in the interaction of the T cell receptor
with HLA class II molecules. By secreting cytokines, helper T-cells can regulate the
immune response against pathogens. For example, Th1 cells activate macrophages
and CD8 T-cells in particular via Interferon-γ, whereas Th2 cells stimulate B cells via
interleukin-4. Th17 cells play an essential role in neutrophil granulocyte activation
through the secretion of interleukin-17. In addition, Th17 cells are responsible for
maintaining intestinal barrier function, which is often disrupted due to cell loss
during HIV infection (Brenchley 2008). Follicular T helper cells play an essential role
in B-cell activation in the germinal centers of lymphoid follicles (Crotty 2019).
A type of CD4 T-cell to be considered separately from classical CD4 T helper cells is
represented by regulatory T-cells (Tregs) associated with immune system suppres-
sion. HIV-1 can also infect these cells, although the significance of infection and
possible depletion of these cells for HIV-1 pathogenesis is the subject of ongoing
research.
28 The Basics

CD4 helper T cells are probably the most crucial target cells of HIV-1; the loss of these
cells is an expression of the increasing immunodeficiency. The CD4 T-cell count is
considered the most important surrogate parameter for the extent of HIV-mediated
immune damage in routine clinical care. The depletion of CD4 T-cells that typically
occurs in peripheral blood during HIV-1 infection can occur for a variety of reasons:
• Apoptosis/pyroptosis as a form of programmed cell death (e.g., as a result of virus-
induced cytotoxic effects, cytotoxic activity of CD8 T lymphocytes, or the release
of proinflammatory cytokines by other infected CD4 T-cells in the environment).
• Medium- to long-term damage to CD4 T-cell regenerative capacity due to
lymphocyte turnover resulting from immune activation.
• Reduced production due to HIV-induced damage to the thymus and the bone
marrow.
• Redistribution of CD4 T-cells from peripheral blood to lymphoid tissues.

Humoral immune response

Antibody-mediated immunity is an essential component of the adaptive humoral
immune system. Antibodies are produced by plasma cells that develop in lymphoid
follicles from activated B cells. Antibodies can specifically bind to a target structure
(epitope) via highly variable regions. In addition, antibodies have constant regions
in which the so-called Fc region (fragment crystallizable) is located.
This composition explains the potential dual functionality of antibodies in the
context of the immune response. By binding to HIV-1 Env, antibodies can prevent
the virus from interacting with its target cell receptors (neutralizing function of
antibodies), interfering with infection and interrupting viral replication. Moreover,
through their Fc region, antibodies can interact with other immune system com-
ponents (Parsons 2018). In addition to possible activation of the complement system,
binding of the Fc region to Fc receptors on immune cells can mediate a cellular
immune response. These cell-mediated mechanisms include ADCC (antibody-depen-
dent cellular cytotoxicity), which can lead to the elimination of HIV-1-infected cells
via NK cells. Similarly, antibodies can promote phagocytosis by macrophages or den-
dritic cells (ADCP, antibody-dependent cellular phagocytosis).
The fact that virtually all people living with HIV form antibodies against various
virus components within a few weeks is exploited by serological tests that diagnose
HIV infection. Many of these antibodies do not immediately affect circulating viruses
because they are directed against viral proteins found intracellularly or because their
binding to the viral envelope protein Env fails to prevent cellular infection (non-
neutralizing antibodies). While neutralizing antibodies are also produced, their
activity is usually relatively specific to the viruses circulating in the individual. It is
offset by the development of viral escape mutations resulting in resistance to the
autologous antibody response (Overbaugh 2012).
During the course of infection, a small proportion of people living with HIV-1
(approx. 20%) develops antibodies that exhibit activity against many different HIV-1
strains (broadly neutralizing antibodies) and are, in rare cases (in so-called elite
neutralizers; frequency approx. 1%), extraordinarily potent. These antibodies are
characterized by targeting relatively conserved regions of the Env surface protein
and the capacity to neutralize many existing HIV-1 variants at very low concentrations
(Gruell 2022). In the few individuals that produce potent and broadly neutralizing
antibodies, these antibodies typically do not result in viral control due to the selection
of viral resistance. However, recombinantly produced broadly neutralizing antibod-
ies represent a promising option for the prevention and therapy of HIV-1 infection
that is currently investigated in numerous clinical trials (see chapter 5.3., section on
Broadly Neutralizing Antibodies).
Pathophysiology of HIV infection 29

HIV-1-induced immune dysfunction

During the course of HIV-1 infection, functional impairments can be demonstrated
for virtually all cellular components of the immune system. In addition, structural
damage to critical lymphoid tissues, such as lymphoid follicles, is often seen (Pantaleo
1993). These changes contribute to the increasing degree of immunodeficiency
characteristic of progressive HIV-1 infection. However, a large proportion of HIV-1-
induced damage to the immune system is probably due to a persistently elevated
level of immune activation during infection. The high immune system stimulation
also likely underlies the increased HIV-associated risk of various other diseases, such
as cardiovascular or hepatic conditions (Tenorio 2014).
An important reason for this immune system stimulation is the depletion of CD4
T-cells in the lymphoid tissue of the gastrointestinal tract (GALT, gut-associated
lymphoid tissue) during acute infection. The damage to the immunological integrity
of the mucosal barrier caused by T-cell depletion can lead to increased transmission
of pro-inflammatory microbial products (e.g., LPS) (Brenchley 2006). The prolonged
stimulation of immune cells can lead to a kind of “immune exhaustion”, charac-
terized by a decrease in proliferative capacity and effector functions. In addition, an
increased expression of anti-inflammatory proteins (e.g., PD-1) or cytokines (e.g.,
IL-10) can typically be observed (Fenwick 2019).

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31

4. Acute HIV infection

H EN DR I K STR EEC K

Acute HIV-1 infection (see also chapter HIV-2) is uniquely positioned in diagnosis
and treatment while generating significant scientific interest in vaccine and cure
research. Approximately two weeks after infection, around 70–80% of individuals
experience transient symptoms frequently mistaken for other viral diseases, such as
flu or mononucleosis, as HIV-1-specific antibodies are often not detectable at this
early stage. Early diagnosis is significant for several reasons: for example, about 50%
of all new infections are caused by newly infected individuals (Brenner 2007); early
ART has long-term immunologic and virologic benefits (see below). Acute HIV infec-
tion can manifest differently when individuals are taking pre-exposure prophylaxis
(PrEP). An accurate diagnosis is essential to prevent PreP-related resistance (see
chapter ART and Prevention).

Definition and classification

Acute HIV-1 infection (AHI) is defined by either a high HIV-1 viral load in the absence
of a positive anti-HIV ELISA or a positive HIV test when the Western blot is positive
in fewer than three bands.
It is essential to differentiate between “acute” HIV infection and “early” HIV-1 infec-
tion (EHI), which refers to infection within the past six months. This is independ-
ent of seroconversion status, but a negative HIV-1 test must have been documented
in the last six months. AHI and EHI are combined under the term “primary HIV-1
infection” (PHI). To objectively compare early changes in the HIV reservoir and
immune system, a classification was introduced (Fiebig 2009) that subdivides the
AHI according to immunopathological features (Figure 1). Here, simply put, stages
I-III correspond to acute and stages IV-VI to early HIV-1 infection. The system is

Figure 1: Schematic progression of acute HIV infection, Fiebig stages. Dashes, gray-shaded bars: median
and interquartile ranges according to Robb 2016.
32 The Basics

based on a distinction between p24 antigen and anti-p24 antibody (second-genera-

tion HIV test). Since fourth-generation tests detect p24 antigen and IgG/IgM anti-
bodies simultaneously, a different classification system incorporating the fourth-gen-
eration test has been proposed (Ananworanich 2013). It distinguishes three stages:
HIV RNA+/4th EIA-/3rd EIA- (stage 1); HIV RNA+/4th EIA+/3rd EIA- (stage 2); HIV
RNA+/4th EIA+/3rd EIA+ (stage 3). Another classification system includes the Signal-
to-Cutoff ratio (Crowell 2021). The classifications of the different stages of acute HIV
infection primarily serve scientific questions, while this distinction is less crucial for
diagnosis and/or therapy.

Clinic
AHI occurs approximately 14 days after infection (Robb 2016) and is associated with
a rapid increase in plasma viremia. Just before and during the viral load peak, the
AHI usually manifests with characteristic clinical symptoms that disappear after
hours to a few days (Hecht 2002). Symptoms (e.g., lymph node swelling, tachycardia)
are noted in up to 94%, even when the acute phase is subjectively asymptomatic
(Robb 2016). Fever between 38° and 40°C persists for approximately 1–8 days.

Table 1: Leading symptoms of acute HIV-1 infection, frequency in % (n.a. = not specified).
Symptom San Francisco East Africa Thailand San Diego (US) Mean
Pike Robb Crowell Hoenigl value
2002 2016 2018 2016
Fever 80 55 77 77 72
Lymph node swelling n.a. 9 14 n.a. 12
Skin rash 51 n.a. 32 19 34
Oral ulcers 37 n.a. 23 n.a. 30
Arthralgia 54 n.a. 23 20 32
Pharyngitis 44 18 53 49 41
Loss of appetite 54 n.a. n.a. n.a. 54
Weight loss > 2.5 kg 32 n.a. 34 22 29
Fatigue 68 42 63 70 61
Headache 54 52 35 n.a. 47
Myalgia 49 n.a. 45 70 55
Cough n.a. 30 53 n.a. 42
Tachycardia n.a. 33 29 n.a. 31

The clinical symptoms of AHI resemble those of mononucleosis (Cooper 1985) but
appear slightly different depending on region, HIV subtype, and in men vs. women
(Robb 2016). Also, the viral load level during AHI determines the severity of
symptomatology (Crowell 2018). Individuals with severe and prolonged persistent
symptomatology rapidly progress to AIDS (Keet 1993).
A maculopapular rash occurs in about one-third of people about 48–72 hours after
the onset of fever and occurs mainly on the trunk, neck region, and face. Furthermore,
painful oral ulcerations, lymphadenopathy, arthralgias, pharyngitis, lassitude,
weight loss, aseptic meningitis, and myalgias (Kahn 1998) have been described;
myocarditis, pancreatitis, or renal failure may also occur in rare cases. In one study,
fever (80%) and fatigue (68%) showed the highest sensitivity for clinical diagnosis,
whereas weight loss (86%) and oral ulcerations (85%) showed the highest specificity
(Hecht 2002). However, the frequency of the symptoms described depends on why
acute HIV infection was tested for in the first place. In the case of an incidental
Acute HIV infection 33

finding during routine testing, the course is often asymptomatic (Sullivan 2012).
Co-infection with other sexually transmitted diseases, such as Mpox or gonorrhea,
can mask acute HIV infection. The initial viral load maximum has reached a median
of 14 days after infection (Robb 2016), typically exceeding 1 million HIV RNA
copies/mL. The maximum predicts subsequent viral load progression and is a criti-
cal factor in long-term prognosis. The early viral load setpoint is reached at a median
of 31 days (18–42 days), marking the onset of early chronic HIV infection.

Diagnostics
Although most of those affected develop symptoms at least briefly, these are often
mild, so diagnosis is often not considered. In addition, the symptoms can be masked
by PrEP (especially when needed). Initial suspicion is thus based on a combination
of history and symptoms, with only a nucleic acid test able to detect AHI at this
stage. The HIV-1 antibody test (3rd generation) is positive on average only after
approximately 14 days post-infection, and thus often only when the viral load drops
again (Robb 2016). In PrEP users, seroconversion may not occur at all.
All tested detection methods for HIV-1 RNA (branched chain DNA, PCR, and Gen-
Probe) show a sensitivity of 100% but yielded false positive results in 2–5% (Hecht
2002). These are primarily below 2,000 HIV-1 RNA copies/mL, well below the high
levels that generally occur during AHI (in our studies, an average of 13 x 106 HIV-1
RNA copies/mL, with a range of 0.25–95.5 x 106). Repeated determination of HIV-1
RNA from the same specimen using the same assay resulted in a negative test result
in all false positive cases. In contrast, detection of p24 antigen has a sensitivity of
only 79%, with a specificity of 99.5–99.96%. The diagnosis of AHI must then be
confirmed with a positive antibody test within the following weeks.
Four different HIV tests are on the market, which can diagnose HIV-1 infection early
with varying degrees of success (see chapter HIV Testing). The first- and second-
generation EIA tests detect only IgG antibodies; they are hardly ever used anymore.
The time window between infection and positive test result is estimated to be
25–35 days (Branson 2012). Third-generation EIAs are somewhat more sensitive

Figure 2: Testing algorithm for current HIV-1 infection.

34 The Basics

because they can detect IgM antibodies; they appear to identify about three-quarters
of AHI (Hecht 2002). Fourth-generation EIAs combine an antibody EIA with a p24
antigen EIA. These identify even those individuals who have not yet produced anti-
bodies. The time between infection and earliest possible diagnosis is shortened to
15–20 days (Branson 2012). Still, a second diagnostic window opens when antibody
and antigen neutralize each other for a short time (Ly 2007).
During the AHI, there is often a marked decrease in CD4 T-cells and B cells.
Occasionally, such low CD4 T-cell counts are observed that opportunistic infections
are already possible at this time (Gupta 1993). Although CD4 T-cell counts rise again
after primary infection, they rarely return to baseline levels without ART. In contrast,
CD8 T-cell counts increase significantly, which can result in a CD4/CD8 ratio of less
than 1.
In summary, the most crucial task in diagnosing AHI is to consider it a differential
diagnosis in the first place and consider the window of time when it cannot yet be
detected. Clinical suspicion then requires HIV-1 testing and possibly repeat deter-
mination of HIV-1 viral load, as shown in Figure 2.

Immunological and virological events

During AHI, robust viral replication occurs, and the viral load often reaches more
than 100 million HIV-1 RNA copies/mL. The initial interaction between HIV and
the host is believed to play a crucial role in subsequent disease progression. Thus,
the initial viral load’s magnitude is associated with the viral load rebound rate after
treatment interruption (Colby 2022). (Colby 2022). Furthermore, the initial phase
provides a unique opportunity to study determinants of HIV transmission, the
evolution and emergence of immune responses, and the emergence of the viral
reservoir.
Unlike hepatitis B or C, AHI is associated with a dramatic cytokine cascade. This pro-
ceeds in waves, activating different arms of the immune responses (Teigler 2018). At
as early as seven days, there is a rapid increase in cytokines of the innate pro-inflam-
matory immune response, followed by TNF-alpha and INF-gamma signaling
pathways, with some very closely associated with increasing viral load (e.g., IP10).
These cytokines, although serving in part to control infection, are likely to contribute
mainly to immunopathogenesis (Stacey 2009). Furthermore, cytotoxic NK (natural
killer) cells are activated (Alter 2007), expand, and can exert antibody-dependent
cell-mediated cytotoxicity (Chung 2011). Neutralizing antibodies directed against
HIV are usually not found during this phase. Several factors may influence HIV-1
replication in the acute phase and, thus, the early viral setpoint. These include the
virus’s replication capacity (viral fitness) (Troyer 2009), genetic factors, and the
various arms of the immune response.
The HIV-1-specific cellular immune response occupies a key position in the control
of HIV replication; thus, the initial drop in viremia is closely temporally related to
the appearance of HIV-1-specific CD8 T-cells (Koup 1994). These can eliminate HIV-
1-infected cells directly by MHC class I-restricted cytolysis or indirectly by limiting
the production of cytokines, chemokines, or other soluble factors (Yang 1997).
Another indication of the antiviral activity of HIV-1-specific cytotoxic T lympho-
cytes (CTL) during AHI is the rapid selection of viral species with mutations of CTL
epitopes. These species, which arise under selection pressure, can be detected in
humans as early as a few weeks after HIV-1 infection and can influence viral fitness
(Price 1997). In particular, the initial CD8 T-cell responses during AHI appear to play
a role; thus, individuals with a strong CTL response during AHI have a significantly
lower early viral setpoint (Streeck 2009). In contrast, no relationship between the
Acute HIV infection 35

breadth or strength of CD8 T-cell responses and viral load was found during chronic
HIV infection (Frahm 2004). Many of these early CTL responses are restricted by HLA
class I alleles that are beneficial to the further course of infection, such as HLA-B57
or HLA-B27 (Altfeld 2006). These immunodominant protective immune responses
are directed against epitopes that are not widely scattered across the HIV-1 genome
but occur in clusters in a defined region of p24 gag (Streeck 2007), a region that
appears to be essential for the stability of the HIV capsid (Schneidewind 2007). The
effectiveness of early CD8 T-cell responses in controlling HIV replication may be
attributed to the presence and assistance provided by antigen-specific CD4 T-cells
(Schieffer 2014). However, it is worth noting that these CD4 T-cells are also prefer-
entially targeted and infected by HIV (Douek 2002). HIV-specific CD4 T-cell responses
with cytotoxic features also expand during the acute phase of HIV infection. They
can directly affect viral replication (Soghoian 2012). Little is known about the role
of these cytolytic CD4 T-cells; they may control HIV infection in macrophages,
whereas CD8 T-cells inhibit HIV in CD4 T-cells. Moreover, CD4 T-cells influence the
efficacy of the HIV-specific CD8 T-cell response via antigen-specific IL-21 secretion
(Chevalier 2010). Furthermore, studies from the LCMV mouse model show that the
development and maintenance of long-lived memory CD8 T-cell response requires
the presence of CD4 T helper cells even during the first hours of generation of new
CD8 T-cell responses (Janssen 2003). However, it is not known precisely which CD4
T-cell signals are necessary to maintain HIV-specific CD8 T-cells. The declining func-
tionality and effectiveness of CD8 T-cells over time correlate directly with the level
of viral load. The gradual loss of function could be indirectly correlated with the
expression of inhibitory receptors, such as programmed death-1 (PD-1) (Day 2006),
which is upregulated on HIV-specific CD8 T-cells. The importance of identifying such
receptors may lie in the exploration of potential immunotherapies that, for example,
reactivate the body’s immune system against HIV by blocking these receptors.
In addition to the host immune response, genetic factors also play a crucial role in
determining susceptibility and resistance to HIV-1 infection and influencing the rate
of disease progression. The most significant of these factors is a deletion at the gene
of the major coreceptor for HIV-1 entry into the CD4 T-cell, the CCR5 chemokine
receptor (see Basics and, in ART, the section on coreceptor antagonists).
In addition to mutations at chemokine receptor genes, several HLA class I alleles
have been associated with lower viral setpoints and slower disease progression, such
as HLA-B27 and -B57 (O’Brien 1997, Kaslow 1996). In contrast, individuals express-
ing a specific isoform of HLA-B35 (HLA-B35px or HLA-B3502/HLA-B3503) show
significantly faster disease progression. The cause of this has not yet been clarified.
Furthermore, it has been shown that certain killer immunoglobulin-like receptors
(KIR), expressed primarily on NK cells but also on T cells, also have a significantly
slower progression course in combination with a group of HLA-B alleles (HLA-Bw4-
80I) (Martin 2007), which may indicate a role of NK cells in HIV immunopatho-
genesis. Indeed, NK cells can recognize HIV-infected cells, exert selection pressure,
and thereby critically influence viral replication (Alter 2011). This suggests that host
genetic factors influence the clinical manifestation of AHI. Host factors are thus
important determinants of subsequent viral setpoint and the rate of disease pro-
gression.

Therapy
The results of the START and TEMPRANO trials demonstrated the benefits of ART.
Although neither study collected specific information on individuals with early infec-
tion, they suggest that ART should generally be started as early as possible. As with
36 The Basics

chronic infection, patients must be willing and able to undergo treatment. If ART
initiation is delayed, close monitoring is essential. There are several reasons for start-
ing ART immediately: First, early ART leads to shortening and alleviating the symp-
tomatic phase. Second, it lowers HIV transmission risk, reduces the number of
infected cells, maintains HIV-1-specific immune responses, and potentially reduces
the viral setpoint in the long term. Smaller studies have shown that ART during AHI
increases HIV-specific immune responses and allows long-term viral suppression.
In addition, early ART can achieve temporary control of viral replication (Grijsen
2012) and significantly increase the CD4 T-cell count in the long term (Hecht 2006).
However, there is usually a viral load rebound later (Streeck 2006). In rare cases,
control of HIV infection can be observed even if ART is discontinued later. However,
these so-called post-treatment controllers (PTC) are rare (Hocqueloux 2010) and
cannot be explained by genetic or immunological characteristics (Saez-Cirion 2013).
Other benefits of early therapy include limiting viral diversification (Delwart 2002)
and improved innate and adaptive immune system functions (Oxenius 2000, Alter
2005, Moir 2010). However, the extent to which early antiviral therapy effectively
limits the viral reservoir remains unclear. While some studies have demonstrated an
effect (Ananworanich 2013), paradoxically, other studies have shown a larger reservoir
when therapy is initiated earlier. With the early initiation of treatment, the reservoir
primarily resides in the T cell zone rather than the B cell follicles, suggesting that
the lack of immune responses may not have sufficiently eliminated the infected cells
(Kroon 2022). Intensification of early therapy (mega-HAART) has not affected
immunologically or reservoir size (Ananworanich 2015).
Treatment of acute HIV infection should follow consensus guidelines. When con-
sidering the treatment of PrEP users, check that resistance to TDF or FTC has not
developed. Due to high viral replication, an agent with a high resistance barrier
should be used in addition to NRTIs. Before initiating ART, a genotypic resistance
test is mandatory, but its result does not necessarily need to delay the initiation of
ART – treatment can be modified later if needed.
CD4 T-cell count and viral load should initially be monitored closely every 2 to
8 weeks after initiation of treatment and every 3 to 4 months after sufficient viral
suppression below the detection limit. ART should be continued indefinitely as per
the guidelines for chronic infection.

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load: findings from a subtype C epidemic, 1995-2009. AIDS 2012;26:175–84.
Teigler JE, Leyre L, RV254/RV217 study groups et al. Distinct biomarker signatures in HIV acute infection associ-
ate with viral dynamics and reservoir size. JCI Insight 2018, 3(10).
Troyer RM, McNevin J, Liu Y, et al. Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte
(CTL) response. PLoS Pathog 2009, 5:e1000365.
Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol 2004, 78:5535-5545.
Yang OO, Kalams SA, Trocha A, et al. Suppression of human immunodeficiency virus type 1 replication by CD8+ cells:
evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms. J Virol 1997, 71:3120-8.
Yerly S, Vora S, Rizzardi P, et al. Acute HIV infection: impact on the spread of HIV and transmission of drug resist-
ance. AIDS 2001, 15:2287-92.
SECTION 2

Antiretroviral
Therapy (ART)
40

5. ART 2023
5.1. Perspective
C H R ISTIAN HOFFMAN N

Hardly any other field of medicine has experienced such a dramatic evolution as
antiretroviral therapy. After the early days, the cautious hopes with AZT, the first
approved drug, in March 1987 (Volberding 1990, Fischl 1990), the Concorde study
in 1994 plunged all involved into a sink of depression for several years. AZT was
largely ineffective. Some participants still talk about the somber, still mood at the
Berlin World AIDS Conference in June 1993. Infected people suffered and died.
Hospices were set up, and AIDS care services were established. AIDS and death were
dealt with. Sure, there was progress – cotrimoxazole, ganciclovir, and fluconazole
saved lives in the short term, but hopelessness still dominated. Between 1989 and
1994, very little improved.
This did not change until September 1995, when two large trials, DELTA from Europe
and ACTG 175 from the US (Delta 1996, Hammer 1996), attracted attention.
It became apparent that two nucleoside analogs were more effective than one, includ-
ing clinical endpoints. On top of that, the first trials of protease inhibitors (PIs),
a new class of drugs developed thanks to knowledge of the molecular structure of
HIV and protease, had been going on for months – preliminary data and many
rumors were circulating. The race between the three companies, Abbott, Roche, and
MSD, culminated in the fall of 1995. The amount of work involved in the pivotal
studies of ritonavir, saquinavir, and indinavir was enormous. Study monitors “lived”
for weeks in the trial centers, and thousands of queries had to be answered until late
at night – between December 1995 and March 1996, all three PIs were approved in
fast-track procedures.
However, many people (including this author) were unaware of what happened
during these months. Although the AIDS rates in many centers had dropped by half
between 1992 and 1996 (Brodt 1997), AIDS remained ever-present, and many were
still dying. Doubts remained. Hopes had already been raised too many times in the
previous years by supposed miracles. No one dared proclaim a breakthrough. In
February 1996, during the 3rd CROI in Washington, when Bill Cameron reported
the first data of the ABT-247 study during the late-breaker session, many held their
breath. The auditorium was absolutely silent. Riveted, those in the audience heard
that adding ritonavir oral solution decreased the frequency of death and AIDS from
38% to 22% (Cameron 1998). These results were sensational compared to anything
else that had ever been published!
The World AIDS Conference in Vancouver a few months later, in June 1996, where
the great potential of PIs came to light, developed into a celebration. Even regular
news channels reported in great depth on the new “AIDS cocktails.” The strangely
unscientific expression “highly active antiretroviral therapy” (HAART) began to
spread irreversibly.
By this time, David Ho, Time magazine’s “Man of the Year” in 1996, had shed light
on the hitherto completely misunderstood kinetics of HIV with his groundbreaking
studies (Ho 1995, Perelson 1996). A year earlier, Ho had coined the slogan “hit early
and hard,” and almost all clinicians were now taking him at his word. With the new
knowledge of the incredibly high turnover of the virus, there was no longer a latency
period – and no life without antiretroviral therapy. Within only three years, 1994–
1997, the proportion of untreated patients in Europe decreased from 37% to 9%,
while the proportion on “HAART” rose from 2% to 64% (Kirk 1998).
5.1. Perspective 41

Things were looking good. By June 1996, a third drug class was introduced when
the first non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, was
licensed. One now had a great selection of medications at hand. Most patients seemed
to tolerate the pills. Twenty pills a day? We could live with that, if that’s what it
took. And how it helped! The number of AIDS cases was drastically reduced. Within
only four years, between 1994 and 1998, the incidence of AIDS in Europe dropped
from 30.7 to 2.5/100 patient-years (Mocroft 2000). Many ubiquitous opportunistic
infections just seemed to disappear. Large OI trials, planned only a few months before,
faltered due to a lack of patients. Hospices, just up and running on donations, shut
down or had to change their focus. The first patients began to leave the hospices
and went back to work. AIDS wards were occupied by other patients.
Sure, in early 1997, some began to complain about a fat belly. But what was that
compared to AIDS? In June 1997, the FDA issued its first warning about diabetes
mellitus with PIs. At the 5th CROI in Chicago in February 1998, old medical wisdom
proved true: No drug that works is without side effects – one poster after another,
whole walls of pictures showed fat abdomens, buffalo necks, thin legs, and faces.
A new term was born: lipodystrophy. A setback, also psychological. Guidelines were
modified; “Hit hard but only when necessary” was the imperative (Harrington 2000).
Lactic acidosis, nephrolithiasis, polyneuropathies, allergies, and the hardly control-
lable diarrhea with many PIs, especially ritonavir, did the rest – clinicians became
more defensive, and 200 CD4 T-cells were considered the new time point for starting
therapy. Could treatment interruptions help to reduce side effects? At the beginning
of the noughties, ART, although life-saving, did not have an excellent reputation.
But fortunately, times have changed again. Modern therapies have become much
better. Integrase inhibitors, in particular – the first, raltegravir, came on the market
in 2007 – have greatly enriched ART. Side effects are less and less of an issue; par-
ticularly, lipodystrophy has become rare. SMART (2006), HTPN052 (Cohen 2011),
and START (2015) have impressively shown that every person with HIV infection
should start ART and stay on it. Even with good immune status, there is less AIDS
with ART, fewer health problems, and a better quality of life. And, of course, there
are fewer transmissions. ART is still the best prevention. TasP, Treatment as
Prevention, has become a generally accepted concept.
The development of therapy remains dynamic. Many drugs that were indispensable
for a long time will now disappear; many already have done so. Pharmacokinetics
are being further optimized, and single-tablet regimens have become the rule. The
first injectable treatments are in use, and antibodies are becoming visible on the
horizon. These new options may once again revolutionize HIV therapy. On the other
hand, patents will expire over the next few years, as will prices and incentives. Patents
for the first-generation INSTIs will expire in the next few years. New drugs will have
a hard time being better than the existing ones (although that has been said before!).
What seemed utopian a few years ago has become a reality: a normal life expectancy
with HIV infection. However, this also means that people with HIV must remain on
treatment forever – a challenge. The comfortable situation today should not be a
reason to relax. A “Plan B” is needed if there is no cure. New drugs are needed. What
about the heart, kidneys, bones, and other organs in an aging population? New strate-
gies are also needed. Where can exposure be reduced? The resistance barrier of some
new agents is so high that the dogma of triple therapy has fallen. On the other hand,
especially when facing decades of therapy, any resistance should be avoided. Careful
studies are necessary to determine in whom de-escalation is possible (and whom it
helps).
And what about “Plan A”, the cure? We still cannot correctly measure or “wash out”
the latent reservoirs in which this tricky virus hibernates. This will not change with
42 ART

gene therapy, promoted by basic researchers (with careless media statements), that
has been raising hopes again and again since around 2016. Gene therapy will prob-
ably not be the solution. Nor will stem cell transplants, a hazardous procedure that
has received much media attention. On the other hand, if you don’t have vision,
you will never reach your goal. At least functional cures in selected cases do not seem
impossible – the HIV Cure chapter will continue to expand. In the meantime, we will
continue to pursue Plan B: keep HIV at bay in the long term. HIV remains a dangerous
opponent. Patients and clinicians will tackle it together. The following sub-chapters
describe how this might be done.
Literature
Brodt HR, Kamps BS, Gute P, et al. Changing incidence of AIDS-defining illnesses in the era of antiretroviral com-
bination therapy. AIDS 1997, 11:1731-8.
Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomized placebo-controlled trial of ritonavir in advanced
HIV-1 disease. Lancet 1998, 351:543-9.
Cohen MS, Ying QC, McCauley M, et al. Prevention of HIV-1 Infection with Early Antiretroviral Therapy. N Engl
J Med 2011; 365:493-505.
Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in
symptom-free HIV infection. Lancet 1994, 343:871-81.
Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or
zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996, 348: 283-91.
Fischl MA, Parker CB, Pettinelli C, et al. A randomized controlled trial of a reduced daily dose of zidovudine in
patients with the acquired immunodeficiency syndrome. N Engl J Med 1990; 323:1009-14.
Hammer SM, Katzenstein DA, Hughes MD, et al. A trial comparing nucleoside monotherapy with combination
therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996,
335:1081-90.
Harrington M, Carpenter CC. Hit HIV-1 hard, but only when necessary. Lancet 2000, 355:2147-52.
Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995, 333:450-1.
Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and
CD4 lymphocytes in HIV-1 infection. Nature 1995, 373:123-6.
INSIGHT START Study Group. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl
J Med 2015; 373:795-807.
Kirk O, Mocroft A, Katzenstein TL, et al. Changes in use of antiretroviral therapy in regions of Europe over time.
AIDS 1998, 12: 2031-9.
Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 2000, 356:291-6.
Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate,
infected cell life-span, and viral generation time. Science 1996, 271:1582-6.
The SMART Study Group. CD4+ Count–Guided Interruption of Antiretroviral Treatment. N Engl J Med 2006;
355:2283-2296.
Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic HIV infection. A controlled trial in
persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990, 322:941-9.
5.2. Overview – Classes of antiretrovirals and specific drugs 43

5.2. Overview – Classes of antiretrovirals and

specific drugs
C H R ISTIAN HOFFMAN N

Currently (June 2023), more than 30 preparations are approved for the treatment of
HIV infection. These come from six different drug classes:
1. Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs).
2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs).
3. Protease inhibitors (PIs)
4. Entry inhibitors (coreceptor antagonists, attachment and fusion inhibitors).
5. Integrase strand transfer inhibitors (INSTIs)
6. Capsid inhibitors
There are also many fixed-dose combinations in which different drugs from differ-
ent classes are combined, generally 1–2 NRTIs with an NNRTI, PI, or INSTI. Since
NRTIs and NNRTIs each target reverse transcriptase, there are currently four main
points of attack in the HIV replication cycle (Figure 2.1): HIV entry into the target
cell, which is further subdivided into at least three sub-steps, and the three enzymes
reverse transcriptase, integrase, and protease.
Here, the individual agents classified by drug class are discussed with their specific
advantages and problems. First-line therapies, switching, salvage therapies, and
experimental agents are discussed in separate chapters. The following table provides
an initial overview of antiretroviral drugs.

Figure 2.1: Targets in the replication cycle of HIV: entry, reverse transcriptase, integrase, and protease
(capsid inhibitors are not yet considered).
44 ART

Table 2.1: Antiretroviral drugs (brand names outside Germany in parentheses).

Trade name Abbr. Agent Name Orig. manufacturer Note
Nucleos(t)ide Reverse Transcriptase Inhibitors (NRTIs)
Emtriva® FTC Emtricitabine Gilead Sciences Generics
Epivir® 3TC Lamivudine ViiV Healthcare Generics
Retrovir® AZT Zidovudine ViiV Healthcare Generics
Viread® TDF Tenofovir Gilead Sciences Generics
Ziagen® ABC Abacavir ViiV Healthcare Generics
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Edurant® RPV Rilpivirine Janssen-Cilag
Intelence® ETV Etravirine Janssen-Cilag
Pifeltro® DOR Doravirine MSD
Sustiva® (Stocrin®) EFV Efavirenz BMS/MSD Generics
Viramune® NVP Nevirapine Boehringer Generics
Protease inhibitors (Pis)
Aptivus® TPV Tipranavir Boehringer Generics
Invirase® SQV Saquinavir Roche Generics
Kaletra® LPV Lopinavir/Ritonavir AbbVie Generics
Prezista® DRV Darunavir Janssen-Cilag Generics
Reyataz® ATV Atazanavir Bristol-Myers Squibb Generics
Entry inhibitors
Celsentri® (Selzentry®) MVC Maraviroc ViiV Healthcare
Fuzeon® T-20 Enfuvirtide Roche
Rukobia® FOS Fostemsavir ViiV Healthcare
Trogarzo® IBA Ibalizumab Theratech only US
Capsid inhibitors
Sunlenca® LEN Lenacapavir Gilead Sciences
Integrase inhibitors (elvitegravir, bictegravir only in the context of combination preparations)
Isentress® RAL Raltegravir MSD
Tivicay® DTG Dolutegravir ViiV Healthcare
Vocabria®+Recambys® CAB Cabotegravir+RPV ViiV Healthcare (+Janssen)
NRTI combination drugs
Combivir® CBV AZT+3TC ViiV Healthcare Generics
Descovy® DVY TAF+FTC Gilead Sciences
Kivexa® (Epzicom®) KVX ABC+3TC ViiV Healthcare Generics
Truvada® TVD TDF+FTC Gilead Sciences Generics
STR combinations (single-tablet regimen)
Atripla® ATP TDF+FTC+EFV Gilead+BMS+MSD Generics
Biktarvy® BIC TAF+FTC+BIC Gilead Sciences
Delstrigo® TDF+3TC+DOR MSD
Dovato® 3TC+DTG ViiV Healthcare
Eviplera® (Complera®) EVP TDF+FTC+RPV Gilead (+Janssen)
Genvoya® TAF+FTC+EVG+COB Gilead Sciences
Juluca® DTG+RPV ViiV (+Janssen)
Odefsey® TAF+FTC+RPV Gilead (+Janssen)
Stribild® STB TDF+FTC+EVG+COB Gilead Sciences
Symtuza® TAF+FTC+DRV+COB Janssen (+Gilead)
Triumeq® TMQ ABC+3TC+DTG ViiV Healthcare
Pharmacoenhancers (boosters)
Norvir® RTV Ritonavir AbbVie Generics
Tybost® COB Cobicistat Gilead Sciences
5.2. Overview – Classes of antiretrovirals and specific drugs 45

As can be seen from the table, there are various single-tablet regimens that contain
a complete ART combination. Some agents are missing because they are not marketed
in all European countries. These include Evotaz® (atazanavir/c), Rezolsta®
(darunavir/c, also Prezcobix®), Viracept® (nelfinavir), Rescriptor® (delavirdine), and
Vitekta® (elvitegravir). In 2022, Trogarzo® (ibalizumab) was withdrawn from the
European market, although it can still be obtained for selected patients through inter-
national pharmacies.
Many other compounds have already disappeared from the market, including the
previously widely used D-drugs HIVID® (ddC), Videx® (ddI), and Zerit® (d4T). At the
end of 2019, sales of the PIs Crixivan® (indinavir) and Reyataz® (atazanavir) were
discontinued, and in 2021, this was seen for Viramune® (nevirapine) and Aptivus®
(tipranavir). However, generics are still available for some of these compounds.
Withdrawal of Trizivir® (AZT/3TC/abacavir) and Telzir® (fosamprenavir) is expected
in 2023, as many other PIs.
In the summer of 2022, the first capsid inhibitor, lenacapavir, was approved, but the
indication is restricted to individuals with limited options. The exact mechanism of
action of capsid inhibitors is still unclear; different steps in the replication cycle are
probably inhibited to different degrees. Although lenacapavir is currently only a
niche drug, a start has been made.

Brand names, generics

Unfortunately, the US FDA and the European EMA sometimes disagree on the assign-
ment of brand names – as a result, brand names sometimes differ from country to
country. In some cases, the manufacturer’s rights do not apply worldwide. For
example, the NNRTI efavirenz is marketed in Germany by the company BMS under
the trade name Sustiva® and in Austria by MSD as Stocrin®. Generics are now avail-
able for nearly all NRTIs and PIs (INSTIs soon expected). Even the first STR Atripla®
is available generically as Padviram®. Although generics may often represent an
appropriate alternative to branded products, this may not always be true. Mandatory
generic switching may lead to confusion and unintended consequences. Specifically,
several studies suggested switching may negatively impact medication adherence
(Straka 2017). However, plausible reasons for staying with the original and expen-
sive preparation do not exist, but any switch needs communication with the person.
Patients can become anxious when pharmacies (obliged to do so in many countries)
issue unfamiliar drug packages without prior explanation and information.
In 2022, due to Russia’s invasion of Ukraine, HIV clinicians in many European coun-
tries have faced a new problem. Ukraine, home to about 250,000 PLWH, has nearly
ten times as many PLWH as neighboring countries. Most Ukrainian refugees living
with HIV take ‘TLD’, a fixed-dose combination (FDC) of TDF, 3TC, and dolutegravir
produced by generic manufacturers. TLD has become the most widely used HIV
regimen in the world but is still unavailable in the European Union. This means that
if people want to stay on dolutegravir, they must be switched to two-pill combina-
tions. The information that their STR is not available in Western Europe is often met
with incomprehension. Given the language barrier, the fact that they are not to be
deprived of anything but that other patent regulations apply here can often not be
conveyed to the people concerned. Mistrust can develop.

Indication restrictions
Definitions for indication areas vary widely. Some agents are not licensed for first-
line therapy: Maraviroc, T-20, tipranavir, etravirine, but also the combination prepa-
ration Atripla® or the combination of dolutegravir and rilpivirine (Juluca®). Also, the
two sustained-release drugs cabotegravir (Vocabria®) and rilpivirine-LA (Rekambys®)
46 ART

are reserved for adults who are “virally suppressed under their stable current anti-
retroviral therapy regimen” and who do not have resistance. The entry inhibitors
ibalizumab and fostemsavir are indicated only for multidrug-resistant cases where
“no other suppressive regimen can be assembled.” The NNRTI rilpivirine should
generally not be prescribed in patients with high viremia, and nevirapine should not
be prescribed for high CD4 T-cell counts. HLA or tropism testing is required for
abacavir or maraviroc. Further restrictions apply to pregnant women, adolescents,
and children; see the relevant chapters for details. Different dosages (Descovy®, but
also Prezista® or Isentress®) must also be considered, whether this is due to interac-
tions, the resistance situation, or renal insufficiency (see chapter Drugs at the end of
this book). Given cost pressures, clinicians are well advised to adhere to the specific
indication areas. Fortunately, this is usually possible due to a wide range of options.

Costs
Antiretroviral drugs have been expensive in many Western countries. However, there
has been a lot of movement in the market in recent years. With the fall of the patent
of tenofovir-DF (TDF) or TDF/FTC (Truvada®) in July 2017, a price war of generic
companies has broken out. Fueled by PrEP approval (many self-paying PrEP users,
public pressure), this competition led to unprecedented price erosion. TDF/FTC,
which was very expensive a few years ago at over 800 euros per monthly pack in
Germany, is now available for around 40 euros. A triple combination of TDF/FTC
plus nevirapine or efavirenz is now available for less than 250 euros/month, a fraction
of the old price – at least when TDF/FTC and, for example, efavirenz are given
separately. In addition to the NRTIs, the old NNRTIs nevirapine, and efavirenz, almost
all PIs are available as generics and have fallen considerably in price. More than half
of all antiretroviral agents are thus generic. For the INSTIs, it will take a little longer;
the raltegravir patent is still valid during 2023, and that for dolutegravir until
2026/27.
Drug patents have been disregarded in some African countries, such as India or
Thailand. Generics are now produced there for almost all drugs. The most prescribed
drug in Ukraine is TLD (see above). In Western countries, however, these prepara-
tions play no role.
It remains to be seen what impact the end of the patents will have on ART in the
near future. Will the development of new agents be worth the cost? New agents must
offer advantages to achieve those higher and higher prices. In many countries, new
agents without significant advantages over preexisting drugs (“me-too drugs”) will
be downgraded to the generic level. The companies know that. A good example is
GSK’s decision not to progress their new maturation inhibitor into late-stage trials
when it became clear that “the candidate was not differentiated enough in the daily
oral HIV market”. In other words, in the era of Bikarvy® and Dovato®, it has become
almost impossible to noticeably improve single-tablet regimens to charge a higher
price.
But will drugs be withdrawn from the market because they are no longer profitable?
The example of Trogarzo® in 2022 will not be the last – Theratechnologies could not
arrive at key pricing and reimbursement conditions in Europe and now only sells
ibalizumab in North America. There is no doubt that antiretroviral therapy is in for
a restructuring.
Sometimes, more than 20,000 euros is the annual price for a therapy for a multi-
resistant virus. The pricing policies of the industry, however, remain difficult to
understand. Discount agreements with health insurers remain obscure. Why some
directly competing preparations cost almost the same to the penny and other agents
in the same class of active ingredients, differ so much cannot be explained by devel-
5.2. Overview – Classes of antiretrovirals and specific drugs 47

opment costs alone. There is no question that much money is still being made with
ART. In 2019, market leader Gilead Sciences made 15 of 22 billion dollars in global
sales with HIV drugs. The market remains competitive, and the existing monopolies
will be exploited as long as possible. Innovations are needed to continue generating
such sales. This is one of the reasons why such intensive research is being conducted
into new options, such as long-acting agents or antibodies – they will indeed be
needed for new profit paradigms when the major INSTI patents expire by the end
of this decade.
However, two aspects should not be forgotten in this debate. First, the enormous
development costs of new drugs, which are estimated by manufacturers at over a
billion dollars in some cases (which is admittedly also disputed). Without the
prospect of profit, not a single agent would be developed. Most of them never make
it to market. An approved compound like T-20 will never recoup the development
costs, which reportedly swallowed up $600 million in development. Second, there
is hardly a more effective therapy than antiretroviral therapy. Estimates in the US
range from $13,000 to $23,000 per QALY (quality-adjusted year of life) year gained
(Freedberg 2001). This is comparatively cheap. Treatments for advanced HIV (AIDS)
hospital and nursing costs can be saved by ART. In the Hanover cohort, total annual
costs per case were reduced from 35,865 to 24,482 euros between 1997 and 2001
(Stoll 2002). In the PROPHET study, treatment costs were still around 20,000 euros
between 2014 and 2017, with a downward trend (Valbert 2020). Patients remain fit
for work, so costs are reduced economically (Sendi 1999).
The bottom line, however, is that ART is expensive. Patients can use supplies and
packs if they switch for strategic reasons (pill reduction or concern about long-term
toxicities). Only monthly packs should be prescribed at the beginning and during a
switch. Only when the ART is well-tolerated and has a constant effect can one resort
to the three-month packs most companies offer. They are usually cheaper than
monthly packs. Larger quantities than for three months should not be prescribed.
48 ART

Nucleoside analogs (NRTIs)

Mode of action
The target of nucleoside analogs (“nukes”) or nucleoside reverse transcriptase
inhibitors (NRTIs) is the HIV enzyme reverse transcriptase. Acting as alternative sub-
strates, they compete with physiological nucleosides, differing from them only by a
minor modification to the ribose molecule. Their incorporation of nucleoside analogs
induces DNA chain termination because durable phosphodiester bridges can no
longer be built to stabilize the double strand. NRTIs are pro-drugs; they are converted
to the active metabolite only after endocytosis, whereby they are phosphorylated to
the effective triphosphate derivatives. AZT and d4T are thymidine analogs, FTC, and
3TC cytidine analogs. A combination of FTC plus 3TC makes no sense because both
compete for the same bases. Abacavir a guanosine analog. TDF and TAF are precur-
sors of tenofovir, a nucleotide analog structurally related to adenosine monophos-
phate, which is phosphorylated intracellularly to the active tenofovir diphosphate
and competes with the natural substrate deoxyadenosine triphosphate in nucleic
acid synthesis.
Nukes were the first HIV drugs on the market – AZT was approved in 1987. Tolerability
is fair. However, frequent complaints in the first few weeks are fatigue, headaches,
and gastrointestinal problems, which vary widely from a mild feeling of fullness to
vomiting and diarrhea (see Side Effects below). Older NRTIs, in particular, caused a
broad spectrum of long-term side effects, ranging from myelotoxicity, lactic acido-
sis, polyneuropathy, and pancreatitis. Metabolic disorders and lipoatrophy have also
been associated with NRTIs. Much can probably be explained by mitochondrial
toxicity (Brinkman 1999). Mitochondrial function requires nucleosides: the
metabolism of these essential organelles is disrupted by the incorporation of false
nucleosides (the drugs), leading to mitochondrial degeneration.
With the NRTIs used today, however, such side effects are rare. TDF, TAF, 3TC, and
FTC still play an essential role, as does abacavir in some cases. On the other hand,
the notorious three toxic “D drugs” (d4T, ddI, ddC) have disappeared completely.
AZT will do so soon.
However, another mechanism may also play a role: in vitro, inhibition of telomerase
by NRTIs has been shown (Hukezali 2012, Leeansyah 2013). Telomerase, a reverse
transcriptase, restores telomeres, those ends of chromosomes consisting of repetitive
DNA and proteins that become shorter with each cell division (aging process). Thus,
NRTIs could promote premature aging of cells. However, clinical data are conflict-
ing (Solomon 2014, Montejano 2018, Stella-Ascariz 2018).
Nucleoside analogs are predominantly renally eliminated and do not interact with
drugs metabolized by hepatic enzyme systems. Therefore, the potential for
interaction is low; however, dose adjustments must be considered with TAF. Doses
of some NRTIs also need to be adjusted in cases of renal failure. There is a high degree
of cross-resistance (see chapter on Resistance).
5.2. Overview – Classes of antiretrovirals and specific drugs 49

Individual agents
Abacavir (Ziagen®, also in Kivexa® or Epzicom®, Trizivir®, Triumeq®, generics avail-
able, abbreviation ABC) is a guanosine analog that is phosphorylated intracellularly
to carbovir triphosphate. As monotherapy, abacavir reduces viral load by approxi-
mately 1.4 logs after four weeks (Harrigan 2000). After initial approval in July 1999,
abacavir was also approved for single daily administration in October 2004. It is
almost exclusively combined with 3TC (available as Kivexa®, as well as generics),
forming a backbone (see below). In a meta-analysis, abacavir was very effective, even
at high viral loads (Cruciani 2014). Since late 2014, it has also been a component of
the single-table regimen Triumeq®, a combination with 3TC and dolutegravir. The
single agent Ziagen® or the combination with AZT and 3TC, Trizivir®, hardly plays
a role anymore.
Abacavir is tolerated relatively well, but nausea occurs slightly more frequently than
with TAF (Gallant 2017). Regarding mitochondrial toxicity, abacavir is more favorable
than, for example, d4T (Hoy 2004). One significant drawback is the hypersensitiv-
ity reaction (HSR) seen with abacavir in 5–8% of Caucasians (in other ethnicities,
incidence is somewhat lower). This allergic reaction is often accompanied by fever
and feeling sick, usually occurring in the first six weeks. HSR can be life-threaten-
ing, especially in cases of re-exposure. In these cases, rapid action within minutes is
required. Severe HSR after a single tablet (De la Rosa 2004) or a break in therapy
when previously tolerated have been described (El-Sahly 2004).
There is a genetic predisposition for this hypersensitivity. People with the HLA allele
B*57:01 may develop HSR up to 80% with ABC (Mallal 2002, Hetherington 2002).
Cases without this HLA type are sporadic (Tangamornsuksan 2015). Abacavir likely
binds to a specific site on the HLA-B*57:01 molecule, altering its specificity and result-
ing in alloreactive T-cell activation. The PREDICT study demonstrated the predictive
value of HLA testing in nearly 2000 patients (Mallal 2008). HLA testing is manda-
tory before starting any ABC-containing ART and should be initiated once in every-
one with HIV. Because it is a genetic test, prior written consent is required. HLA-B57
status should be prominently noted in the medical record. Since the institution of
broad HLA testing, HSR is rarely observed today (Roen 2018).
Once the problem with HSR was resolved, abacavir came under pressure again in
2008. Since then, numerous cohort studies have consistently reported a nearly two-
fold increased risk of myocardial infarction, especially with newly initiated abacavir
therapy. Although this effect was not seen in meta-analyses of clinical trials (Nan
2018), it remained evident in more recent cohorts (Dorjee 2018). The prothrombo-
genic pathomechanisms can now be plausibly explained, involving both aggrega-
tion and activation of platelets (Mallon 2018, O’Halloran 2018, Taylor 2019). We
have replaced abacavir with other options in most patients, especially those at high
risk for cardiovascular events. The higher the risk, the faster and more active the
switch. In times of dual therapies, abacavir has mainly become dispensable.
AZT (zidovudine, Retrovir®, also in Combivir® and Trizivir®, generics available)
was the first antiretroviral drug ever on the market in 1987. In the 1990s, AZT was
among the most widely used drugs; it now plays little role. Compared with newer
NRTIs, AZT is less well tolerated, especially with regard to gastrointestinal complaints.
Myelotoxicity, which should not be underestimated even at current lower dosages
of 500–600 mg/day, is sometimes manifested by marked anemia (blood count
checks!), and MCV (mean corpuscular volume of erythrocytes) is almost always
elevated with long-term use. Countless studies have shown that lipoatrophy
improves when switching from AZT to other therapies (see chapter 5.7. Management
of side effects). In addition to poor tolerability, another disadvantage is twice daily
50 ART

dosing. Thus, its use today is reserved in cases of resistance. In the case of the teno-
fovir mutation K65R, AZT can be used due to its viral hypersensitivity, and lower
doses may be sufficient for this purpose. Also, because of its good CSF penetration,
it is still occasionally used in HAND or PML to reduce viral load in the CNS as effec-
tively as possible.
ddC (zalcitabine, Hivid®) was the third NRTI in 1992. Weak efficacy and problems
with pharmacokinetics and side effects led to ddC being withdrawn from the market
in 2006 – the first withdrawal in HIV medicine.
ddI (didanosine, Videx®) was the second NRTI in 1991. Its effectiveness is
comparable to that of AZT. Due to its toxicity (gastrointestinal symptoms, polyneu-
ropathies, pancreatitis, lipoatrophy), distribution in Europe was discontinued in 2020.
d4T (stavudine, Zerit®) was the second thymidine analog and as effective as AZT.
Its higher long-term toxicity compared with other NRTIs manifested as polyneu-
ropathies and lipoatrophy, but also as lactic acidosis. In Europe, it was discontinued
in 2019. Why is it still mentioned? There are still people suffering from d4T-induced
polyneuropathies.
3TC (lamivudine, Epivir®, also part of Combivir®, Delstrigo®, Kivexa® or Epzicom®,
Trizivir®, Triumeq®) was licensed in August 1996 as the fifth NRTI in Europe. 3TC
(the colloquial abbreviation describes the chemical formula 2’-deoxy-3’-thiacytidine)
is a very well-tolerated cytidine analog. Its primary disadvantage is the rapid devel-
opment of resistance: the point mutation M184V, likely to develop after only a few
weeks on monotherapy, is sufficient for resistance against 3TC (Eron 1995). Therefore,
the full effect of 3TC only emerges in combination with other drugs (which admit-
tedly is true for most). In extensive clinical studies such as NUCB 3002 or CAESAR,
3TC significantly improved disease progression and survival (Staszewski 1997).
The M184V mutation, which is also most likely to be found in the virological failure
of modern ART regimens, not only has disadvantages but may also increase
AZT-resistant viruses’ susceptibility (Miller 2002). More importantly, M184V reduces
viral fitness and flexibility (see Salvage Therapy). It may be prudent to remain on
3TC to conserve the M184V mutation through selection pressure and reduce the
replicative capacity of HIV. Further viral resistance mutations may be prevented
(Stirrup 2020).
Although the half-life is not quite as long, the antiviral potency of 3TC is equiva-
lent to that of its main competitor, FTC (see below). A meta-analysis including three
studies that directly compared the two compounds (with identical backbones) found
no relevant clinical differences (Ford 2017). Thus, 3TC and FTC are interchangeable,
both with excellent tolerability. Because of this, the choice between 3TC and FTC is
usually made by adjunctive therapy, as both agents are available in different
combination preparations. The most common use of 3TC in classical triple thera-
pies today is in the STRs Triumeq® (with dolutegravir and abacavir) and Delstrigo®
(doravirine, TDF). However, 3TC is also used in dual therapies. Within the GEMINI
and TANGO trials, it was as effective in fixed combination with dolutegravir
(Dovato®) as a classic triple therapy in both treatment-naïve and pretreated indi-
viduals without resistance (Cahn 2019, van Wyk 2020). Dovato® was approved in
the summer of 2019 and is now among the most frequently prescribed STRs. Also,
with boosted PIs such as darunavir or lopinavir, 3TC seems sufficient as the only
NRTI, although there are no fixed combinations in Western Europe.
It is important to note that 3TC dosage must be reduced in renal insufficiency. It is
often forgotten that fixed combinations (usually 300 mg 3TC) must be discontin-
ued with a creatine clearance of < 50 mL/min. Another effect of 3TC is its efficacy
against HBV, which can be used in co-infections. However, given the rapid devel-
5.2. Overview – Classes of antiretrovirals and specific drugs 51

opment of HBV resistance, 3TC should be combined with another HBV-active NRTI,
most likely tenofovir. The combination of ABC+3TC is, therefore, not recommended
in HBV co-infection.
FTC (emtricitabine, Emtriva®, also in Truvada®, Descovy®, Atripla®, Biktarvy®,
Eviplera® or Complera®, Genvoya®, Odefsey®, Stribild®, and Symtuza®) is another
well-tolerated cytidine analog that was approved in October 2003. FTC is biochem-
ically very similar to 3TC but has a longer half-life. Clinically, however, there are no
relevant differences. According to a comprehensive meta-analysis, the two com-
pounds are interchangeable, and potential differences are negligible (Ford 2017). As
with 3TC, efficacy is abrogated by the M184V mutation. There is also a moderate
efficacy against HBV. Tolerability is good, and interaction potential is low (Frampton
2005). FTC has a comparatively low affinity for mitochondrial polymerase, so the
risk of mitochondrial toxicity is probably relatively low. It is important to note that
with a creatinine clearance of less than 30 mL/min, the dose of FTC must be adjusted.
FTC is probably the most widely used substance in HIV therapy today, given the
many fixed combinations available (NNRTIs, PIs, INSTIs, mostly with TDF or TAF).
In contrast, the single substance as Emtriva® plays practically no role, and the con-
comitant therapy almost always decides for or against FTC. In recent years, FTC has
also been evaluated in the context of dual therapies. Still, the data situation is much
less conclusive than for 3TC – manufacturer Gilead continues to rely entirely on
triple therapy. FTC is also used extensively in PrEP; most large PrEP studies were con-
ducted with FTC (and not with 3TC).
TAF (tenofovir alafenamide fumarate, included in Descovy®, Biktarvy®, Odefsey®,
Genvoya®, Symtuza®, as single agent Vemlidy® only for hepatitis B) is a pro-drug
of tenofovir. Tenofovir has a phosphoric acid residue in addition to pentose and
nucleic base and is, therefore, referred to as a nucleotide analog. In contrast to TDF
(see below), TAF is first converted to tenofovir intracellularly and not already in
plasma, resulting in higher tenofovir concentrations in peripheral blood cells. With
TAF, plasma tenofovir levels in the blood are 90% lower, while intracellular levels
are about five-fold higher. So, with the same efficacy, the adverse effects on the kidney
and bones of TDF are reduced (Review: Wang 2016). Since 2016, TAF has been part
of various combination preparations; as a single agent, it is only approved for
hepatitis B.
The overall effect is comparable to that of TDF (Sax 2015, Gallant 2016), and the
renal tolerability is probably better. In two large Phase III trials in treatment-naïve
patients (with FTC and elvitegravir/c), TAF had less impact than TDF on bone mineral
density and renal biomarkers (Sax 2015). In ART-experienced patients, proteinuria
and bone density improved with switching from TDF to TAF, both in the presence
and the absence of moderate renal damage – see Table 2.2 (Mills 2016, Pozniak 2016).
A meta-analysis found a benefit in renal events and bone markers only with boosted
regimens; overall differences were small (Hill 2018). In at least two studies, an approx-
imately 5% increased rate of headache was observed compared to TDF (Gallant 2016,
Mills 2016). In one double-blind study, switching from abacavir to TAF did not affect
renal or bone biomarkers (Winston 2018). TAF is not a substrate of renal tubule trans-
port systems. Thus, no accumulation is expected. The drug can be dosed normally,
even in moderate renal insufficiency (clearance up to 30 mL/min). Renal monitor-
ing is less stringent than under TDF (see below). On the other hand, TAF has recently
been associated with weight gain (Venter 2019, DeJesus 2019, Sax 2019).
TAF levels are influenced by concomitant therapy. Therefore, unlike TDF, two dif-
ferent TAF doses are available (10 and 25 mg). In combination with boosted PIs or
elvitegravir/c, 10 mg TAF is sufficient. The combination drugs Genvoya® (with
52 ART

elvitegravir/c) and Symtuza® (with darunavir/c) each contain 10 mg, whereas

Biktarvy® (with bictegravir) and Odefsey® (with rilpivirine) contain 25 mg TAF. The
dose also needs to be adjusted for some other drugs. Drugs such as rifampicin,
rifabutin, and even St. John’s wort, all of which induce P-glycoprotein (P-gp), can
significantly decrease the plasma concentration of TAF. They should not be given
together; in these cases, TDF is recommended.
Since 2016, some TDF-containing combinations have been replaced by TAF-con-
taining ones, i.e., Truvada® by Descovy®, Eviplera® by Odefsey® and Stribild® by
Genvoya®. Many countries nevertheless did not consider any of these preparations
to have proven additional benefits, neither for patients who were naïve to therapy
nor for pre-treated patients. This is particularly relevant given the price decline of
the generically available Truvada® (TDF/FTC). In 2021, Gilead has withdrawn its
application for TAF/FTC as PrEP in the EU. This is likely due to the differences com-
pared to generic TDF/FTC that would not be acceptable to European health systems.
TDF (tenofovir disoproxil fumarate, Viread®, also in Truvada®, Atripla®,
Delstrigo®, Eviplera® or Complera®, Stribild®) is, like TAF, a precursor of tenofovir.
Since 2017, many generics have existed, some very cheap, especially for the combi-
nation of TDF/FTC. Of note, some generic manufacturers do not use the fumarate
as the water-soluble salt but rather as a succinate or maleate, so that the abbrevia-
tion TDF is, strictly speaking, incorrect (but will remain here for the sake of
simplicity). As a phosphonate, TDF is first freed from the phosphonate moiety by a
serum esterase and activated intracellularly by two phosphorylation steps.
TDF is well tolerated, and its affinity for mitochondrial polymerases is low (Suo 1998).
In extensive studies, TDF was superior to older NRTIs like AZT, mainly due to better
tolerability (Review: Dadi 2017). Switching to TDF may help improve lipoatrophy
and dyslipidemia (see below, section 5.7). Another advantage is its sustained efficacy
against HBV, which led to its approval for hepatitis B in 2008. Other potential indi-
cations include mother-to-child prevention and, more recently, PrEP (see relevant
chapters). Since its approval in 2001, TDF has been one of the most widely used
agents in HIV medicine.
However, with widespread use, problems also have come to light. The most impor-
tant is the potential nephrotoxicity of TDF (see HIV and Nephrology). Though renal
dysfunction is mostly mild and often reversible (Review: Hall 2011), detailed renal
monitoring instructions are available for all TDF-containing preparations. Before
initiation, creatinine clearance should be calculated, and renal function (creatinine
clearance and serum phosphate) should be monitored at 2–4 weeks, 3 months, and
every 3 to 6 months after that – or more frequently if abnormalities and/or renal
risk are evident. However, severe renal abnormalities are rare. In a meta-analysis of
11 randomized trials, discontinuation rates due to renal events were 0.6% (17/2,689)
with TDF versus 0.1% (2/3,771) with TAF (Hill 2018). Moreover, an increased risk of
renal events was found only with boosted regimens. In the Swiss cohort, 46 of 2,592
individuals (1.6%) had to discontinue TDF due to renal toxicity after an average of
442 days (Fux 2007). Renal failure on TDF is also observed in the setting of Fanconi
syndrome, a defect of proximal tubule transport. Patients with renal damage should
not receive TDF. This applies also to elderly individuals and those who weigh less,
as well as those with boosted PIs (Young 2012) and with potentially nephrotoxic
co-medication. For example, a worryingly high incidence of acute renal failure has
been observed with co-administration of diclofenac (Bickel 2013). TDF has also long
been associated with changes in bone biomarkers and bone damage (see Side Effects).
So far, many healthcare systems do not see any additional benefit for TAF compared
to TDF. Think twice about switching for no reason! An argument in favor of staying
with TDF is the fact that the dose of the co-medication does not have to be adjusted.
5.2. Overview – Classes of antiretrovirals and specific drugs 53

Moreover, the data and experience regarding long-term use are greater for TDF (as
well as on PrEP) than for TAF. A newer finding is that, unlike TAF, TDF does not seem
to cause any (or less) weight gain. In meta-analyses, patients on TDF gained
significantly less weight (Sax 2019, DeJesus 2019). Whether this is caused by a toxic,
“catabolic” effect of TDF or a direct effect of TAF is still unclear.

The choice of the NRTI backbone

Classical ART regimens have contained a “nuke backbone”, i.e., usually two nucle-
oside/nucleotide analogs. This is mainly a historical artifact: NRTIs were the first HIV
drugs, and by the time PIs or NNRTIs came on the market, the administration of two
NRTIs was established as the standard. With the current knowledge of the toxicity
of some NRTIs, this concept is increasingly being questioned. With Juluca® or
Dovato®, regimens are now available that contain only one or even no NRTI (see De-
escalation). They are mainly used in treatment-experienced patients.
In treatment-naïve individuals, a classic backbone of two NRTIs remains the stan-
dard. By far, the most important backbones are TAF or TDF plus FTC or 3TC and,
with declining popularity, ABC/3TC. 3TC alone can also be considered (see below).
No other NRTI backbones play a significant role and are no longer recommended;
they are discussed at the end of this section.
Thus, when choosing the backbone of two NRTIs, there are only two questions: TAF
or TDF? Is there a case for abacavir? In the following section, the data on this topic
is briefly summarized.

TDF/FTC, TAF/FTC or TDF/3TC?

There are convincing data for combining one of the two tenofovir prodrugs, TDF or
TAF plus FTC; these are currently the most widely used NRTI backbones. Both teno-
fovir prodrugs are used exclusively with FTC, again for historical (as well as) patent
reasons. Since the introduction of Delstrigo® in 2019, TDF+3TC has also become a
frequently used backbone in Europe. Worldwide, TLD (TDF/3TC/dolutegravir) is the
most widely used HIV regimen.
Incompatibilities or intolerability for FTC or 3TC practically never occur; both agents
are interchangeable (Ford 2017). Direct comparisons with older, previously widely
used backbones such as AZT/3TC do not exist for TAF/FTC, but only for TDF/FTC.
In the Gilead 934 study (Gallant 2006), TDF+FTC and AZT+3TC (plus efavirenz in
each case) were compared in 509 therapy-naive individuals. After 48 weeks, a viral
load below 50 copies/mL was achieved more frequently with TDF+FTC (80% versus
70%), mainly due to better tolerability. After 144 weeks, lipoatrophic side effects were
less frequent with TDF+FTC than with AZT+3TC (Arribas 2008).
Numerous studies have been devoted primarily to comparing TDF+FTC and
TAF+FTC, each combined with different third agents (see Table 2.2). Most studies
were conducted by the manufacturer, Gilead Sciences. All showed comparable viro-
logical efficacy of both backbones, with differences in tolerability.
To conclude, there is a moderate improvement in renal function with TAF compared
to TDF after 48 weeks. The difference in GFR is 4–5 mL/min (a lower decrease in
therapy-naive patients or an increase in experienced patients switching to TAF). Some
renal markers (tubular proteinuria) are also somewhat more favorably affected.
Positive effects are also observed with regard to bone density. Total cholesterol, on
the other hand, is somewhat more favorably affected by TDF. Still, the choles-
terol/HDL ratio or the rate of individuals requiring a lipid-lowering drug remains the
same. At least two studies found a slightly higher rate of headache with TAF. Regarding
clinical endpoints (renal failure, fractures, cardiovascular events, mortality), no
study has shown differences between TAF and TDF; these events were too rare.
54 ART

Table 2.2: Randomized Phase II/III trials of TDF+FTC versus TAF+FTC (comparable virologic efficacy in
all studies).
Study Setting Significant outcomes for TAF versus TDF in terms
of kidneys, bone, lipids
ART-naive patients
GS-292-102 n=170 RF better (GFR drop –6 vs. –11 mL/min), BM better,
(Sax 2014) plus EVG/c cholesterol worse, slightly more nausea with TAF
GS-292-104/111 n=1,733 RF better (GFR drop –6 vs. –11 mL/min), BM better,
(Sax 2015) plus EVG/c cholesterol slightly worse, AEs overall same
GS-299-102 n=153 RF better (GFR drop –3 vs. –11 mL/min), BM better,
(Mills 2015) plus DRV/c cholesterol slightly worse, AEs overall same
AMBER n=725 RF better (approx. 3 mL/min difference), BM better,
(Eron 2018) plus DRV/c cholesterol slightly worse (lipid-lowering drugs rarely
necessary), AEs same
ADVANCE n=702 RF almost the same, BM better, AEs same, but more
(Venter 2019) plus DTG weight gain with TAF
ART-experienced patients with < 50 HIV RNA copies/mL, switch to TAF
GS-1089 n=668 RF better (GFR increase +8 vs. +3 mL/min), BM better,
(Gallant 2016, plus various cholesterol slightly worse, AEs overall same, results
Post 2017) (DRV/r > NVP > RAL) independent of the third agent
GS-366-1216 n=630 RF better (GFR increase +5 vs. +1 mL/min), BM better,
(Orkin 2017) plus RPV fewer AEs overall.
EMERALD n=1,141 RF better, BM better, limitations*
(Orkin 2017) plus various PIs
GS-292-109 n=1,436 RF slightly better, also BM, lipids slightly worse, study
(Mills 2016) plus various open-label, with limitations in terms of TAF/TDF*
(EVG/r, EFV, ATV/r)
* In these studies, only one subgroup replaced TDF exclusively with TAF; in the other patients, the third
substance was also replaced with DRV/c or EVG/c. GFR = glomerular filtration rate, RF = renal function,
BM = bone markers, AEs = adverse events.

In a meta-analysis of 11 randomized trials, discontinuation rates due to renal events

were 0.6% (17/2,689) with TDF versus 0.1% (2/3,771) with TAF (Hill 2018). However,
an increased risk of TDF was found only with boosted regimens; this was also true
for bone events. Thus, at least in unboosted regimens, TAF+FTC and TDF+FTC/3TC
can be considered equivalent.
Another controversial issue is weight gain with TAF, which was more pronounced
than TDF in several meta-analyses (Sax 2019, DeJesus 2019). Some data point to TAF,
and other data attribute a “catabolic”, weight-reducing, effect to TDF. Or, to put it
another way, when TAF is used, weight gain is particularly measurable if TDF was
previously used (see Side Effects).
The data available to date were insufficient for many European health authorities to
assign even a small additional benefit to TAF compared with TDF. According to the
updated EACS guidelines of October 2021, TAF should be preferred to TDF if
cardiovascular disease, osteoporosis, progressive osteopenia, or a high risk for these
is present. TAF should also be given preference in the presence of concomitant
medication with nephrotoxic drugs or previous TDF toxicity.
5.2. Overview – Classes of antiretrovirals and specific drugs 55

Given the massive price reduction of generic TDF since 2017, clinicians should
rethink switching to TAF without justification and/or without the risk factors defined
by EACS, laid out above. This is especially true for the NRTI fixed combination
TAF/FTC (Descovy®). However, the costs are often identical for patented STRs that
differ only in TAF and TDF (Eviplera and Odefsey®, STRIBILD® and Genvoya®).

TAF or TDF/FTC or ABC/3TC?

The backbone ABC/3TC, available as Kivexa® or Epzicom® in a fixed combination
(numerous generics now exist), is also used. In the double-blind randomized trial,
CNA30024, ABC+3TC were as effective as AZT+3TC (DeJesus 2004). ABC/3TC has
also been compared with TDF/FTC in several randomized trials in treatment-naive
and -experienced patients. A recent study compared ABC+3TC with TAF+FTC in
pre-treated patients (see Table 2.3).

Table 2.3: Randomized trials TDF/FTC or TAF/FTC versus ABC/3TC.

Study Setting Main results
ART-naive patients
HEAT Double-blind (n=688) Non-inferiority of ABC/3TC vs. TDF/FTC shown,
(Smith 2009) plus LPV/r AEs same in both arms
ACTG 5202 Double-blind (n=1858) TDF/FTC better at high VL, also more AEs with
(Sax 2011) plus EFV or ATV/r ABC/3TC
ASSERT Open-label (n=385) TDF/FTC virologically better. Under ABC/3TC,
(Stellbrink 2010) plus EFV more AEs overall but fewer renal, bone AEs
ART-experienced patients
GS 1717 Double-blind (n=556) TAF/FTC virologically non-inferior, no differences
(Winston 2018) plus various in lipid profile, renal and bone biomarkers
STEAL Open-label (n=357) Effectiveness equal, but more AEs with ABC/3TC
(Martin 2009) VL <50 than with TDF/FTC (including cardiovascular,
but smaller decrease in bone density)
BICOMBO Open-label (n=333) Non-inferiority of ABC/3TC versus TDF/FTC
(Martinez 2009) VL <200 >6 mo not shown, more AEs
VL = viral load in copies/mL, AE = adverse events.

As can be seen, the data are mixed. In HEAT and STEAL, ABC/3TC and TDF/FTC were
largely equivalent, but in ACTG 5202, ASSERT, and BICOMBO, ABC/3TC were
somewhat inferior, especially at high baseline viral load (Sax 2011). However, careful
analyses suggested this was probably not due to antiviral potency (Grant 2013).
Severe adverse events are somewhat more frequent with ABC/3TC. However, in some
studies, such as BICOMBO or ACTG 5202, HLA testing was not performed, which
significantly reduces the risk of abacavir HSR and is now standard.
Despite different settings, the overall differences between TDF/FTC and ABC/3TC
were insignificant. With regard to lipodystrophy, there are also unlikely to be rele-
vant differences (McComsey 2011, Curran 2012). However, in randomized trials,
lipids improved significantly when switching from ABC/3TC to TDF/FTC, combined
with PIs (Campo 2013) or efavirenz (Moyle 2015). Whether this also translates into
fewer cardiovascular events remains unclear. On the other hand, more adverse effects
on bone density were seen with TDF/FTC use in different settings (Haskelberg 2012,
Rasmussen 2012, Tebas 2015). Renal function is also less negatively affected by
ABC/3TC (Stellbrink 2010, Wyatt 2015). In summary, the advantages of ABC/3TC
56 ART

over TDF/FTC are fewer renal and bone events, whereas the disadvantages are a worse
lipid profile and possibly more cardiovascular events.
But what about TAF/FTC? In GS 1717, a double-blind study of virologically success-
fully treated patients switching from ABC/3TC to TAF/FTC showed no apparent effect
on renal and bone biomarkers (Winston 2018). Lipid profiles were also comparable.
Given the considerable price difference of TAF compared with abacavir, this study
suggested no clear rationale for switching from abacavir to TAF.
Table 2.4. lists the advantages and disadvantages of the three common backbones
that could affect treatment decisions. Not so much potency as the risk profile and
co-morbidities usually determine the direction. Avoid TDF for kidney problems and
osteoporosis; for cardiovascular risks and hepatitis B, avoid abacavir. According to
some experts, abacavir is still a preferred agent, especially in children and adolescents
(Jesson 2022).

Table 2.4: Overview of the most important backbones.

Backbone Preparations (STR = single-tablet regimen), main pros and cons
TAF+FTC Descovy®, in STRs Biktarvy® (with bictegravir), Odefsey® (with rilpivirine),
Genvoya® (with elvitegravir/c), Symtuza® (with darunavir/c)
Pros: No or minor nephrotoxicity or bone density reduction, flexibility (used in various
STRs), good efficacy against HBV
Cons: High cost, little long-term data, interactions (different TAF doses to consider),
no beneficial effects on lipids, probably more weight gain with TAF than with TDF
TDF+FTC Generics available, Truvada®, in STRs Eviplera® (with rilpivirine), Atripla® (with
efavirenz), Stribild® (with elvitegravir/c)
Pros: Flexibility (various STRs), positive effect on lipids, good long-term data, good
efficacy against HBV, lower weight gain than with TAF
Cons: Potential nephrotoxicity, bone density reduction
TDF+3TC Generic available in the STR Delstrigo® (with doravirine). Outside the EU and the US,
also in “TLD” (with dolutegravir)
Pros: Positive effect on lipids, good long-term data, effective against HBV
Cons: Potential nephrotoxicity, bone density reduction
ABC+3TC Generic available, Kivexa®, in the STR Triumeq® (with dolutegravir)
Pros: Low cost of ABC generics, no nephrotoxicity/bone density reduction, good
long-term data
Cons: HSR (HLA-B57 test mandatory), possible increased cardiovascular risk,
somewhat low efficacy in highly viremic individuals, only one STR available, 3TC
not sufficient for HBV co-infection

Backbones not recommended

It should be emphasized that most of the above studies refer to first-line therapy.
Other backbones may be necessary in pre-treated patients due to resistance and/or
intolerance. However, this is the case only very rarely.
AZT/3TC (Combivir®) was the standard backbone of first-line therapy for many
years. It is no longer recommended, given its poorer tolerability compared to TDF
and ABC (Gallant 2006, Pozniak 2006). In addition, once-daily administration is not
feasible. Its use is usually only considered in particular (scarce) resistance situations.
With the fall of patents, several generic preparations have been available since 2013.
For AZT+FTC, there are no data and no aspects that justify its use. TDF+ABC, as a
combination, is likely to be problematic due to the rapid development of resistance.
5.2. Overview – Classes of antiretrovirals and specific drugs 57

FTC+3TC and, of course, a combination of TDF+TAF are antagonistic and should

not be implemented. ABC+FTC or TAF+3TC makes no sense. They might be useful
in exceptional cases, for example, if there is intolerance for one of the two cytidine
analogs, FTC or 3TC. In clinical routine, however, this rarely occurs. All therapies
with d-drugs (d4T, ddI, ddC) are also explicitly not recommended.

Literature on nucleoside and nucleotide analogs

Arribas JR, Pozniak AL, Gallant JE, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared
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58 ART

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Mathias AA, Hinkle J, Menning M, Hui J, Kaul S, Kearney BP. Bioequivalence of efavirenz/emtricitabine/tenofovir
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60 ART

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Mode of action
The NNRTIs were first described in 1990. As with NRTIs, the target enzyme is reverse
transcriptase (RT). However, NNRTIs bind directly and non-competitively to the RT
at a position near to but distinct from the substrate binding site for nucleosides. The
resulting complex blocks the catalyst-activated binding site of the reverse transcrip-
tase. This, in turn, can bind fewer nucleosides, slowing down polymerization
significantly. In contrast to NRTIs, NNRTIs do not require activation within the cell.
The first-generation NNRTIs nevirapine, delavirdine, and efavirenz entered the
market in 1996–1999. Although studies such as ACTG 241 or INCAS showed early
efficacy (D’Aquila 1996), the start was rather hesitant. This was due to the early obser-
vation that functional monotherapy, adding an NNRTI to a failing regimen, had
practically (and unsurprisingly) no effect. Moreover, resistance develops frequently
and rapidly – if an NNRTI-based regimen shows insufficient viral suppression, cross-
resistance to other NNRTIs can quickly develop. Mothers who had taken nevirapine
only once as part of transmission prophylaxis showed resistance rates as high as 65%
(Cunningham 2002, Jourdain 2004, Johnson 2005). This may affect the success of
subsequent NNRTIs (Lockman 2010).
In a large meta-analysis, NNRTIs were as effective as PIs (Borges 2016). However, viro-
logic failure is more common, especially in the context of resistance. Facing resist-
ance rates as high as 2–6% in treatment-naïve patients, significantly higher than PIs
or INSTIs, some guidelines have now completely removed NNRTIs from first-line
therapy. In some countries like Germany, only rilpivirine was recommended until
2019 – limited to patients with viremia below 100,000 copies/mL. In early 2019, a
new agent was added to the market, doravirine, which was non-inferior to the PI
darunavir in a head-to-head comparison. Resistance was rarely seen with this NNRTI
– doravirine has the potential to revitalize this drug class, displaying a higher resist-
ance barrier than rilpivirine, and has no food restrictions.
In the event of virological failure, any NNRTI should be rapidly discontinued to
avoid further resistance mutations; the replicative capacity of HIV is not affected by
NNRTI mutations, unlike some PI or NRTI mutations (Piketty 2004). In Europe, the
rate of transmitted NNRTI resistance is relatively stable at about 5% (Miranda 2022),
so resistance testing results should be available before starting therapy. As “mainte-
nance” therapy, however, NNRTIs are very effective, and if virologic suppression is
good, switching to an NNRTI-containing regimen can be a good option (see chapter
5.7. and 5.8.). Doravirine and rilpivirine are preferred. Efavirenz and nevirapine are
no longer recommended for which generics are available (for efavirenz, in STRs).
Delavirdine has never played a significant role, and etravirine is only considered in
certain resistance situations.
All NNRTIs are metabolized by the cytochrome P450 system (Usach 2013). Although
not as strong as PIs, some interactions are to be expected.

Individual agents
Delavirdine (Rescriptor®) was 1997 the second NNRTI to be licensed by the FDA.
In Europe, an application for licensure was rejected because of insufficient efficacy
data. In any case, it is no longer prescribed because of the high number of pills.
Doravirine (MK-1439, Pifeltro®, also in Delstrigo®) is an NNRTI launched by MSD
in early 2019. It is effective against wild-type viruses and some NNRTI-resistant muta-
tions (K103N, Y181C, G190A, and E138K) but not against Y188L. It likely has a
higher resistance barrier than rilpivirine or efavirenz (Feng 2016). Doravirine appears
effective against some rilpivirine-resistant viruses, and vice versa; the resistance pro-
5.2. Overview – Classes of antiretrovirals and specific drugs 61

files are not entirely overlapping (Smith 2016). Doravirine resistance is uncommon
among NNRTI-experienced patients, confirming a distinguishing resistance pattern
within NNRTIs. However, previous efavirenz and etravirine experience poses a higher
risk of doravirine resistance (Sterrantino 2019). Doravirine has a reasonably long
half-life; once-daily administration is feasible, and unlike rilpivirine, absorption is
independent of food intake (Wilby 2018).
In a pilot study, viral load decreased by 1.3–1.4 logs after 7 days of monotherapy
(Schürmann 2016). However, a Phase II study testing different doses from 25 to 200
mg doravirine vs. efavirenz found no clear dose-response relationship. Tolerability
was better than with efavirenz, and efficacy was comparable. For further develop-
ment, the decision was made to use 100 mg (Gatell 2019). In two double-blind,
randomized Phase III trials, doravirine showed good efficacy as a first-line therapy.
In DRIVE-FORWARD, it performed well compared with darunavir/r (each combined
with 2 NRTIs), surprising not only with an excellent response even in highly viremic
patients but also with a low resistance rate. Tolerability was good, and the lipid profile
was more favorable than with darunavir/r (Molina 2018). In DRIVE-AHEAD, the fixed
combination of TDF/3TC/doravirine was non-inferior to and better tolerated than
Atripla®, while the lipid profile was more favorable (Orkin 2019). Again, few cases
of resistance occurred in this study, with a combined rate of 9/747 (1.2%) in first-
line therapy in both studies (FORWARD and AHEAD), indicating a relatively high
resistance barrier. In DRIVE-Shift, patients on different therapies (first or second line
of therapy, no known resistance mutations) switched to doravirine. Virologic
suppression remained sustained (Johnson 2019) for years (Kumar 2021).
Doravirine can be dosed normally in renal impairment. A small PK study showed
no relevant difference in levels with a GFR of less than 30 mL/min (Ankrom 2018).
The interaction potential is not particularly pronounced. Concomitant administra-
tion of rifampicin and other strong CYP3A inducers will likely decrease doravirine
levels. There are no interactions with dolutegravir or atorvastatin (Wilby 2018). Also,
no QT prolongations were found with high doses (as with rilpivirine).
At the end of 2018, doravirine was approved by EMA, both in the fixed combina-
tion with TDF/3TC (Delstrigo®) and as a single agent (Pifeltro®). The latter is likely
to play only a minor role given the many STRs available and is reserved for special
situations (resistance or intolerance). Taken together, doravirine seems to have over-
come some of the weaknesses of older NNRTIs (low resistance barrier, food restric-
tions) and has gained an important role in HIV therapy as an STR.
Efavirenz (Sustiva®, also in Atripla® as well as in numerous generics) was 1999 the
third NNRTI to be approved. At that time, the 006 study showed superiority to indi-
navir (Staszewski 1999). Efavirenz also still performed well in comparison to lopinavir
(Riddler 2008). However, comparisons against modern agents such as rilpivirine,
doravirine, or various INSTIs showed partial inferiority, primarily due to tolerability.
To reduce the frequent CNS side effects, it is recommended to be taken in the evening
before sleep. Dizziness and lightheadedness are very common, as are vivid dreams
or nightmares. In one study, after four weeks, 66% reported dizziness, 48% reported
abnormal dreams, 37% reported drowsiness, and 35% reported insomnia (Fumaz
2002). Efavirenz appears to disrupt the sleep architecture (Gallego 2004). Potentially
hazardous tasks such as driving or operating machinery are not advised. The side
effects correlate with high plasma levels (Marzolini 2001), and there appears to be a
genetic predisposition, especially in people of African descent (Haas 2004). The mech-
anism of CNS toxicity is unclear; toxic metabolites may contribute to neurotoxicity
(Tovar-y-Romo 2013). Other problems are sometimes painful gynecomastia (Rahim
2004) and adverse lipids effects compared to other NNRTIs (Behrens 2014). Potential
teratogenicity (Ford 2011) has not been clinically demonstrated.
62 ART

Efavirenz should be replaced unless the patient requests explicitly continuation. It

is no longer recommended in first-line therapy. A dose reduction to 400 mg, which
improved tolerability in a randomized trial (ENCORE 2015), has not gained accept-
ance.
Etravirine (Intelence®, formerly TMC-125) is a diaryl pyrimidine (DAPY) analog
developed by Janssen-Cilag. In 2008, it was the first second-generation NNRTI.
Approval is limited to experienced individuals on boosted PI regimens. Etravirine
works well against classic NNRTI resistance mutations such as K103N (Andries 2004).
It may remain effective in nevirapine failure rather than after efavirenz (Cozzi-Lepri
2012). The resistance barrier is higher than for other NNRTIs because etravirine can
bind more flexibly to reverse transcriptase through conformational changes
(Vingerhoets 2005). Mutations at the enzyme’s binding site are thus less likely to
affect binding.
In Phase I/II studies, etravirine reduced viral load by as much as 0.89 logs in indi-
viduals with NNRTI mutations (Gazzard 2003). However, a Phase II trial of benefit
after NNRTI failure was terminated because etravirine remained significantly infe-
rior to individually selected PIs (Ruxrungtham 2008). Two Phase III trials (DUET-1
and -2) led to the approval of etravirine. In these, 1,203 individuals with treatment
failure, NNRTI resistance, and at least three primary PI resistances received either
etravirine or placebo, each combined with darunavir/r (Lazzarin 2007, Madruga
2007). In addition, at least two individually selected NRTIs and, optionally, T-20 were
given. After 96 weeks, 57% achieved a viral load below 50 copies/mL with etravirine,
compared to 36% with a placebo (Katlama 2010). However, the effect was markedly
lower with an increasing number of existing NNRTI mutations.
The tolerability of etravirine is pretty good, and in the DUET studies, it was compa-
rable to placebo. Only the typical NNRTI rash (primarily mild) was observed more
frequently, with 19% versus 11% (Katlama 2010). In October 2009, the company
issued a warning letter following sporadic cases of severe allergy (toxic epidermal
necrolysis, DRESS syndrome). Switching from efavirenz to etravirine may help reduce
CNS side effects of efavirenz and improve lipids (Fätkenheuer 2012).
The recommended dosage is one tablet of 200 mg twice daily, which should be taken
with a meal to increase absorption. The tablets can be dissolved. Single-dose admin-
istration seems possible (Fätkenheuer 2012) but has not been approved. Since
Janssen-Cilag also manufactures the competitor drug rilpivirine, there is no huge
interest in further development.
In the case of NNRTI resistance, etravirine needs other active agents to avoid being
rapidly burned up. According to the product information, it should be combined
with a boosted PI (preferably darunavir, not tipranavir). Darunavir should be com-
bined with ritonavir rather than cobicistat, as darunavir/c levels drop with etravirine
(Moltó 2017). However, the drug is sometimes given without PIs in clinical routine care.
Nevirapine (Viramune®, generics available) was the first NNRTI approved in 1997,
and the combination with AZT+ddI is the first published triple combination
(D’Aquila 1996). In 2NN, nevirapine was as effective as efavirenz (van Leth 2004),
in ARTEN as effective as atazanavir/r – however, more resistance mutations were
observed in the setting of virological failure (Soriano 2011). The resistance barrier is
so low that nevirapine should no longer be used in first-line therapy.
Marked GGT elevations are very common and may subject patients to false appear-
ances of excess alcohol consumption.
Nevirapine causes elevation of liver enzymes in up to 20% of people, which occa-
sionally can be severe. It should always be dosed gradually, and transaminases should
be checked every two weeks for the first eight weeks. Exanthema (rash) occurs in
5.2. Overview – Classes of antiretrovirals and specific drugs 63

15–20%, requires discontinuation in up to 7%, and cannot be prevented by

antihistamines or steroids (Launay 2004). Treatment can often be continued if an
isolated rash or transaminase elevation (up to 5 times normal) occurs. But caution
is needed if both co-occur! In the case of rash, discontinuation is recommended even
with mildly elevated transaminases (> 2-fold norm). The first 18 weeks are critical,
though liver toxicity may occur later. People with chronic hepatitis are at risk, as are
women with low body weight (Usach 2013). There is an increased risk, especially
with good immune status. For women with CD4 T-cells above 250/µl, the risk is
increased 12-fold (11% vs. 1%); for men, the risk increases above 400 CD4 T-cells/µl
(6% vs. 1%). Nevirapine should not be started above these levels. In contrast, the
risk does not appear to be increased in pre-treated individuals. Genetic predisposi-
tion is likely, but no test can reliably predict intolerance. In 2011, an extended-release
formulation was approved that allows single daily dosing. However, dose reduction
during the first 14 days is still required. It is important to note that the matrix may
be excreted undigested and visible in the stool. Generics have been available since
2013. Although ong-gone from first-line therapy, some patients have been success-
fully treated with nevirapine for over two decades (there are better options today).
Rilpivirine (Edurant®, also available in Eviplera® or Complera®, in Odefsey® and
Juluca®, or as a long-acting injection Rekambys®) was licensed in November 2011.
Like etravirine, the compound is a DAPY NNRTI effective against isolated NNRTI
resistance such as K103N or G190A and has a longer half-life of 40 hours. In a Phase
IIa study, viral load dropped by 1.2 log levels after 7 days of monotherapy without
a dose-dependent effect (Goebel 2005). At 25 mg, the lowest dose was chosen, which
is not only significantly lower than all other NNRTIs but may be too low in some
cases (Aguri 2016).
Two double-blind, randomized Phase III trials (ECHO and THRIVE) in 1368 treat-
ment-naïve patients showed comparable efficacy to efavirenz, with better tolerabil-
ity after 96 weeks (Cohen 2011, Molina 2011, Behrens 2014). Lipids were also less
adversely affected (Tebas 2014). In a third large open-label study (STaR) in 786 treat-
ment-naïve patients, non-inferiority was shown for Eviplera® compared to Atripla®.
After 48 weeks, viral load was undetectable in 89%, compared to 82% with Atripla®,
which was less tolerated due to efavirenz' CNS side effects (Cohen 2014). However,
resistance mutations and virologic failure were observed more frequently with
rilpivirine than with efavirenz: 9% versus 5% in ECHO/THRIVE and 4% versus 1%
in STaR (Cohen 2012+2014). Resistance mutations affected NNRTIs and NRTIs
(Rimsky 2012), especially when viremia was high. Therefore, in most guidelines,
approval in treatment-naïve individuals was restricted to those presenting with viral
loads below 100,000 copies/mL.
In late 2013, approval was extended to pre-treated patients. In the SPIRIT trial, 476
patients with good viral suppression either switched to rilpivirine or remained on
their boosted PI regimen (maximum of two prior therapies allowed). The switch was
successful, and lipids improved (Palella 2012). Viral suppression persisted in 18/19
individuals with a historical K103N, i.e., an NNRTI mutation (Porter 2016). However,
in experienced patients with viral suppression, pre-existing resistance mutations
must be considered before switching to a rilpivirine-containing STR. The presence
of resistance mutations to both NRTIs and NNRTIs is associated with an increased
risk of virological rebound, highlighting the need for an accurate selection of patients
before simplification (Armenia 2017).
Overall, rilpivirine is well-tolerated. Mild CNS symptoms may occur but are
significantly less pronounced than with efavirenz. The QT prolongation observed
with high doses does not appear relevant with the current dosage, and the risk of
teratogenicity is low.
64 ART

The most commonly used preparation is Odefsey®, the fixed combination of TAF+FTC
and rilpivirine. In patients with adequate viral suppression, it was virologically non-
inferior in two large double-blind randomized trials (GS-1216 and 1160) compared
to the continuation of Eviplera® (TDF/FTC/rilpivirine) and Atripla® (TDF/FTC/
efavirenz). Switching to Odefsey® had positively affected bone density (Orkin 2017,
DeJesus 2017).
Another drug is Juluca®, the fixed combination of dolutegravir and rilpivirine. Juluca®
was licensed 2018 as the first dual therapy (2DR) in pre-treated patients. Two large
Phase III trials (SWORD I+II) tested Juluca® against the continuation of successful
ART. Virologic failure was rare, and INSTI resistance did not occur (Aboud 2019).
However, CNS side effects were more likely to lead to discontinuation (7% overall
at 100 weeks), and mild side effects were also more common under this 2DR regimen.
Ultimately, it has remained unclear for whom Juluca® is useful.
Rilpivirine has become an important agent, especially with Odefsey®. The
disadvantage in everyday life is that food intake is necessary to ensure sufficient
absorption. A high-calorie drink or protein snack is not enough; it must be a meal
with 500 kcal (Crauwels 2013). This can cause problems with irregular lifestyles or
diets. Rilpivirine is, therefore, unsuitable for adherence problems. A new field of
development for rilpivirine is long-acting, which is used as a depot injection
(Rekambys®, see below).

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efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial. Antivir Ther 2019, 24:425-435.
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Martinez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors
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66 ART

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5.2. Overview – Classes of antiretrovirals and specific drugs 67

Protease inhibitors (PIs)

Mode of action
The HIV protease cuts the viral gag-pol polyprotein into functional subunits. If the
protease is inhibited and proteolytic splicing is prevented, non-infectious virus
particles will result. With the knowledge of the molecular structure of the protease
encoded by the virus, the first protease inhibitors were designed in the early nineties;
these agents were modified to fit precisely into the active site of the HIV protease
(review: Youle 2007).
Protease inhibitors (recognizable by the suffix “-navir”) revolutionized HIV therapy
in the mid-1990s. At least three studies with clinical endpoints demonstrated the
efficacy of indinavir, ritonavir, and saquinavir (Hammer 1997, Cameron 1998,
Stellbrink 2000). Although PIs were initially criticized for their high pill burden and
side effects (see below), they remain an essential component of antiretroviral
therapies. The most widely used PI is darunavir, for which Symtuza®, the first fixed
combination with 2 NRTIs, has been available since 2017. Atazanavir and lopinavir
are also still used occasionally, tipranavir only in rare resistance situations. The other
PIs are only mentioned here because some patients remain on these regimens.
Besides gastrointestinal side effects, all PIs used in long-term therapy show tolera-
bility problems – to a greater or lesser extent, all are associated with lipodystrophy
and dyslipidemia (Review: Nolan 2003). Cardiovascular disease (Lundgren 2017) and
sexual dysfunction have also been attributed to PIs (Schrooten 2001), although the
data does not remain unchallenged (Lallemand 2002, Bavinger 2013).
PIs are less susceptible to resistance compared to NNRTIs and INSTIs. Among boosted
PIs, resistance is rarely observed in first-line therapy, and the genetic barrier is very
high. This is true not only for lopinavir/r (Hammer 2006) but also for atazanavir/r
(Malan 2008) and darunavir/r (Ortiz 2008). Boosted PIs are used mainly in cases of
high viral load and adherence problems. With first-generation PIs, cross-resistance
was often quite pronounced. However, with darunavir (and tipranavir), second-
generation PIs, they work well in the presence of most PI resistances (see below).
Except for atazanavir, all PIs must be boosted to achieve sufficient drug levels with
ritonavir or cobicistat (see below). As a consequence, many interactions need to be
considered not only for antiretroviral combinations but also for concomitant
medication (see Interactions).

Boosting PIs with ritonavir or cobicistat – why and how?

Ritonavir is a potent inhibitor of isoenzyme 3A4, a cytochrome P450 enzyme system
subunit. By inhibiting these gastrointestinal and hepatic enzyme systems, the key
pharmacokinetic parameters of almost all PIs can be significantly increased (here-
inafter “boosted”) to achieve a maximum concentration, trough level, and half-life
(Kempf 1997). The interaction between ritonavir and the other PIs allows pill
reduction, reduces the necessary frequency of intake, and makes absorption partially
independent of food intake. The daily dosing regimen is simplified. For some PIs,
this has made single-dose administration possible. Ritonavir is also used in COVID-
19 therapy to boost the SARS-CoV-2 PI nirmatrelvir (Paxlovid®).
In 2014, a second PI booster, cobicistat, was licensed. It was originally developed as
a booster for the integrase inhibitor elvitegravir within the fixed combination
Stribild® and was launched as such in 2013. However, 150 mg of cobicistat induced
similar levels of atazanavir and darunavir compared to ritonavir (Elion 2011, Kakuda
2014). In a double-blind, randomized trial of 692 treatment-naïve patients starting
with TDF+FTC+atazanavir that was boosted with either cobicistat or ritonavir, the
efficacy and tolerability of both boosters were comparable (Gallant 2013). Based on
68 ART

these data, cobicistat is also available as a stand-alone product (Tybost®). Approval

remains limited to atazanavir and darunavir. Cobicistat is more soluble and appears
to be suitable for additional STRs. Thus, it is no longer found only in Stribild® and
Genvoya®, but since 2017, also in the fixed combination Symtuza® with darunavir.
The moderate creatinine increases seen under cobicistat reflect a reduced tubular
secretion and not an impaired renal function (German 2013). Usually, boosting with
100–400 mg of ritonavir or 150 mg of cobicistat is indicated by an “/r” or “/c” follow-
ing the agent’s name.

Table 2.5: Common protease inhibitor doses with boosters.

Doses (mg) Pills*/day Comment
Atazanavir/r or /c 1 x 300/100** 1x2 No limitation
Darunavir/r 2 x 600/100 2x2 No limitation
Darunavir/r or /c 1 x 800/100** 1 x 1-2 Only with limited mutations
Fosamprenavir/r 2 x 700/100 2x2 Hardly ever used
Fosamprenavir/r 1 x 1400/200 1x4 Only approved in the USA (PI-naïve)
Lopinavir/r 2 x 400/100 2x2 Only fixed booster combination
Lopinavir/r 1 x 800/200 1x4 Only with a few PI mutations
Saquinavir/r 2 x 1,000/100 2x3 Hardly ever used
Tipranavir/r 2 x 500/200 2x4 Only approved in pre-treated patients
* Pill numbers, including boosters. ** Instead of 100 mg ritonavir, 150 mg cobicistat is possible
(one tablet each). For darunavir/c, there is a STR fixed combination with TAF+FTC.

Boosting is also associated with risks. There is a high degree of variability in plasma
levels among individuals. Trough levels and peak levels are elevated, which may lead
to more side effects. If in doubt (lack of efficacy, side effects), plasma levels should
be measured in cases of boosting, especially in patients with severe hepatic disease,
because the extent of the interaction cannot be predetermined in individual cases.
Nowadays, switching from a PI to other options is usually much more accessible
than fiddling around with the PI dose. This question only arises in rare, complex
cases and definitely needs an expert opinion.

Individual agents
Atazanavir (formerly Reyataz®, generics) was the first once-daily PI in 2004. In the
CASTLE study in 883 treatment-naïve patients, atazanavir/r was virologically equiv-
alent to lopinavir/r, with better lipid profiles and gastrointestinal tolerability (Molina
2010). In ACTG 5237, it was also mainly equivalent to darunavir/r, although weaker
and less well-tolerated than raltegravir (Lennox 2014). In GS-236-103, atazanavir/r
was comparable to elvitegravir/c (DeJesus 2012), but in the two large studies, WAVE
and ARIA, it performed worse than elvitegravir/c and dolutegravir in treatment-naïve
women (Squires 2016, Orrell 2017).
Atazanavir is the only PI for which boosting is not mandatory. According to a meta-
analysis, unboosted atazanavir (400 mg instead of 300/100 mg) is no worse than
boosted PIs (Baril 2014). Still, approval in Europe is limited to patients with no pre-
vious virologic failure or resistance mutations; otherwise, it is, after all, somewhat
worse than lopinavir/r (Cohen 2005). The high resistance barrier is probably lower
if atazanavir is not boosted.
A meal is required for adequate absorption; PPIs and tenofovir are not recommended
with unboosted atazanavir (Fournier 2013). A significant problem is bilirubin
elevations, which reach grades 3–4 in about 30% and are even more frequent with
boosters (Squires 2004). Quite a few patients develop icterus. The mechanism is
5.2. Overview – Classes of antiretrovirals and specific drugs 69

similar to the conjugation disorder in Meulengracht disease, and an otherwise harm-

less genetic defect has been identified (Rotger 2005). Although hyperbilirubinemia
is rarely severe (Eholie 2004), atazanavir should be discontinued in the presence of
icterus and marked bilirubin elevation (> 5–6 x above normal). In Thai patients, in
whom exposure is higher than in Caucasians, the atazanavir dose was successfully
reduced in a large study. Hyperbilirubinemia decreased, and virologic control
persisted (Bunupuradah 2016). Atazanavir has favorable effects on the lipid profile
compared to older PIs. There is no difference compared to darunavir or raltegravir
(Lennox 2014). One study in PI/r-treated subjects showed no effect on abdominal
fat from switching to atazanavir/r (Moyle 2012), and another, compared with
efavirenz, even showed an increase in visceral fat (McComsey 2011).
The resistance profile of atazanavir is similar to that of other PIs (Schnell 2003).
Primary resistance is at I50L, a mutation that does not affect the sensitivity of other
PIs (Colonno 2003). Overall, atazanavir is rarely used today, primarily because of
hyperbilirubinemia and moderate performance compared with INSTIs. Due to a lack
of demand, BMS discontinued the originator drug Reyataz® at the end of 2019. Some
generics are still circulating.
Darunavir (Prezista®, generics, also in Rezolsta®, Symtuza®) is a PI developed by
Janssen-Cilag. It is now the only PI of significance. Darunavir has impressive activity
against PI-resistant viruses (Koh 2003). In February 2007, two Phase IIb trials in nearly
600 patients led to accelerated approval in Europe, initially for pre-treated patients
(Clotet 2007). Despite numerous resistance mutations, the viral load in the 600 mg
group (600/100 BID) remained below 50 copies/mL in 46% of the participants at
48 weeks – a significantly better result than the control PI (10%). The substance also
performed well in the DUET studies, in which darunavir was combined with
etravirine. In the TITAN study of 595 individuals pre-treated predominantly with PIs
(but lopinavir-naive), 71% had a viral load below 50 copies/mL after 48 weeks,
compared with 60% on lopinavir (Madruga 2007). Virologic failure and resistance
to concomitant agents were significantly less frequent under darunavir. Interestingly,
PI mutations did not compromise efficacy (De Meyer 2008+2009). New resistance
mutations during therapy are sporadic (El Bouzidi 2016).
In 2008, darunavir’s license was expanded to treatment-naïve individuals. In
ARTEMIS, darunavir was at least as effective as lopinavir when given once daily (Mills
2009). Once-daily dosing is also feasible in ART-experienced patients, provided no
darunavir resistance exists (Cahn 2011, Lathouwers 2013). In first-line therapy,
darunavir has been tested primarily against integrase inhibitors. In FLAMINGO and
ACTG 5237, almost no resistance mutations were observed, confirming its high resist-
ance barrier. However, in both studies, darunavir performed slightly worse than
dolutegravir and raltegravir (Clotet 2014, Lennox 2014).
Darunavir is well-tolerated. The typical PI gastrointestinal side effects tend to be
moderate; diarrhea is usually milder than with other PIs (Clotet 2007, Madruga 2007).
Dyslipidemias and liver elevations seem to play a minor role. On the other hand,
the rash develops in 5–15%. Cohort studies suggest a slightly increased cardiovas-
cular risk (Lundgren 2017). However, a large case-control study found no increased
CV risk when adjusting for other factors such as ART history (Costagliola 2019).
Unlike for abacavir, there is no (well) explained pathomechanism so far. Bias would
thus be conceivable – darunavir is preferentially used in late presenters.
Boosting is also possible with cobicistat. The combination (Rezolsta®) without any
NRTI backbone is approved in Europe but is not marketed in most countries. A fixed
drug combination (FDC) of TAF/FTC/darunavir/c, Symtuza®, has been available since
2017. Two large Phase III trials led to the approval of this FDC. In AMBER, Symtuza®
70 ART

was as effective as single agents in first-line therapy (Orkin 2019), and in EMERALD,
switching from PI/r regimens in patients with virological suppression was also
successful (Eron 2019), regardless of pre-existing resistance (Lathouwers 2020).
Symtuza® should be taken with food, which improves bioavailability (Crauwels
2019). The potency of darunavir is, of course, not unlimited. With more than three
resistance mutations at codons 32, 47, 50, and 87 (De Meyer 2006), efficacy is reduced
significantly (Pozniak 2008). In treatment-experienced patients with darunavir-asso-
ciated mutations, twice-daily dosing (600/100 mg BID) is recommended based on
an analysis of subjects with triple-class experience with one or more primary PI resist-
ance mutations (Clotet 2007).
Again, darunavir is now the only PI of significance, primarily due to Symtuza®, the
only PI-containing STR to date. Various generics are available for the single agent.
The resistance barrier is among the highest among antiretroviral therapies, making
it particularly suitable in cases of adherence problems or any risk of treatment failure.
In the salvage setting and in the presence of pre-existing resistance, darunavir is
almost indispensable. Increasingly, it is also being investigated in the context of dual
therapies, either with 3TC or with INSTIs.
Lopinavir/r (Kaletra®, generics available) was the only PI with a fixed booster dose
of ritonavir when approved in April 2001. Worldwide, it is still a commonly
prescribed PI. Since October 2009, it has been approved for single-dose use, but only
in the absence of or limited PI mutations (Flexner 2010). In treatment-naïve patients,
randomized trials such as ARTEMIS or CASTLE showed no advantage over other
boosted PIs such as darunavir (Mills 2009) or atazanavir (Molina 2008). In ACTG
5142, lopinavir/r was even inferior to or less well-tolerated than the NNRTI efavirenz
(Riddler 2008). It was slightly weaker in pre-treated individuals compared to
darunavir/r (Madruga 2007, De Meyer 2009).
Resistance in first-line therapy is rare (Conradie 2004, Friend 2004). The resistance
barrier is high, and probably 6–8 cumulative PI resistances are necessary for treatment
failure (Kempf 2002). Major problems are gastrointestinal side effects (diarrhea). In
addition, patients frequently develop notable dyslipidemias with lopinavir, which
are more pronounced than with atazanavir (Molina 2008, Mallolas 2009) and
darunavir (Mills 2009). There are also numerous interactions to consider (see
Interactions). In recent years, lopinavir has hardly been used due to high pill counts
and gastrointestinal problems.
Ritonavir (Norvir®) was the first PI whose efficacy was demonstrated with clinical
endpoints (Cameron 1998). However, as a sole PI, ritonavir is obsolete because
tolerability is poor. As gastrointestinal complaints and perioral paresthesias can be
very disturbing, ritonavir is now only given to boost other PIs. The “baby dose”
(1–2 x 100 mg) commonly used for this purpose is better tolerated. Due to the strong
enzyme induction, many interactions and contraindications exist (see Interactions).
Metabolic disturbances are also more common than with other PIs. Caution is advised
in the presence of hepatic dysfunction. Ritonavir recently experienced a renaissance
in COVID-19 therapy – to boost the SARS-CoV-2 PI nirmatrelvir (Paxlovid®).

Obsolete – these PIs should (or can) no longer be prescribed

Amprenavir (Agenerase®) was the fifth PI in Europe in June 2000. It was replaced
by fosamprenavir (see below) in 2004 and withdrawn from the market.
Fosamprenavir (Telzir®, US: Lexiva®) is more absorbable than amprenavir. It was
approved in 2004 at a dose of 2 x 700 mg plus 2 x 100 mg ritonavir daily (2 x 2 pills).
Unboosted or once-daily dosing was not licensed in Europe. Fosamprenavir/r is
slightly weaker than lopinavir/r in pre-treated patients. Fosamprenavir no longer
5.2. Overview – Classes of antiretrovirals and specific drugs 71

plays a role: there is no advantage over other PIs. According to the manufacturer, it
will be withdrawn from the market at the end of 2023.
Indinavir (Crixivan®) is one of the oldest, initially widely used PIs. Due to its skin
and kidney problems (nephrolithiasis!), its need for 3 liters of water per day, and
twice-daily administration, it was discontinued in 2019.
Nelfinavir (Viracept®) was the fourth PI in 1998. Due to high pill counts, diarrhea,
and lower antiviral potency, the agent was not very used. Roche let the approval
expire in January 2013.
Saquinavir (Invirase 500®, formerly Invirase®, Fortovase®) was the first PI to be
licensed in 1995 and is still one of the few agents whose efficacy has been demon-
strated based on clinical endpoints (Stellbrink 2000). The hard-gel (Invirase®) and
soft-gel (Fortovase®) capsules were replaced in 2005 by Invirase 500® tablets, which
reduced the daily pill count to six (2 x 2 tablets with 500 mg plus 2 x 100 mg ritonavir).
In GEMINI, Invirase 500® was as effective as lopinavir/r (Walmsley 2009). In 2014,
a warning about QT prolongation was published. The dose should be increased during
the first week with ECG monitoring – hardly practical in everyday life. There is no
advantage over other PIs. Saquinavir should no longer be used.
Tipranavir (Aptivus®) was the first non-peptide PI approved in Europe in July 2005
for heavily pre-treated patients. Its moderate oral bioavailability requires boosting
with ritonavir; 2 x 200 mg (2 x 2 pills!) of ritonavir should be used (McCallister 2004),
each with a meal. Tipranavir is effective against PI-resistant viruses, even with
multiple mutations (Larder 2000). Two Phase III studies (RESIST) in 1483 intensively
pre-treated patients with at least one primary PI mutation led to approval, in which
tipranavir was superior to a comparator PI (Hicks 2006).
Major side effects are dyslipidemias, which are more pronounced than with com-
parator PIs, and in some cases, significant increases in transaminases. In first-line
therapy, tipranavir also performed worse than lopinavir/r for this reason (Cooper
2016). The indication, therefore, remains limited to “heavily pre-treated adults with
viruses resistant to multiple PIs.” It should be discontinued or avoided if transami-
nases are elevated. In addition, there are unfavorable interactions (see Interactions):
Abacavir or etravirine levels decrease, and the combinations should be avoided.
Tipranavir is practically no longer needed in salvage therapy today, thanks to new
options.

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navir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006
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with indinavir-related toxicity. Eur J Clin Pharmacol 2007;63:901-8.
Youle M. Overview of boosted protease inhibitors in treatment-experienced HIV-infected patients. J Antimicrob
Chemother 2007;60:1195-205.
74 ART

Integrase inhibitors
Mode of action
Integrase, along with reverse transcriptase and protease, is one of the three key
enzymes in the HIV-1 replication cycle. This enzyme consists of 288 amino acids, is
encoded by the HIV pol gene, and is involved in integrating viral DNA into host
DNA in the cell nucleus (Nair 2002). In human cells, there is probably no enzyme
comparable to integrase. At least four steps lead to viral DNA integration (Review:
Engelman 2018). Different integrase inhibitors may theoretically inhibit all these
steps. Briefly, these steps are:
1. Binding the integrase enzyme in the cytoplasm to the viral DNA. This results in
a relatively stable so-called pre-integration complex (pre-integration complex, PIC)
→ this step can be inhibited by binding inhibitors such as pyrano-dipyrimides.
2. 3’-processing: In the first catalytic step, the integrase removes a dinucleotide
at each end of the viral DNA, producing new 3’-hydroxyl ends within the PIC →
so-called processing inhibitors are styryl quinolones or diketo acids.
3. Strand transfer: After the transport of the PIC from the cytoplasm through a
nuclear pore into the cell’s nucleus, integrase binds to the host chromosomal DNA.
By doing this, integrase mediates irreversible binding of viral and cellular DNA →
this step is inhibited by the approved integrase inhibitors, so-called strand transfer
inhibitors (INSTIs, ending in “-gravir”).
4. Gap repair: The combination of viral and host cell DNA is an intermediate product
with gaps repaired by host cell repair enzymes. This probably no longer requires
integrase → but repair can be inhibited by, for example, methylxanthines.
After the principle of strand transfer inhibition was elucidated (Hazuda 2000),
raltegravir became the first INSTI to be licensed in December 2007. Since then, four
others have become available: elvitegravir, dolutegravir, bictegravir, and cabotegravir.
As with all new drug classes, some questions remain. While efficacy and tolerability
appear good in the short and medium term, nothing is known about long-term
toxicities. Mainly, mild neuropsychiatric events occur (Hoffmann 2019), as does
substantial weight gain sometimes, especially in combination with TAF (Hill 2019,
Sax 2019). Pathways or mechanisms remain largely unclear. Another issue is the
relatively low resistance barrier with first-generation INSTIs, raltegravir and elvite-
gravir. This is especially evident with pre-existing resistance (Eron 2009). Cross-class
resistance is possible.
There are also problems with measuring plasma levels, where the large inter- and
individual variability does not allow reliable statements to be made (Cattaneo 2012).
Once resistance is present, INSTIs, like NNRTIs, should be discontinued, as replica-
tion capacity is unlikely to be affected and further mutations prevented (Wirden
2009). Despite these problems, it is hard to imagine HIV therapy without INSTIs.
Given their high potency and good tolerability, many are already talking about the
INSTI era. The individual agents are discussed below.

Individual agents
Bictegravir (formerly GS-9883, a component of Biktarvy®) was developed by Gilead
Sciences. Since its approval in June 2018, bictegravir has been available exclusively
as Biktarvy®, a fixed-dose combination with TAF+FTC. Unlike elvitegravir, bictegravir
does not require boosting; moreover, its half-life of 18 hours allows for daily once-
daily dosing. The antiviral efficacy of bictegravir in monotherapy was over 2 logs
(Gallant 2017). It has efficacy against some INSTI-resistant isolates. However, the
resistance profile broadly matches that of dolutegravir (Tsiang 2016, Saladini 2019).
5.2. Overview – Classes of antiretrovirals and specific drugs 75

As first-line therapy, TAF/FTC/bictegravir was tested in large Phase III trials, mainly
against dolutegravir. In GS-1489, it was compared to ABC/3TC/dolutegravir
(Triumeq®,) and in GS-1490 against dolutegravir plus TAF/FTC. In both studies,
Biktarvy® was virologically non-inferior to the comparator at 96 weeks and tolerated
well. There were few discontinuations, infrequent virologic failure, and not a single
case of resistance (Wohl 2019, Stellbrink 2019).
There are also good data for pre-treated patients. In GS-1878, pre-therapy consisted
of boosted PIs such as darunavir/r and atazanavir/r (Daar 2018); in GS-1844, it was
Triumeq® (Molina 2018); and in GS-1961, a women-only study, it was almost
exclusively elvitegravir (Kityo 2018). In all studies, virologic suppression persisted.
In addition to women, other chronically under-represented groups have been studied
in randomized trials, including Black Americans (Hagins 2021) and people over
65 years of age (Maggiolo 2022).
Tolerability was good, even slightly better than dolutegravir (Wohl 2019). In
GS-1878, more patients mainly reported mild headache (12% versus 4%). The double-
blind, randomized GS-4030 trial explicitly allowed resistance to NRTIs, NNRTIs, and
PIs to determine the potential of Biktarvy® in pre-existing resistance (Sax 2021).
Subjects were enrolled on dolutegravir-containing regimens, randomized to either
Biktarvy® or dolutegravir plus TAF+FTC. Efficacy remained good despite significant
resistance in some cases, particularly in the NRTI backbone – bictegravir and dolute-
gravir appear to have similar salvage potential.
The tolerability of the combination is good, but Biktarvy® is also associated with
weight gain, which is likely to be similar to that of dolutegravir (Sax 2019).
Neuropsychiatric side effects have also been seen in the first few months, as with
dolutegravir, with about 3% discontinuing therapy because of this (Hoffmann 2020).
There is a small potential for interaction. Bictegravir is not eliminated renally.
Overall, bictegravir is a highly effective INSTI that does not require a booster and
has displaced elvitegravir and other agents in our daily practice. However, a significant
advantage over dolutegravir has not been identified, except that bictegravir is avail-
able in a TAF-based STR. Unlike dolutegravir, however, flexible use is impossible; only
one fixed combination exists.
Cabotegravir (GSK744, Vocabria® or Cabenuva®, as PrEP also Apretude®) is an INSTI
that is very similar to dolutegravir. It is used exclusively as a long-acting injection in
combination with the NNRTI rilpivirine (Rekambys®, cabotegravir plus rilpivirine
long-acting, “CARLA”). CARLA requires two intramuscular injections each, every 1–2
months. PK studies found a half-life of 21–50 days after intramuscular injection. Levels
are still detectable in plasma for many months after discontinuation (Stellbrink 2018).
Strong cross-resistance exists with the second-generation INSTIs dolutegravir and
bictegravir. Especially against INSTI mutations occurring among first-generation
INSTIs raltegravir and elvitegravir, cabotegravir appears to have somewhat lower
potency (Saladini 2019, Smith 2019).
As monotherapy, single injections decreased viral load by 2.2–2.3 logs (Spreen 2013).
In the LATTE pilot study, 243 treatment-naïve individuals received two NRTIs and
various oral doses of cabotegravir or efavirenz. Subsequently, patients switched to
CARLA or remained on efavirenz plus 2 NRTIs. After 48 weeks, 82% achieved a viral
load below the detection limit, compared with 71% on the standard efavirenz
regimen (Margolis 2015). In LATTE-2, a Phase IIb trial, 309 individuals received either
CARLA every 4 or 8 weeks or oral ART with cabotegravir plus ABC+3TC after
induction. The rates of undetectable viral load at 96 weeks were even higher in the
injection arms (87% and 94%, respectively) than with oral ART (84%). However,
injection site reactions were observed in nearly all participants and were still
76 ART

“moderate” in 15% (Margolis 2017). Nevertheless, treatment satisfaction among the

participants was high, even after five years (Smith 2022).
Two large Phase III trials in 2019 ultimately led to approval. In ATLAS, 705 people
had been successfully pre-treated with different ART regimens for a mean of four
years (Swindells 2020); in FLAIR, 629 treatment-naïve people had initially received
several months of induction therapy with Triumeq®, and 566 were randomized
(Orkin 2020+2021). Half remained on the old ART in each trial, and the other half
switched to quad-weekly injections. Both ATLAS and FLAIR showed non-inferiority
of CARLA. The rate of undetectable viral loads at week 48 was comparable (93–96%).
Still, there were a few overall virologic failures in the LA arm in both trials, some of
which even showed a combination of NNRTI and INSTI resistance. Even if these were
primarily Russian patients with HIV subtype A – CARLA received its first minor dents
here. Plasma levels during treatment failure were relatively low but not too low to
explain the failure. In November 2017, ATLAS was expanded to include ATLAS-2M.
This trial compared four- versus eight-week injections of CARLA and demonstrated
non-inferiority of the 8-week arm at 96 weeks (Hunter 2021). Consequently, the
approval of cabotegravir covers 4- and 8-week administration.
Sufficient levels are also achieved in the CNS (Letendre 2019). Administration is safe
even in severe renal insufficiency (Parasrampuria 2019). Concomitant administra-
tion of rifabutin is possible, and levels remain adequate (Ford 2019). In contrast, this
is probably not true with rifampicin (Rajoli 2019).
Cabotegravir is also being developed as PrEP. It was superior to conventional PrEP
in large Phase III trials and has been approved in the US since 2022 under the trade
name Apretude® (Landovitz 2022, see PrEP).
Dolutegravir (Tivicay®, part of Dovato®, Juluca®, Triumeq®) is a second-generation
INSTI developed by ViiV Healthcare and the first to enable once-daily, unboosted
INSTI administration in 2014. In a Phase IIa study, during ten days of monotherapy,
the viral load dropped by up to 2.5 logs (Min 2011).
Treatment-naïve patients: In SPRING-2, a double-blind, randomized trial against
raltegravir BID, 81% versus 76% were below detection at 96 weeks, with equal
tolerability. Less resistance was observed in the case of treatment failure (Raffi 2013).
In SINGLE, the fixed combination of ABC/3TC/dolutegravir (Triumeq®) was slightly
better than TDF/FTC/efavirenz in 833 treatment-naive individuals (Walmsley 2013).
In FLAMINGO, dolutegravir was virologically superior to darunavir/r (Clotet 2014),
and in the women-only ARIA trial, it was superior to atazanavir (Orrell 2017). In two
other Phase III trials, dolutegravir-containing regimens were as effective as bictegravir
(Wohl 2019, Stellbrink 2019). In the GEMINI trials, a two-drug combination with
dolutegravir/3TC was also sufficient in many patients, even those with high viral
loads (Cahn 2019, Eron 2020).
Pre-treated patients: In the double-blind, randomized SAILING trial of 715 PLWH with
plasma viremia of at least 400 copies/mL on ART (half with triple-class resistance),
dolutegravir was virologically superior to raltegravir (Cahn 2013). Even in the case
of INSTI resistance, there is still efficacy – the VIKING trials showed that in patients
with raltegravir and elvitegravir resistance, higher doses of dolutegravir can help
overcome resistance (Eron 2013, Castagna 2014). With 100 mg of dolutegravir, a
substantial proportion still achieved a viral load below the detection limit.
On the other hand, dual combinations (see below) with rilpivirine (Aboud 2019) or
3TC (van Wyk 2020) have proven effective in the context of de-escalation approaches.
Dolutegravir is well-tolerated, even at higher doses (Castagna 2014). Mild creatinine
elevations are due to inhibition of a renal transporter system. Relatively typical side
effects are neuropsychiatric events and (usually mild) sleep disturbances, in our
experience, occurring mainly in women and the elderly (Hoffmann 2017). Relatively
5.2. Overview – Classes of antiretrovirals and specific drugs 77

high rates of (mild) side effects were also reported in STRIIVING and SWORD (Trottier
2017, Aboud 2019). However, switching from boosted PIs improves lipids (Gatell
2017). Significant weight gain was observed with TAF (Venter 2019, Sax 2019), but
the cause is still unclear. In contrast, a higher risk of neural tube defects in newborns
reported in Botswana has not been further seen (Zash 2019).
The resistance barrier is higher than for other INSTIs (Hightower 2011). The effect
persists with some INSTI resistance but decreases with raltegravir-type mutations at
codon 148 (Castagna 2014+2017, Anstett 2017). Relevant interactions with boosted
PIs do not exist, but the NNRTI etravirine significantly reduces levels (Song 2011).
For rifampicin, a dose increase is necessary (Dooley 2013). Absorption remains
unaffected by food intake (Song 2012).
Dolutegravir is undoubtedly one of the most important and frequently prescribed
antiretroviral agents. Since 2018, WHO HIV treatment guidelines have recommended
the combination of TDF, 3TC, and dolutegravir (“TLD”, not available in Western
Europe) as the preferred first-line regimen for initiating ART among adults and
adolescents. Advantages of dolutegravir are the high resistance barrier and the
dispensable booster, as well as its flexibility: with Juluca® (plus rilpivirine) and
Dovato® (plus 3TC), two dual therapies are available (see below) – whether STR, 2DR
or single agent, dolutegravir allows for an individualized therapy.
Elvitegravir (a component of Stribild® and Genvoya®) is an INSTI developed by
Gilead Sciences. The compound is chemically similar to quinolone antibiotics (Sato
2006) and must be boosted, allowing daily single-dose administration. To be
independent of the monopoly booster ritonavir, elvitegravir was developed together
with the new pharmacoenhancer cobicistat. In an initial study, viral load decreased
by about 2 logs after ten days of monotherapy (DeJesus 2006). It showed an excellent
effect in pre-treated patients compared to a boosted PI (Zolopa 2010).
In two Phase III trials in ART-naïve patients, the “QUAD” pill (Stribild®), a fixed com-
bination of the four Gilead compounds elvitegravir, cobicistat, TDF, and FTC, was
as effective as TDF/FTC plus efavirenz (Sax 2012) or atazanavir (DeJesus 2012).
Stribild® was approved in June 2013. In two other large Phase III trials, there were
significantly fewer renal and osseous side effects on the new “QUADTAF” pill
Genvoya®, in which TAF replaces TDF. Genvoya® was approved in early 2016 and
primarily replaced Stribild® (Sax 2015).
In pre-treated patients, elvitegravir achieved comparable effects to raltegravir in a
double-blind, randomized Phase III trial in over 700 individuals with resistance (Elion
2013). Switching from virologically effective PI and NNRTI therapy is also possible,
as shown in two large studies (Arribas 2014, Pozniak 2014). However, in these studies,
participants were on first- or second-line therapy, and pre-existing resistance was
allowed only in a minimal manner. This was also true in another trial, in which the
participants were switched from different regimens from other trials to Genvoya®
(Mills 2016). Thus, caution is warranted in patients with intensive pre-treatment
and/or resistance. In pre-treated patients with renal damage, proteinuria and bone
mineral density improved when switching from TDF to TAF, supporting safety in
this population (Pozniak 2016).
Elvitegravir is well tolerated, with no specific side effects that can be attributed to
the agent alone. Patients who switched from NNRTI therapy to elvitegravir reported
more headaches and nausea (Pozniak 2014), but this was not the case when switching
from a PI (Arribas 2014). Slightly more diarrhea is likely to occur than with other INSTIs.
Regarding resistance mutations, there are at least two resistance pathways via T66I
or E92Q (Shimura 2008). For the most part, the resistance profiles of elvitegravir and
raltegravir overlap, and cross-resistance is likely (DeJesus 2007, Garrido 2012).
The resistance barrier is likely lower than among second-generation INSTIs. Relevant
78 ART

interactions with elvitegravir hardly exist; the interactions are almost exclusively
caused by the booster cobicistat. Many agents that CYP3A metabolizes are
contraindicated or should be avoided (Nguyen 2016).
With the approval of Biktarvy®, elvitegravir has lost ground since 2018. The main
disadvantages are the lower resistance barrier, the rigidly fixed combination, and,
most importantly, the interaction risk due to the booster. There are hardly any reasons
left that currently speak in favor of elvitegravir. The single agent elvitegravir
(Vitekta®) is not marketed in many countries, although it is approved in Europe.
Raltegravir (Isentress®) was the first INSTI licensed in December 2007. It has broad
activity against R5- and X4-tropic HIV-1 strains and against HIV-2. Ten days of
monotherapy decreased viral load by approximately 2 logs (Markowitz 2006). Two
identically designed trials, BENCHMRK-1 and -2, initially led to approval in pre-
treated patients (Cooper 2008, Steigbigel 2008). A total of 699 individuals with triple-
class resistance received either 2 x 400 mg raltegravir or placebo for optimized
therapy. After 16 weeks, 79% versus 43% achieved a viral load below 400 copies/mL.
Without a single active agent, the rate was still 57% (versus 10%). Even after five
years, the effects were visible (Eron 2013). However, raltegravir was inferior to dolute-
gravir in the SAILING study in intensively pre-treated patients (see above).
Raltegravir was also successful in ART-naïve patients. In STARTMRK, raltegravir was
superior to efavirenz, both virologically and in terms of tolerability. The effects per-
sisted for more than five years (Rockstroh 2013). Raltegravir has also been approved
for first-line therapy since September 2009. In SPRING-2, it was slightly weaker than
dolutegravir (see above). In the three-arm ARDENT trial, it performed superior to
atazanavir/r and darunavir/r (Lennox 2014). Because viral load declines more rapidly
with raltegravir than with PIs and NNRTIs (Siliciano 2009), it has also been studied
in eradication approaches (see section on Cure in 5.4).
Tolerability of raltegravir is excellent and possibly even better than other INSTIs,
including neuropsychiatric events and sleep disturbances; in BENCHMARK, it was
comparable to placebo. Anecdotal evidence exists for rhabdomyolysis or hepatitis
(Dori 2010, Tsukada 2010). Renal insufficiency does not require dose adjustment.
There appear to be three resistance pathways at codons N155, Q148, and Y143, which
are localized in the catalytic core of the integrase. Resistance emerges quickly
compared to second-generation INSTIs, with broad cross-resistance with elvitegravir
(Anstett 2017). With pre-treatment and especially in the case of NRTI resistance, the
ice is thin: in SWITCHMRK (Eron 2010), viral breakthroughs occurred in 6% after
switching from lopinavir/r to raltegravir. Although the smaller SPIRAL study could
not replicate these findings (Martinez 2010), this argues against an overly naïve
switch from boosted PIs to raltegravir.
The recommended dose is one tablet of 400 mg twice daily, regardless of food intake.
The once-daily 800 mg dose was slightly weaker in QDMRK (Eron 2011), but a refor-
mulated dose (1 x 2 tablets of 600 mg) showed non-inferiority in the double-blind
randomized ONCEMRK trial in 802 patients (Cahn 2017). As a consequence, once-
daily dosing was approved in 2017.
Raltegravir is neither an inducer nor an inhibitor of the cytochrome 450 enzyme
system. Relevant interactions are unlikely (Rizk 2014). Thus, raltegravir remains an
option for interaction-prone co-medication, such as tuberculosis (Grinsztejn 2014)
or chemotherapies. Combination with rifampicin seems possible (Wenning 2009).
However, raltegravir levels increase 3–4-fold when PPIs such as omeprazole are given
concomitantly – but the clinical relevance is unclear (Iwamoto 2009).
Raltegravir is an excellently tolerated drug with good efficacy and low interaction
potential. A disadvantage is that it is not available in fixed combinations. In addi-
tion, the resistance barrier is lower than for second-generation INSTIs.
5.2. Overview – Classes of antiretrovirals and specific drugs 79

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5.2. Overview – Classes of antiretrovirals and specific drugs 83

Entry inhibitors
Mode of action
There are three key sites in the entry of HIV into the CD4 T-cell:
1. Binding via the envelope protein gp120 to the CD4 receptor (“attachment”).
2. Binding to co-receptors,
3. The fusion of virus and cell

Figure 1: HIV entry into the CD4 host cell showing the three crucial steps.

All three entry steps can be inhibited. Step 1 is inhibited by attachment inhibitors,
step 2 by co-receptor antagonists, and step 3 by fusion inhibitors. All three drug
classes are called entry inhibitors. Entry inhibitors were the fourth drug class in anti-
retroviral therapy after NRTIs, NNRTIs, and PIs. Unlike the other classes, they do not
act intracellularly but instead start earlier in the replication cycle of HIV – a
circumstance that hopefully improves tolerability. With maraviroc, T-20, ibalizumab,
and fostemsavir, four fundamentally different agents are now on the market, dis-
cussed here. For further entry inhibitors, especially the exciting field of broadly neu-
tralizing antibodies, please refer to the coming ART chapter, 2024/2025.

Attachment Inhibitors
The docking of the HIV glycoprotein gp120 to the CD4 receptor is the first step in
HIV entry. Theoretically, the docking (attachment) or interaction of gp120 and CD4
can be inhibited in various ways – for example, both the CD4 receptor and the
binding site of gp120 can be blocked. Consequently, the attachment inhibitors are
heterogeneous, and it is impossible to speak of a single substance class. In the early
1990s, experiments were conducted with soluble molecules that prevent the docking
of HIV to CD4 T-cells (Daar 1990, Schooley 1990). Unfortunately, what initially
looked good in the laboratory did not work in humans, probably due to the short
half-life of soluble CD4 (a few minutes). Polymorphisms in the gp120 gene can cause
natural resistance in some viruses (Charpentier 2012).

Individual agents
Fostemsavir (Rukobia®, GSK3684934, formerly BMS-663068) is a prodrug of BMS’s
attachment inhibitor temsavir (BMS-6265209). It is a successor to BMS-488043,
which was stopped in 2004. As a “small molecule” it binds reversibly to gp120 of
HIV and prevents a conformational change of this molecule, which is necessary for
docking to the CD4 T-cell. Thus, it does not bind to the CD4 receptor-like ibalizumab
(see below), but to the virus. The effect extends across R5 and X4-tropic viruses.
Viral load in monotherapy decreases between 1.2 and 1.8 logs (Nettles 2012).
Unfortunately, significant interindividual variations were seen. In a Phase IIb trial,
251 pre-treated individuals with at least 1,000 copies/mL viremia received TDF,
84 ART

raltegravir, and various doses of fostemsavir (600–1,200 mg) or atazanavir/r. In the

experimental arms, approximately 70% achieved viral suppression comparable to
the control arm (Thompson 2017).
Since fostemsavir inhibits various transporter proteins (including those for statins),
interactions are to be expected, and dose adjustments are necessary (Landry 2016).
Another problem could be the rapid development of resistance; the binding site of
gp120 is one of the most variable sites. Resistance was found in some individuals
who had never been treated with attachment inhibitors due to natural polymor-
phisms in the gp120 gene (Charpentier 2012). The resistances have been characterized
in more detail (Zhou 2013) and probably involve HIV subtype O (Alessandri-Gradt
2018). No cross-resistance appears to exist to other entry inhibitors. However, in the
above Phase II study, resistance occurred more frequently in the fostemsavir arm
(predominantly affecting raltegravir) than with atazanavir (Lataillade 2017).
In the meantime, the substance was acquired by ViiV Healthcare. The trend is sharply
toward salvage therapy: in the Phase III BRIGHTE trial, 371 pre-treated individuals
with treatment failure (> 400 copies/mL) and three-class failure were treated with
fostemsavir and optimized background ART. All were intensively treatment-experi-
enced, with less than half still having more than one active agent available. After
96 weeks (Lataillade 2020), 60% achieved a viral load below 40 copies/mL, compared
with 37% in the subgroup with no option. The response rates were not only depend-
ent on the number of active agents in the optimized adjuvant ART but also on viral
load and CD4 T-cells. The higher the viremia, the lower the CD4 T-cells the lower
the rates (Ackerman 2021).
Overall, tolerability of fostemsavir is good, with rare side effects beyond grade 1 and
predominantly gastrointestinal and headache.
In early 2021, the EMA granted approval for “adults with multidrug-resistant HIV-1
infection for whom no other suppressive antiretroviral treatment regimen is avail-
able.” This has made fostemsavir a potentially important salvage option. Given the
sharply limited indication and the twice-daily administration, fostemsavir has led
to a niche existence. The full potential of this compound may never be realized.
Ibalizumab (formerly TNX-355, Trogarzo®) is a monoclonal antibody that binds
directly to the CD4 receptor, preventing HIV entry. It must be infused, in the case
of ibalizumab, at two-week intervals for 30–60 minutes each. Unlike other attach-
ment inhibitors, ibalizumab does not appear to prevent the binding of gp120 to CD4
but rather the subsequent conformational change and, thus, the binding of gp120
to CCR5 and CXCR4. Thus, it is more of a post-attachment inhibitor. One question
is whether the functionality of CD4 T-cells is affected. Reportedly, the binding site
of ibalizumab to CD4 is also localized differently from the binding sites of the natural
CD4 ligands, the HLA class II molecules. Thus, CD4 T-cells should be able to perform
their normal functions. Developed first by Biogen starting in 1997, then by Tanox,
TaiMed Biologics, and most recently Theratechnologies, ibalizumab is the antibody
with the most clinical experience.
In a placebo-controlled Phase II study (Norris 2006), intensively pre-treated patients
received an infusion of two different doses (10 or 15 mg/kg) or placebo every two
weeks in addition to optimized ART. After 48 weeks, there was a sustained viral load
decline of approximately one log level in both active arms. In a Phase IIb study, ibal-
izumab was given every 2 or 4 weeks in 113 intensively pre-treated patients. At week
24, 59% and 31% achieved viral loads below 50 copies/mL (Khanlou 2011). In another
study, 43% of 40 intensively pre-treated individuals achieved a viral load below
50 copies/mL after 24 weeks – with bi-weekly infusions. Virologic success mainly
persisted for 48 weeks (Emu 2018). Tolerability was good. Subcutaneous administration
5.2. Overview – Classes of antiretrovirals and specific drugs 85

is also being studied but may be somewhat weaker (Lin 2017). Likely, bolus admin-
istration is also possible instead of infusions (DeJesus 2022).
Trogarzo® was approved in the EU in September 2019 for the treatment of people
with “multidrug-resistant HIV for whom no other suppressive regimen can be
composed”. However, given the low numbers of these cases, the annual therapy costs
of more than 100,000 euros, and the required biweekly infusions, very few patients
received the infusions in Europe.
Unfortunately, Theratech decided to withdraw the drug from the market and focus
on North America because “the pricing and reimbursement conditions in key
European countries were not satisfactory”. For the few cases in which ibalizumab is
still necessary, an import on a named patient basis is possible. In this case, it is essen-
tial to clarify the coverage of costs by the health insurance company beforehand.
With the introduction of fostemsavir and lenacapavir, two new options have become
available, probably making ibalizumab less important.

Co-receptor antagonists
In addition to the CD4 receptor, HIV needs so-called co-receptors to enter the target
cell. The two most essential co-receptors are CCR5 and CXCR4, discovered in the
mid-1990s (Alkhatib 1996, Deng 1996, Doranz 1996). They were named after the
natural chemokines that generally bind to them. Their nomenclature is derived from
the amino acid sequence. For CCR5 receptors, it is the “CC chemokines” MIP and
RANTES; for CXCR4 receptors, it is the “CXC chemokine” SDF-1. HIV variants use
either CCR5 or CXCR4 receptors for entry into the target cell and are referred to as
R5 or X4 viruses, respectively. R5 viruses predominantly infect macrophages
(formerly “M-tropic” viruses), while X4 viruses predominantly infect T cells
(formerly “T-tropic” viruses). “Dual-tropic” viruses can use both receptors; there are
mixed populations of R5 and X4 viruses. In most people with HIV infection,
R5 viruses are found in the early stages; X4 viruses, which can probably also infect
a broader range of cells, appear later. They are also found almost exclusively in X4/R5
mixed populations. The R5 to X4 tropism change is often accompanied by disease
progression (Connor 1997, Scarlatti 1997).
In some individuals, there is congenital reduced expression of the CCR5 receptor.
This is due to a 32-base pair deletion in the CCR5 gene (Δ32 mutation). People with
such a gene defect are less likely to become infected with HIV, and if infected, pro-
gression to AIDS is slower (Dean 1996, Liu 1996, Samson 1996). The absence of the
CCR5 receptor due to this gene defect remains largely without disease significance.
Drug-induced CCR5 receptor blockade by CCR5 (co-receptor) antagonists is an attrac-
tive therapeutic target. In 2008, the case of an HIV patient with acute myeloid
leukemia and allogeneic stem cell transplantation whose healthy stem cell donor
was homozygous for the Δ32 mutation was published. After transplantation, the viral
load remained below the detection limit for more than ten years without ART (Hütter
2009, Allers 2011).
In therapy-naive people, R5 populations are present in about 80–90%; in pre-treated
patients, it is about 50% (Hoffmann 2007). Receptor tropism correlates with the stage
of infection. The higher the CD4 T-cells and the lower the viral load, the more likely
R5 viruses are present. In contrast, pure X4 populations are almost only present in
advanced disease stages. Above 500 CD4 T-cells/µl, they are found in only 6%, but
at less than 25 CD4 T-cells/µl, they are found in over 50% (Brumme 2005), which
is why CCR5 antagonists should be used rather early in the disease course. They are
often unsuitable as a salvage strategy for advanced infection (and X4 viruses).
86 ART

Tropism testing
Although CCR5 antagonists seem not to have adverse effects in X4/R5 mixed
populations (see below), for cost reasons, testing before therapy is necessary to clarify
whether the use of a CCR5 antagonist makes sense (see Resistance).
Commercial assays are available for phenotypic tropism determination, but they are
laborious, succeed only with a minimum of 500–1,000 virus copies/mL, and take
several weeks. The technically simpler and more cost-effective genotypic tropism deter-
mination has been validated and largely replaced phenotypic testing in routine
testing. Since 2013, it has been a health insurance benefit. It focuses on the V3 loop
of the envelope protein gp120, as HIV binds to the co-receptor with this region.
However, tropism does not appear to be determined solely by the sequence of the
V3 loop – viruses with identical V3 loops can differ in tropism (Low 2007). A
significant advantage of genotypic testing is that it is also possible and valid from
proviral DNA and thus in the presence of viral suppression. Measurement from provi-
ral DNA examines the genetic material of HIV integrated into the genome of infected
cells (Soulié 2010, Poveda 2017).

Tropism shift and other consequences

Under CCR5 antagonists, a selection-related shift toward X4 viruses is observed in
patients with virologically unsuccessful therapy. These X4-tropic viruses are likely
selected from pre-existing pools (Westby 2006). In a pilot study in which infected
individuals with X4/R5 mixed populations received maraviroc, CD4 T-cells increased
compared with placebo (Saag 2009) – so HIV progression while on CCR5 antagonists
caused by the X4 shift seems rather unlikely.
Although people with the congenital Δ32 gene defect are generally healthy, there
are fears that blocking the co-receptor with drugs will have negative consequences.
After all, this chemokine receptor must be good for something. People with the Δ32
deletion have been investigated in countless studies to determine whether certain
diseases are more frequent (or less frequent) in them. There is no clear association –
the most intense discussion has been of an increased incidence of West Nile virus
infections (Glass 2006). A meta-analysis found no adverse effects of maraviroc on
immune function (Ayoub 2007). Because the Δ32 deletion appears protective for
rheumatoid arthritis (Prahalad 2006), maraviroc has been tested in rheumatoid
arthritis, but without success.

Figure 2: Effect of the allosteric CCR5 antagonist maraviroc. Binding into a transmembrane pocket
spatially alters the receptor molecule, making it impossible for the viral protein gp120 to bind to the
receptor. Thus, the receptor is not simply occupied. R5A = CCR5 antagonist.
5.2. Overview – Classes of antiretrovirals and specific drugs 87

Early observations of excellent CD4 T-cell increases under maraviroc led to the
hypothesis that CCR5 antagonists might serve as immune modulators. However, a
meta-analysis found no evidence of improved immune reconstitution (Pichenot
2012). In ANRS 146 (OPTIMAL), additional administration in 409 late presenters
with AIDS or low helper cells resulted in no immunologic, virologic, or clinical
benefits (Lelievre 2017).

Individual agents
Maraviroc (Celsentri®, US: Selzentry®) was the first and only CCR5 antagonist
approved for the treatment of HIV infection in September 2007. Maraviroc binds
allosterically to the receptor (Figure 2). With maraviroc monotherapy, the viral load
fell by approximately 1.6 log levels after 10–15 days (Fätkenheuer 2005). Maraviroc
is ineffective against non-R5 viruses; however, CD4 T-cells surprisingly increased in
one study (Saag 2009). Two almost identical Phase III trials, MOTIVATE-1 and -2, led
to the approval of maraviroc. These enrolled 1,049 patients with R5 viruses and at
least 5,000 copies/mL who were either pre-treated with three classes and/or had viral
resistance to three classes (Gulick 2008, Fätkenheuer 2008). Maraviroc was admin-
istered either 300 mg once daily, 150 mg twice daily, or placebo to an optimized
therapy – in which, however, agents such as darunavir or raltegravir were not allowed.
After 48 weeks, the proportions with a viral load below 50 copies/mL were
significantly higher in the maraviroc arms than on placebo (46% and 43% vs. 17%,
respectively). The effect was also seen in high viral load and multiple resistance
(Fätkenheuer 2008) and remained stable over 96 weeks (Hardy 2010). Tolerability
did not differ from placebo. Moreover, the selection-induced shift to X4 viruses,
observed in half without virological therapeutic success, had no adverse conse-
quences.
Maraviroc has also been tested in treatment-naïve patients (Cooper 2010, Sierra-
Madero 2010). In the MERIT trial, 721 subjects received either efavirenz or maraviroc
300 mg twice daily in addition to AZT+3TC (a once-daily arm was stopped early due
to poor efficacy). Virologic failure was observed more frequently (12% versus 4%).
Although CD4 T-cells increased more significantly, non-inferiority to efavirenz was
not achieved. Surprisingly, the difference in efficacy was observed only in Southern
Hemisphere countries. The retrospective analysis also showed that nearly 4% had
shown a shift from R5- to dual-tropic virus in the weeks between screening and base-
line. Among these people, the response was particularly poor. According to retro-
spective studies, the difference between maraviroc and efavirenz would not have
been relevant with better tropism testing (Cooper 2010). The FDA approved
Maraviroc in November 2009, including treatment-naïve patients. In Europe, EMA
did not consider this data sufficient, and approval remained restricted to pre-treated
patients. Consequently, ViiV has tried tirelessly to find new ways to establish
maraviroc for broader patient groups. In 2014, the MODERN trial, an attempt to use
the drug in a nuke-sparing strategy with maraviroc+darunavir/r as first-line therapy,
had to be terminated prematurely. The effect was somewhat weaker than standard
therapy (Stellbrink 2016). The approach of PI/r and maraviroc also proved inferior
to standard therapy in pre-treated patients (Rossetti 2017, Pett 2018).
Maraviroc is well tolerated, even with long-term use (Gulick 2014). In MERIT,
discontinuation rates due to adverse events were only 4% vs. 14% with efavirenz.
Lipid profiles were also more favorable (MacInnes 2011).
Data on resistance are limited. Mutations in the genes responsible for the V3 loop
of the envelope protein gp120 provide complete resistance, and the viruses can
remain R5-tropic – so a shift to X4 is unnecessary. The mutations are primarily local-
ized at the tip of the loop. They could help the virus either bind to the CCR5 recep-
88 ART

tor spatially altered by maraviroc or increase the affinity of the viruses for unbound
CCR5 receptors (Westby 2007). Overall, the resistance barrier appears relatively high
(Jubb 2009). Importantly, for practice, the recommended maraviroc dose is based on
the concomitant therapy. For boosted PIs (except tipranavir), the usual dose of
2 x 300 mg is halved, whereas for efavirenz (or other enzyme inducers such as
rifampicin or carbamazepine), it must be doubled. No dose adjustments are neces-
sary with INSTIs. Given the need for tropism testing, the limited approval (in Europe),
and the not entirely straightforward dosing, the use of maraviroc in HIV therapy
remains limited despite its excellent tolerability.

Fusion Inhibitors
Fusion inhibitors prevent the final step of HIV’s entry into the target cell. This fusion
of virus and cell is complex. After binding to the CD4 and co-receptor, a conforma-
tional change is triggered in the viral transmembrane protein gp41. This gp41 protein
then impales a hairpin-like junction into the cell membrane, its two “arms” – the
C-terminal region anchored in the virus, the N-terminal region hooked to the cell
membrane – folding together to pull the virus envelope and cell membrane toward
each other. Just before folding, gp41 is in an intermediate position: the two arms are
unfolded for a moment – forming targets for fusion inhibitors (Root 2001).

Individual agents
T-20 (enfuvirtide, Fuzeon®) is the prototype among FIs and has been approved in
Europe since May 2003 in antiretroviral pre-treated adults. As a relatively large
peptide, it must be injected subcutaneously daily. T-20 binds to the intermediate
structure of the HIV protein gp41, which is formed when HIV fuses with the target
cell. In early studies of intravenous monotherapy, the viral load fell by 1.6–2 logs in
a dose-dependent manner (Kilby 1998+2002).
Two Phase III trials in 995 intensively pre-treated patients with mostly multidrug-
resistant viruses led to the approval of subcutaneous administration (Lalezari 2003,
Lazzarin 2003). In TORO-1, the viral load decreased by 0.94 log levels after 48 weeks,
and in TORO-2 by 0.78 log (Nelson 2005). In other studies, T-20 showed a virolog-
ical benefit (see Salvage Therapy) with tipranavir, darunavir, maraviroc, or raltegravir.
An unexpected finding in the TORO trials was the accumulation of lymph-
adenopathies and bacterial pneumonia (Trottier 2005). The binding of T-20 to
granulocytes is suspected as the cause. Major side effects are the obligatory (98% in
TORO), often painful skin reactions at the injection sites. Many patients refuse to
continue with T-20 at some point (see Side Effects section). The development of a
bioinjection system in which T-20 is pressed into the skin has been discontinued.
Injecting the double dose only once daily is not recommended: trough levels are too
low (Thompson 2006).
Resistance occurs relatively quickly but appears to reduce viral fitness (Lu 2002).
Point mutations affecting a short sequence in the gp41 gene are sufficient (Mink
2005). Since T-20 is a large peptide, antibodies are produced. However, these do not
impair efficacy (Walmsley 2003).
Can latent reservoirs be emptied with T-20? After initially positive reports, more
recent studies dashed these hopes (Gandhi 2010, Morand-Joubert 2012). Cost also
remains an important issue. Due to the complex manufacturing process – according
to the company, T-20 is “one of the most complicated agents” ever produced – the
price of ART is much higher.
Overall, due to the cumbersome application process, T-20 practically no longer plays
a role. In salvage, it can be valuable in individual cases, but it can almost always be
replaced by INSTIs (De Castro 2009, Grant 2009).
5.2. Overview – Classes of antiretrovirals and specific drugs 89

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90 ART

Landry I, Zhu L, Abu Tarif M, et al. Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug
BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/ Pharmacodynamics of the Active Moiety,
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2020, 7:e740-e751.
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92 ART

Capsid inhibitors
The viral genome and viral enzymes of HIV are enclosed in a capsid, a cone-shaped
envelope consisting of p24 rings containing the viral genome and viral enzymes.
Although it is still unclear exactly when “uncoating” of the capsid occurs after uptake
into the cell, the capsid is essential for replication. It plays a critical role in many
aspects of the HIV-1 replication cycle, including reverse transcription, cytoplasmic
transport, nuclear entry and maturation of the virion, and interaction with many
host factors essential for infection (McFadden 2021, Selyutina 2022).
The p24 gene encodes the gag capsid, which remains highly conserved at key sites
across all HIV subtypes. Gag polymorphisms or other mutations in the gag cleavage
site do not appear to affect efficacy, nor do mutations against other drug classes
(Margot 2021).
Agents that influence the stability of the capsid are known as capsid inhibitors. After
many years in which the pharmaceutical industry cut its teeth on developing effective
prototypes, there has been movement in research in recent years. With lenacapavir,
the first capsid inhibitor was approved in 2022. After NRTIs, NNRTIs, PIs, INSTIs,
and entry inhibitors, a sixth class of active ingredients entered the market.

Individual agents
Lenacapavir (Sunlenca®, formerly GS-6207) is a novel, potent, and long-acting first-
in-class HIV-1 capsid inhibitor granted breakthrough therapy designation by the FDA
in 2019. It is manufactured by Gilead Sciences and is an improved analog of the pro-
totype GS-CA1. Mutations selected in vitro with GS-6207 remained sensitive to other
antiretroviral agents, and some appear to impair replication significantly (Yant 2019).
As monotherapy, lenacapavir delivered a mean maximal HIV-1 RNA reduction of an
impressive 2.2 logs at ten days (Link 2020). However, the half-life is at least as impres-
sive. Sufficient levels can be achieved over six months with a single subcutaneous
administration. Weekly oral administration also appears possible. It was looked at
in two large clinical studies, CALIBRATE and CAPELLA.
CALIBRATE, an open-label Phase II trial, enrolled 182 treatment-naïve individuals
who received lenacapavir subcutaneously (every six months) or orally (each with
different combination partners). In the combined lenacapavir arms, viral load at
week 28 was 94% below 50 copies/mL (100% in the control arm with bictegravir).
Two of 103 people treated subcutaneously with lenacapavir discontinued treatment
due to injection site reactions (Gupta 2021).
In CAPELLA, 72 extensively pre-treated patients on failing ART were treated with
lenacapavir SC every six months or placebo (Segal-Maurer 2022). Two weeks after
the first injection, viral load had fallen by at least 0.5 log levels in 88% compared
with 17% on placebo. Despite very limited options in the optimized background
therapy, up to 81% achieved viral loads below 50 copies/mL, including 4/6 individ-
uals in whom lenacapavir was the only active agent (Molina 2021). At 52 weeks,
however, 9/72 participants had emergent lenacapavir resistance; four re-suppressed
while maintaining lenacapavir use (Ogbuagu 2023). Injection site reactions were the
most common problems but rarely led to discontinuation.
Resistance appears to be predominant at codons 67 and 74 (Margot 2022, Bester
2022) and was also observed in 2/157 therapy-naive individuals (Gupta 2022) –
possibly indicating that the resistance barrier is not very high with this agent.
Providers should pay attention to drug-drug interactions when initiating lenacapavir.
Lenacapavir is a substrate for Pgp, CYP3A, and UGT1A1 and a moderate inhibitor of
CYP3A (review: Tuan 2023).
5.2. Overview – Classes of antiretrovirals and specific drugs 93

In August 2022, the EMA approved lenacapavir based on the CAPELLA data. The
tablets are intended as a “lead-in” before the first depot injection. As with fostem-
savir, the indication is limited to “adults with multi-drug-resistant HIV-1 infection
in whom no other suppressive antiviral regimen can be composed”. For manufacturer
Gilead, this is likely just a start: the development project suggests that lenacapavir
will be developed further, both as an oral agent (GS6289, an exciting study in
combination with bictegravir as STR) and further as a long-acting agent. Studies in
combination with broadly neutralizing antibodies are also being planned. In the
Purpose Phase III trials, lenacapavir is also tested as PrEP every six months SC com-
pared to TAF/FTC and TDF/FTC in a placebo-controlled setting in women and MSM.

Literature on capsid inhibitors

Bester SM, Adu-Ampratwum D, Annamalai AS, et al. Structural and Mechanistic Bases of Viral Resistance to HIV-
1 Capsid Inhibitor Lenacapavir. mBio. 2022 Oct 3:e0180422.
Gupta SK, et al. Long-acting subcutaneous lenacapavir dosed every six months as part of a combination regimen
in treatment-naïve people with HIV: interim 16-week results of a randomized, open-label, phase 2 induction-
maintenance study (CALIBRATE). IAS 2021. Abstract OALB0302.
Gupta SK, Sims J, Brinson C, et al. Lenacapavir as part of a Combination Regimen in Treatment-Naïve People with
HIV: Week 54 Results. Abstract 138, CROI 2022.
Link JO, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature 2020, 584:614-618.
Margot N, Ram R, Rhee M, Callebaut C. Absence of Lenacapavir (GS-6207) Phenotypic Resistance in HIV Gag
Cleavage Site Mutants and in Isolates with Resistance to Existing Drug Classes. Antimicrob Agents Chemother
2021, 65:e02057-20.
Margot NA, Naik V, VanderVeen L, et al. Resistance analyses in Highly Treatment-Experienced People with HIV
Treated with the Novel Capsid HIV Inhibitor Lenacapavir. J Infect Dis 2022 Sep 9:jiac364.
McFadden WM, Snyder AA, Kirby KA, et al. Rotten to the core: antivirals targeting the HIV-1 capsid core.
Retrovirology 2021, 18:41.
Ogbuagu O, Segal-Maurer S, Ratanasuwan W, et al. Efficacy and safety of the novel capsid inhibitor lenacapavir
to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial. Lancet HIV 2023, S2352-3018(23)00113-3.
Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1
Infection. N Engl J Med 2022, 386:1793-1803.
Selyutina A, Hu P, Miller S, et al. GS-CA1 and lenacapavir stabilize the HIV-1 core and modulate the core inter-
action with cellular factors. iScience 2021, 25:103593.
Tuan J, Ogbuagu O. Lenacapavir: a twice-yearly treatment for adults with multidrug-resistant HIV infection and
limited treatment options. Expert Rev Anti Infect Ther 2023; 21:565-570.
94 ART

5.3. ART 2024+: Beyond the horizon

C H R ISTIAN HOFFMAN N

Almost all people living with HIV can be treated adequately. Nevertheless, there is
still a need for new drugs. Not only for the few for whom the new drug classes do
not work but, in principle, for all patients. As things stand, HIV therapy must be
taken for the rest of the patient’s life; it remains unclear whether the current drugs
will suffice. New drugs that are less toxic and easier to take than today’s STRs must
be developed. To get closer to the long-term goal of eradication, they should be more
potent than the current ones. For a while, many companies shifted away from HIV
and toward hepatitis C, but there is now renewed movement in HIV research after
the end of the HCV boom – the HIV pipeline is full. However, the increasing price
erosion of generic drugs will have a negative impact. The incentive to develop new
drugs will decrease. It has become tough to show an additional benefit that could
justify higher prices. We do not need 20 single-tablet regimens (STRs). The following
is an overview of the most exciting agents as of early 2023 – probably incomplete!

Long-acting drugs
Long-acting (LA) drugs are delayed-release and thus have a very long effect. They are
mainly being developed to address treatment fatigue from the burden of daily pills
and improve convenience. LA drugs could be used both as PrEP and for adherence
issues, as well as for anyone who prefers a “monthly injection” or even a “three-
monthly injection” vs. taking tablets daily (reviews: D’Amico 2020, Clement 2020).
With the approval of Vocabria® and Rekambys® (US and Canada: Cabenuva®), the
combination of cabotegravir and rilpivirine given every 4 or 8 weeks for pre-treated
patients has been available since late 2020; they are discussed later in the de-escala-
tion strategies. Lenacapavir (Sunlenca®, see section above) is also approved as a six-
monthly injection for multi-drug resistance, but it must be combined with other
oral therapies. Experimental agents are briefly discussed below.
Dolutegravir-LA – is being tested as a nano-formulation. This involves packaging a
hydrophobic and lipophilic prodrug of dolutegravir into nanoparticles. In mice,
parenteral administration allowed sufficient levels for up to 2 months (Sillman 2018).
New manufacturing processes or technologies allow even annual doses in animal
models (Deodhar 2022).
Rilpivirine-LA – the NNRTI rilpivirine is well suited as an LA formulation because
it accumulates in plasma and other compartments for a long time, more than other
antiretroviral agents (Jackson 2013). Rilpivirine is also detectable in vaginal fluid for
a long time, which makes it attractive as PrEP (Jackson 2015). It is approved as
Recambys®. Nanoformulations also appear possible and feasible; in animal studies,
decent levels could be achieved for over 25 weeks by a single intramuscular injec-
tion (Hilaire 2019).
Islatravir (formerly MK-8591 or EfdA) is a nucleoside RT translocation inhibitor
(NRTTI) that accumulates long in PBMC and macrophages. PK data in monkeys
suggest a once-yearly administration may be feasible with an LA formulation (see
below for new NRTIs).
Numerous other agents are in development as LA formulations. Raltegravir-LA was
highly protective when injected subcutaneously in animal studies. Two weeks after
a single injection, levels were comparable to oral raltegravir (Kovarova 2016).
Atazanavir-LA, as a nanodispersion, showed higher tissue accumulation in animal
studies (IM injection) than by conventional ART even after two weeks (Dash 2012,
5.3. ART 2024+: Beyond the horizon 95

Puligijja 2015). The effect is significantly enhanced by a kinase inhibitor (Zhang

2016).
Albuvirtide is a fusion inhibitor. In combination with lopinavir, 5/9 patients
achieved a viral load below the detection limit in a pilot study of weekly injections
(Zhang 2016). In another study, it worked even in pre-treated patients (Su 2022).
Other long-acting systems: Increasingly, attempts are being made to deliver long-
acting HIV drugs by means other than injections. Transdermal is just one way
(Review: Weld 2020). Implants with TAF and FTC replenished through the skin have
already been tested in monkeys as PrEP (Chua 2017). Degradable implants applied
under the skin with an implant have also been successful in animal studies (Durham
2017). The methods are partially similar to long-term contraceptives, in which
hormone implants are inserted directly under the skin as a plastic rod a few cen-
timeters long with an applicator (Schlesinger 2016).

Capsid inhibitors
Lenacapavir was the first agent in this class to reach the market in 2022. Therefore,
the development of capsid inhibitors is expected to pick up speed. Capsid inhibitors
are also used for other viral infections, such as bersacapavir for hepatitis B (in Phase
II trials) or vapendavir for enteroviruses. The drugs developed for HIV target different
binding sites of the capsid, but almost all are still pre-clinical (review: McFadden 2022).
GS-CA1 was described in 2017 as a substance with a long half-life that binds directly
to the HIV-1 capsid. It is the precursor of lenacapavir and appears in many articles;
it is mentioned here only for form.
PF74 is Pfizer’s prototype (Blair 2010). PF74 never reached the clinic but demon-
strated submicromolar efficacy and serves as the backbone for some of the most
promising current agents, including PF74 analogs with enhanced efficacy, particularly
against CA mutants that exhibit resistance to PF74. The peptidic backbone of PF74
is also at the heart of lenacapavir. Given the rapid development of resistance and a
short half-life, work is underway to improve the molecule (McFadden 2022).
VH4004280 is a capsid inhibitor of ViiV that can be given orally. A Phase I study in
healthy volunteers is ongoing, and a Phase II study in PLWH is planned to start in
late 2023. Another candidate (VH4011499) is also reportedly already in clinical trials.
Various administration routes are being explored to extend the dosing schedule
beyond every two months via the parenteral route or every week or longer via oral
administration.
Ebselen is a capsid inhibitor attributed to have diverse antiviral properties (Thenin-
Houssier 2016).
Literature on Long-acting and Capsid Inhibitors
Blair WS, Pickford C, Irving SL, et al. HIV capsid is a tractable target for small molecule therapeutic intervention.
PLoS Pathog. 2010;6:e1001220.
Chua CX, Jain P, Hu M, et al. Transcutaneous refillable nanofluidic implant for constant delivery of HIV PrEP.
Abstract 422LB, 24th CROI 2017, Seattle.
Clement ME, Kofron R, Landovitz RJ. Long-acting injectable cabotegravir for the prevention of HIV infection.
Curr Opin HIV AIDS 2020, 15:19-26.
D’Amico R, Margolis DA. Long-acting injectable therapy: an emerging paradigm for the treatment of HIV infec-
tion. Curr Opin HIV AIDS 2020, 15:13-18.
Dash PK, Gendelman HE, Roy U, et al. Long-acting nanoformulated antiretroviral therapy elicits potent anti-
retroviral and neuroprotective responses in HIV-1-infected humanized mice. AIDS 2012, 26:2135-44.
Deodhar S, Sillman B, Bade AN, et al. Transformation of dolutegravir into an ultra-long-acting parenteral prodrug
formulation. Nat Commun 2022, 13:3226.
Durham PG, Gatto G, Johnson L, et al. In Vitro -In Vivo Evaluation of a Biodegradable Implant Containing TAF
for HIV PrEP. Abstract 420LB, 24th CROI 2017, Seattle.
Hilaire JR, Bade AN, Sillman B, et al. Creation of a long-acting rilpivirine prodrug nanoformulation. J Control
Release 2019 Oct;311-312:201-211.
96 ART

Jackson A, McGowan I. Long-acting rilpivirine for HIV prevention. Curr Opin HIV AIDS 2015, 10:253-7.
Jackson AG, Else LJ, Mesquita PM, et al. A compartmental pharmacokinetic evaluation of long-acting rilpivirine
in HIV-negative volunteers for pre-exposure prophylaxis. Clin Pharmacol Ther 2014, 96:314-23.
Kovarova M, Swanson MD, Sanchez RI, et al. A long-acting formulation of the integrase inhibitor raltegravir pro-
tects humanized BLT mice from repeated high-dose vaginal HIV challenges. J Antimicrob Chemother 2016,
71:1586-96.
McFadden WM, Snyder AA, Kirby KA, et al. Rotten to the core: antivirals targeting the HIV-1 capsid core.
Retrovirology 2021, 18:41.
Owen A, Rannard S. Strengths, weaknesses, opportunities and challenges for long acting injectable therapies:
Insights for applications in HIV therapy. Adv Drug Deliv Rev. 2016 Feb 23.
Puligujja P, Balkundi SS, Kendrick LM, et al. Pharmacodynamics of long-acting folic acid-receptor targeted riton-
avir-boosted atazanavir nanoformulations. Biomaterials 2015, 41:141-50.
Schlesinger E, Johengen D, Luecke D. A Tunable, Biodegradable, Thin-Film Polymer Device as a Long-Acting Implant
Delivering Tenofovir Alafenamide Fumarate for HIV Pre-exposure Prophylaxis. Pharm Res 2016, 33: 1649–1656.
Sillman B, Bade AN, Dash PK, et al. Creation of a long-acting nanoformulated dolutegravir. Nat Commun. 2018
Feb 6;9:443.
Su B, Yao C, Zhao QX, et al. Long-acting HIV fusion inhibitor albuvirtide combined with ritonavir-boosted lopinavir
for HIV-1-infected patients after failing the first-line antiretroviral therapy: 48-week randomized, controlled, phase
3 non-inferiority TALENT study. J Infect 2022, 85:334-363.
Thenin-Houssier S, Mitchelle de Vera I, Pedro-Rosa L, et al. Ebselen, a Small-Molecule Capsid Inhibitor of HIV-1
Replication. Antimicrob Agents Chemother. 2016, 60:2195-208.
Zhang G, Guo D, Dash PK, et al. The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes
for long-acting antiretroviral therapy. Nanomedicine 2016, 12:109-22.
Zhang H, Jin R, Yao C, et al. Combination of long-acting HIV fusion inhibitor albuvirtide and LPV/r showed
potent efficacy in HIV-1 patients. AIDS Res Ther. 2016 Feb 10;13:8.
5.3. ART 2024+: Beyond the horizon 97

New nucleoside analogs (NRTIs)

Finding NRTIs with good activity against resistant viruses that do not have mito-
chondrial toxicity seems challenging. For a long time, it seemed doubtful that a new
agent in this class would ever make it to the market, and many have already
disappeared into obscurity. With islatravir, an innovative new substance, this could
change.
Apricitabine (ATC, AVX-754, formerly SPD-754) is a heterocyclic cytidine analog
that remains effective despite many NRTI mutations. With monotherapy, viral load
decreased by 1.2–1.4 logs (Cahn 2006), compared with 0.7–0.9 logs for the M184V
mutation (Cahn 2010). ATC was well tolerated (Gaffney 2009) and was much less
toxic than BCH-10652, which causes severe degenerative dermatopathy in monkeys
(Locas 2004). In May 2010, negotiations with major pharmaceutical companies
failed, and further development was halted.
Censavudine (festinavir, BMS986001), a thymidine analog, is a purportedly less
toxic derivative of d4T. The original name, “festinavir”, was changed to avoid
confusion with PIs. Censavudine is reported to have good activity against HIV-2
(Smith 2015). In a Phase II trial testing different doses against TDF, there was more
resistance and evidence of lipoatrophic changes (Gupta 2016), so BMS lost interest.
According to the Japanese company Oncolys, it will now continue in Phase II in
neurogenerative diseases (!), while there is no talk of further investigation into HIV.
Elvucitabine (or ACH-126,443) is a cytidine analog from Achillion Pharmaceuticals.
It is an enantiomer of dexelvucitabine (Reverset) and is effective in vitro for numer-
ous NRTI resistances (Fabrycki 2003). Of interest is its long half-life of 150 hours.
In HIV-infected individuals with the M184V mutation, viral load decreased by
0.7–0.8 logs after 28 days in a small, double-blind study. However, the study was ter-
minated because leukopenia and skin rashes occurred with 100 mg elvucitabine
(Dunkle 2003). In Phase II in 77 treatment-naive patients (with efavirenz and TDF),
elvucitabine was roughly comparable in efficacy to 3TC over 96 weeks (DeJesus 2010).
Achillion is reportedly collaborating with companies in China, although further
development is unclear.
Fozivudine is a prodrug of AZT that is activated intracellularly to AZT monophos-
phate. The company Heidelberg Pharma conducted clinical trials. In a Phase II trial,
for example, fozivudine was only moderately effective – at the highest dose, the viral
load fell by just under 0.7 log levels (Girard 2000) – too little for further develop-
ment? In one Phase II trial in Tanzania and Côte d’Ivoire published in 2017, combined
with 3TC and efavirenz, it was just as effective and, at the same time, less myelo-
toxic than AZT (Kroidl 2017).
Islatravir (MK-8591 or EfdA, 4’-ethynyl-2-fluoro-deoxyadenosine) is a nucleoside
RT translocation inhibitor (NRTTI) that inhibits reverse transcriptase in a complex
and novel manner. The mechanism of action relies both on immediate chain
termination through inhibition of translocation, a step required for RT before any
incorporation of a new nucleotide, and on delayed chain termination once islatravir
has been incorporated into the primary strand by RT. The chemical structure and
novel mechanism of action thus distinguish it from all previously approved NRTIs
and result in a unique resistance and PK profile (Markowitz 2020). The resistance
barrier appears to be high (Diamond 2022).
It is being developed by MSD, which acquired islatravir in 2012 from the Japanese
company Yamasa, a soy sauce manufacturer (!). The effort is immense; the develop-
ment has picked up speed compared to other NRTIs. Quite obviously, there seems
to be a lot of promise. Mutations such as M184V do not negatively affect islatravir
98 ART

(Oliveira 2017, Diamond 2022), and HIV-2 is also inhibited. The half-life of orally
administered islatravir is 150 hours; the compound accumulates in PBMC and
macrophages. With a single dose of only 10 mg, viral load decreased by 1.6 log levels
after seven days (Schürmann 2021).
In a Phase IIa trial in treatment-naïve patients, three different doses of islatravir
(0.25–2.25 mg daily) were combined with doravirine+3TC and were tested against
a standard therapy of doravirine+TDF+3TC (Molina 2021). If virological efficacy
was good, randomization to a 2DR of islatravir+doravirine occurred at week 24. At
48 weeks, efficacy was comparable to the standard arm across all subgroups (gender,
ethnicity, CD4 T-cells, viral load). 5/90 patients developed virologic failure; all
remained below 80 copies and without resistance. Tolerability has been excellent
over 96 weeks to date (Molina 2022).
The compound was highly protective in macaques as PrEP (Markowitz 2019). PK
data in monkeys, moreover, suggest that with an LA formulation, even once-yearly
dosing may become feasible. The dose will be flexible, with long intervals: weekly
tablets, tri-monthly injections, and subdermal depot – all seem possible. Seemed.
The ambitious Phase III program (in which doravirine and islatravir were tested
against bictegravir/TAF/FTC) was abruptly halted in November 2021: completely
unexpected lymphopenias and CD4 T-cell declines were seen in some participants.
The FDA subsequently halted all ongoing studies. The causes of the lymphopenias
remain unclear, but they appear to occur primarily at high doses and are reversible.
It may be possible that islatravir triphosphate accumulates in lymphocytes and trig-
gers cell death at very high drug concentrations (Squires 2023). The 0.75 mg dose
was initially taken forward for larger phase 3 studies. Still, after the development
pause, Merck decided to skip all PrEP studies and focus on testing a 0.25 mg dose of
islatravir. A Phase 3 study now compares doravirine and a lower islatravir dose to
bictegravir/TAF/FTC in previously untreated PLWH. More studies are planned.
Despite these drawbacks, islatravir remains one of the most interesting new com-
pounds in HIV medicine. It will be interesting to see what is possible with lower drug
doses.
Phosphazide (Nikavir) is an NRTI developed in Russia (and approved there since
1999) that closely resembles AZT (Skoblov 2003). After 12 weeks of monotherapy
with 400 mg, viral load decreased by 0.7 log levels. Because phosphazide is a prodrug
of AZT, an additional activation step is required. The D67N mutation appears to
reduce efficacy (Machado 1999). Other studies showed efficacy with ddI and nevi-
rapine (Kravtchenko 2000) or saquinavir (Sitdykova 2003). However, detecting an
advantage over AZT is difficult – better tolerability has not been demonstrated.
Racivir is a cytidine analog initially developed by Pharmasset. It is a mixture of FTC
and its enantiomer. There may be different resistance pathways for the two enan-
tiomers, which could complicate the development of resistance (Hurwitz 2005).
Combined with d4T and efavirenz, a good effect was seen after two weeks (Herzmann
2005). In a study of 42 patients with the M184V mutation, viral load decreased by
0.4 log levels after 28 days (Cahn 2007). After Gilead acquired Pharmasset, nothing
more was heard, and further development is questionable.
Rovafovir etalafenamide (or GS-9131) is a new NRTI developed by Gilead Sciences
with good efficacy against diverse NRTI resistance (K65R, L74V, M184V, or even com-
binations) that can be given once daily (White 2017, Ibanescu 2019). Rovafovir is a
cyclic nucleoside phosphonate, and the prodrug of GS-9148, but a Phase II trial in
Uganda was stopped early in April 2020 due to lack of efficacy – probably the end.
Tenofovir exalidex (TXL, formerly CMX 157) is a pro-drug of tenofovir, “HDP-
tenofovir” (hexadecyloxypropyl ester), similar to TAF and probably not as nephro-
5.3. ART 2024+: Beyond the horizon 99

toxic. TXL is being developed by ContraVir Pharmaceuticals in New Jersey. In vitro,

it was effective against TDF resistance, including K65R (Lanier 2010); it may be given
once weekly. It is also being developed for hepatitis B; in Phase I studies, it was pretty
well-tolerated, with HBV DNA dropping by about 2 logs (Tanwandee 2017). Where
it goes from here is unclear. Do we still need tenofovir? The companies involved will
watch the development of dual therapies very closely.
Out of sight, out of mind – the following NRTIs will not be developed further:
• Adefovir dipivoxil from Gilead, little effect against HIV, nephrotoxicity
• Amdoxovir (DAPD), too toxic
• Dexelvucitabine (Reverset) from Incyte, 2006, pancreatitis
• Dioxolanthymine (DOT) as a thymidine analog too unattractive
• dOTC from Biochem Pharma, toxicity in monkeys
• FddA (lodenosine) from Bioscience, 1999, liver/kidney damage
• Fosavuldine from Heidelberg Pharma, too toxic
• KP-1461 from Koronis Pharmaceuticals, June 2008, due to ineffectiveness
• Lobucavir from BMS, carcinogenicity
• MIV-210 from Medivir/Tibotec, October 2007, tested as an HBV drug
• MIV-310 (alovudine) from Boehringer, March 2005, disappointing Phase II study
• SPD-756 (BCH-13520) and SPD-761
• Stampidine by Parker Hughes, company broke, nobody wants a new d4T

Literature on new NRTIs

Cahn P, Altclas J, Martins M, et al. Antiviral activity of apricitabine in treatment-experienced HIV-1-infected
patients with M184V who are failing combination therapy. HIV Med 2010 Nov 3. [Epub ahead of print]
Cahn P, Cassetti I, Wood R, et al. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretro-
viral-naive, HIV-infected patients. AIDS 2006, 20:1261-8.
Cahn P, Sosa N, Wiznia A, et al. Racivir demonstrates safety and efficacy in patients harbouring HIV with the
M184V mutation and >3 TAM. Abstract 488, 14th CROI 2007, Los Angeles.
Cihlar T, Laflamme G, Fisher R, et al. Novel nucleotide human immunodeficiency virus reverse transcriptase
inhibitor GS-9148 with a low nephrotoxic potential: characterization of renal transport and accumulation.
Antimicrob Agents Chemother 2009, 53:150-6.
Cihlar T, Ray AS, Boojamra CG, et al. Design and profiling of GS-9148, a novel nucleotide analog active against
nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phospho-
noamidate prodrug, GS-9131. Antimicrob Agents Chemother 2008;52:655-65.
DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine phase II 48-week interim results show safety and effi-
cacy profiles similar to lamivudine in treatment-naive HIV-1 infected patients with a unique pharmacokinetic
profile. Abstract H-892, 48th ICAAC 2008, 2008.
DeJesus E, Saple D, Morales-Ramirez J, et al. Elvucitabine vs lamivudine with tenofovir and efavirenz in anti-
retroviral-treatment-naïve HIV-1 infected patients: 96-week final results. Abstract 511, 17th CROI 2010, San
Francisco.
Diamond TL, Ngo W, Xu M, et al. Islatravir Has a High Barrier to Resistance and Exhibits a Differentiated Resistance
Profile from Approved Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Antimicrob Agents Chemother 2022,
66:e0013322.
Dunkle LM, Gathe JC, Pedevillano DE, et al. Elvucitabine: potent antiviral activity demonstrated in multidrug-
resistant HIV infection. Antiviral Therapy 2003, 8:S5.
Fabrycki J, Zhoa Y, Wearne J, et al. In vitro induction of HIV variants with reduced susceptibility to elvucitabine
(ACH-126,443,beta-L-Fd4C). Antiviral Therapy 2003, 8:S8.
Gaffney MM, Belliveau PP, Spooner LM. Apricitabine: a nucleoside reverse transcriptase inhibitor for HIV infec-
tion. Ann Pharmacother 2009, 43:1676-83
Girard PM, Pegram PS, Diquet B, et al. Phase II placebo-controlled trial of fozivudine tidoxil for HIV infection:
pharmacokinetics, tolerability, and efficacy. J AIDS 2000, 23:227-35.
Gupta SK, McComsey GA, Lombaard J, et al. Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse
transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial. Lancet
HIV 2016, 3:e13-22.
Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R. KP-1212/1461, a nucleoside designed for the treatment of
HIV by viral mutagenesis. Antiviral Res 2005, 67:1-9.
Herzmann C, Arasteh K, Murphy RL, et al. Safety, pharmacokinetics, and efficacy of (+/-)-beta-2’,3’-dideoxy-
5-fluoro-3’-thiacytidine with efavirenz and stavudine in antiretroviral-naive HIV-infected patients. Antimicrob
Agents Chemother 2005, 49:2828-33.
Hurwitz SJ, Otto MJ, Schinazi RF. Comparative pharmacokinetics of Racivir, (+/-)-beta-2’,3’-dideoxy-5-fluoro-3’-
thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans. Antivir Chem Chemother 2005, 16:117-27.
100 ART

Ibanescu RI, Oliveira M, Spira B, et al. Favourable outcome of in vitro selections with novel prodrug GS-9131.
Abstract 482, CROI 2019, Seattle.
Kravtchenko AV, Salamov GG, Serebrovskaya LV, et al. The first experience of HAART with phosphazid + didano-
sine + nevirapine in HIV-infected patients in Russia. Abstract 3, 5th Int Conf Drug Therapy 2000, Glasgow, Scotland.
Kroidl A, Ello F, Mgaya J, et al. Virological efficacy of 24-week fozivudine-based regimen in ART-naive patients
from Tanzania and Côte d’Ivoire. AIDS 2017, 31:501-509.
Lanier ER, Ptak RG, Lampert BM, et al. Development of hexadecyloxypropyl tenofovir (CMX157) for treatment
of infection caused by wild-type and nucleoside/nucleotide-resistant HIV. Antimicrob Agents Chemother 2010,
54:2901-9.
Locas C, Ching S, Damment S. Safety profile of SPD754 in cynomolgus monkeys treated for 52 weeks, Abstract
527, 11th CROI 2004, San Francisco. [Link]
Machado J, Tsoukas C, Salomon H, et al. Antiviral activity and resistance profile of phosphazid – a novel prodrug
of AZT. Abstract 594, 6th CROI 1999, Chicago. [Link]
Markowitz M, Gettie A, St Bernard L, et al. Once-weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques
from Intrarectal SHIV109CP3 Challenge. J Infect Dis 2019 Jun 7.
Markowitz M, Grobler JA. Islatravir for the treatment and prevention of infection with the human immunodefi-
ciency virus type 1. Curr Opin HIV AIDS 2020, 15:27-32.
Michailidis E, Marchand B, Kodama EN, et al. Mechanism of inhibition of HIV-1 reverse transcriptase by
4’-Ethynyl-2-fluoro-2’-deoxyadenosine triphosphate, a translocation-defective reverse transcriptase inhibitor.
J Biol Chem 2009, 284:35681-91
Molina JM, Yazdanpanah Y, Afani Saud A, et al. Brief Report: Efficacy and Safety of Oral Islatravir Once Daily in
Combination With Doravirine Through 96 Weeks for Treatment-Naive Adults With HIV-1 Infection Receiving
Initial Treatment With Islatravir, Doravirine, and Lamivudine. J Acquir Immune Defic Syndr 2022, 91:68-72.
Molina JM, Yazdanpanah Y, Afani Saud A, et al. Islatravir in combination with doravirine for treatment-naive
adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b,
randomised, double-blind, dose-ranging trial. Lancet HIV 2021, 8:e324-e333.
Oliveira M, Brenner BG, Xu H, et al. M184I/V substitutions and E138K/M184I/V double substitutions in HIV
reverse transcriptase do not significantly affect the antiviral activity of EFdA. J Antimicrob Chemother 2017,
72:3008-3011.
Ray AS, Vela JE, Boojamra CG, et al. Intracellular metabolism of the nucleotide prodrug GS-9131, a potent anti-
human immunodeficiency virus agent. Antimicrob Agents Chemother 2008, 52:648-54.
Salie ZL, Kirby KA, Michailidis E, et al. Structural basis of HIV inhibition by translocation-defective RT inhibitor
4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA). PNAS 2016, 113: 9274-9.
Schürmann D, Rudd DJ, Zhang S, et al. Safety, pharmacokinetics, and antiretroviral activity of islatravir (ISL, MK-
8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to
treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel trial. Lancet HIV 2020
Jan 3.
Sitdykova YR, Serebrovskaya LV, Kravchenko AV. Immune reconstitution on treatment of HIV-infected patients
with phosphazid, didanosine and saquinavir/ritonavir once daily in Russia. Abstract 2.7/1. 9th EACS 2003, Warsaw,
Poland.
Skoblov Y, Karpenko I, Shirokova E, et al. Intracellular metabolism and pharmacokinetics of 5’-hydrogenphos-
phonate of 3’-azido-2’,3’-dideoxythymidine, a prodrug of 3’-azido-2’,3’-dideoxythymidine. Antiviral Res
2004;63:107-13.
Smith RA, Raugi DN, Wu VH, et al. The Nucleoside Analog BMS-986001 Shows Greater In Vitro Activity against
HIV-2 than against HIV-1. Antimicrob Agents Chemother 2015, 59:7437-46.
Tanwandee T, Chatsiricharoenkul S, Thongsawat S, et al. Pharmacokinetics, Safety and Tolerability of Tenofovir
exalidex (CMX157), a Novel Prodrug of Tenofovir, Administered as Ascending Multiple Doses to Healthy
Volunteers and HBV-Infected Subjects. Abstract PS040, EASL 2017, Amsterdam.
White KL, Margot M, Stray K, et al. GS-9131 is a novel NRTI with activity against NRTI-resistant HIV-1. Abstract
436, 24th CROI 2017.
5.3. ART 2024+: Beyond the horizon 101

New NNRTIs and PIs

There has been some progress in the development of NNRTIs recently (impressive
review: Zhuang 2020). With the approval of doravirine, an NNRTI entered the market
for the first time in years. However, given the massive use of INSTIs worldwide, the
overall share of NNRTIs and PIs is declining. There is hardly anything in sight for
PIs; the market seems to have remained saturated since the approval of darunavir
(Pokorná 2009).
AIC 292 is a new NNRTI that attracted attention at ICAAC in 2013 (Wildum 2013)
and is being developed by AiCuris from Wuppertal. It differs chemically from other
NNRTIs as diaryl pyrazole carboxamide and is effective against NNRTI resistances
such as K103N or Y181C. In Phase I, the compound was well tolerated up to 1,400 mg,
half-life is 20 hours. The decisive factor for further development will be whether one
of the major HIV players shows interest. Most recently, this was not the case. AiCuris
meanwhile concentrated on preparations against herpes viruses.
Elsulfavirine (Elpida®) is an NNRTI developed by Viriom in Russia and marketed
there or in other countries such as Ukraine (Al-Salama 2017). It is the prodrug of the
active compound VM-1500A with a long half-life of 8 days. In a phase IIb study, 118
people were randomized to 20 mg of elsulfavirine once daily in a double-blind fashion
against efavirenz; all received TDF+FTC. After 48 weeks, 81% versus 74% had achieved
viral loads below 400 copies/mL (Murphy 2017). Tolerability was good; in particu-
lar, there were few CNS side effects with elsulfavirine. This was sufficient for approval
by Russian health authorities. Numerous formulations are under investigation,
including fixed combinations and long-acting preparations.
GS-PI1 is a PI from Gilead Sciences still in preclinical stages with the potential for
unboosted once-daily administration. It appears to have a high resistance barrier,
and common PI mutations do not affect its efficacy (Link 2017). Perhaps Gilead is
finally finding interest in developing new PIs.
MK-8507 is being or has been developed as a new NNRTI by MSD with islatravir
(Kandala 2021). It probably also has efficacy against NNRTI-RAMs. In a phase I trial,
18 participants were treated. The mean 7-day reduction in HIV-1 RNA after a single
dose ranged from 1.2 to 1.5 log10 copies/mL (Schürmann 2022). One study was
stopped because of lymphopenia (see islatravir). Currently, the future is unclear.
RDEA806 is an NNRTI from Ardea Bioscience. The resistance barrier is reportedly
high, and the interaction potential is low (Hamatake 2007). Monotherapy studies
showed a drop of over 1.8 logs after seven days, with good tolerability (Moyle 2010).
The data are promising enough for further development. However, after the pur-
chase of Ardea by AstraZeneca, the new owner seems to have lost interest.
TMC-310911 is a PI from Tibotec. In vitro data look good (Dierynck 2012). Healthy
subjects tolerated the compound well; there was an excellent dose-PK relationship
(Hoetelmans 2014). In PLWH, viral load decreased by approximately 1.5 log levels
after 14 days of monotherapy (boosted with ritonavir) (Stellbrink 2014). It remains
to be seen whether this is sufficient for further development.

The great NNRTI and PI die-off – discontinued agents:

• AG-001859 – PI from Pfizer
• Atevirdine – NNRTI, Upjohn focused on delavirdine
• BIRL355 BS – NNRTI from Boehringer, in 2007 Problems with metabolites
• Brecanavir – PI stopped by GSK in late 2006 due to poor PK data
• Calanolide A – NNRTI from Sarawak, probably too weakly effective
• Capravirine (AG1549) – NNRTI from Pfizer, too weak
102 ART

• DPC 961 – NNRTI, subjects’ suicidal thoughts, DPC 963.

• Emivirine (MKC-442, Coactinon) – from Triangle, too weak (Me-too).
• Fosdevirine (GSK 761, formerly IDX-899), NNRTI of ViiV – seizures.
• HBY-097, NNRTI from Hoechst-Bayer, unfavorable side effects
• JE-2147 (AG1776, KNI-764) – PI from Pfizer, nothing new since 1999.
• KNI-272 (kynostatin) – PI, unfavorable PK data.
• Lersivirin, NNRTI of ViiV, nausea, no benefits (me-too).
• Loviride, NNRTI from Janssen Pharmaceuticals, too weak in CAESAR
• MIV-150, Medivir/Chiron, NNRTI, poorly bioavailable
• Mozenavir (DMP-450) – PI from Gilead, Me-too (no benefits apparent).
• PL-110 (MK8122) – PI from MSD, they are dedicated to other compounds
• PNU 142721, Pharmacia & Upjohn, NNRTI, Efavirenz too similar (Me-too).
• RO033-4649 – PI from Roche, probably too similar to saquinavir
• TMC 120 (dapivirine), NNRTI from Tibotec, poor oral availability.
Literature on new NNRTIs and PIs
Al-Salama ZT. Elsulfavirine: First Global Approval. Drugs 2017, 77:1811-1816.
Dierynck I, Van Marck H, Van Ginderen M, et al. TMC310911, a novel HIV type 1 protease inhibitor, shows in
vitro an improved resistance profile and higher genetic barrier to resistance compared with current protease
inhibitors. Antimicrob Agents Chemother 2011, 55:5723-31.
Hamatake R, Zhang Z, Xu W, et al. RDEA806, a potent NNRTI with a high genetic barrier to resistance. Abstract
1662, 47th ICAAC 2007, Chicago.
Hoetelmans RM, Dierynck I, Smyej I, et al. Safety and pharmacokinetics of the HIV-1 protease inhibitor TMC310911
coadministered with ritonavir in healthy participants: results from 2 phase 1 studies. JAIDS Acquir 2014, 65:299-305.
Kandala B, Fancourt C, Ananthula HK, et al. Model-informed dose selection for islatravir/MK-8507 oral once-
weekly phase 2b study. Poster 376, CROI 2021, 6–10 March 2021.
Link JO, Kato D, Moore M, et al. Novel HIV PI with high resistance barrier and potential for unboosted QD oral
dosing. Abstract LB433, CROI 2017, Seattle.
Margolis DA, Eron JJ, DeJesus E, White S, Wannamaker P, Stancil B, Johnson M. Unexpected finding of delayed-
onset seizures in HIV-positive, treatment-experienced subjects in the Phase IIb evaluation of fosdevirine
(GSK2248761). Antivir Ther. 2014;19(1):69-78.
Moyle G, Boffito M, Stoehr A, et al. Phase 2a randomized controlled trial of short-term activity, safety, and phar-
macokinetics of a novel nonnucleoside reverse transcriptase inhibitor, RDEA806, in HIV-1-positive, antiretrovi-
ral-naive subjects. Antimicrob Agents Chemother 2010, 54:3170-8.
Murphy RL, A.V. Kravchenko SV, Orlova-Morozova EA, et al. Elsulfavirine as compared to efavirenz in combina-
tion with TDF/FTC: 48-week study. Abstract 452LB, 24th CROI 2017, Seattle.
Pokorná J, Machala L, ezá ová P Konvalinka J. Current and Novel Inhibitors of HIV Protease. Viruses 2009, 1:1209-
1239. [Link]
Schürmann D, Jackson Rudd D, Schaeffer A, et al. Single Oral Doses of MK-8507, a Novel Non-Nucleoside Reverse
Transcriptase Inhibitor, Suppress HIV-1 RNA for a Week. J Acquir Immune Defic Syndr 2022, 89:191-198.
Stellbrink HJ, Arasteh K, Schürmann D, et al. Antiviral activity, pharmacokinetics, and safety of the HIV-1 pro-
tease inhibitor TMC310911, coadministered with ritonavir, in treatment-naive HIV-1-infected patients. J Acquir
Immune Defic Syndr 2014, 65:283-9.
Wildum S, Paulsen D, Thede K, et al. In vitro and in vivo activities of AIC292, a novel HIV-1 nonnucleoside reverse
transcriptase inhibitor. Antimicrob Agents Chemother 2013, 57:5320-9.
Zhuang C, Pannecouque C, De Clercq E, Chen F. Development of non-nucleoside reverse transcriptase inhibitors
(NNRTIs): our past twenty years. Acta Pharm Sin B. 2020 Jun;10(6):961-978.
5.3. ART 2024+: Beyond the horizon 103

New integrase inhibitors

Integrase strand transfer inhibitors (INSTIs) have become one of the most essential
classes of HIV therapy, if not the most important. However, the efficacy of even
second-generation INSTIs is also limited by resistance and thus not infinite. There
has now been great progress in better understanding the resistance mechanisms
(Cook 2020, Passos 2020), hopefully leading to the development of even better INSTIs.
However, inhibition of strand transfer is not the only mechanism of action to inhibit
integrase. Integrase inhibitors that target other sites are also being developed.
ALLINIs (or LEDGINs, NCINIs) are integrase inhibitors that bind allosterically, i.e.,
not directly to the catalytically active site of the integrase, but to a conserved binding
pocket for a cellular cofactor, called LEDGF/p75 (human lens epithelium-derived
growth factor). This supports viral replication by binding the integrase to chromatin.
The principle was first described in 2010 (Christ 2010). Currently, there is no
consensus on what to call this new class, with some referring to LEDGINs, others to
ALLINIs (allosteric INIs), NCINIs (non-catalytic INIs), MINIs (multimerization INIs),
or INLAIs (integrase-LEDGF allosteric inhibitors). Currently, the term ALLINI seems
to be gaining acceptance.
The binding of HIV-1 integrase to viral RNA, a crucial step for forming infectious
viruses, is disrupted (Singh 2022). Non-infectious viruses are formed. Surprisingly,
another effect of LEDGINs is later than expected in the replication cycle and is more
similar to that of PIs or maturation inhibitors (Tsiang 2012, van Bel 2014, Gupta
2016). Thus, the effect is not only in the interaction between LEDGF/p75 and
integrase but additionally in a disruption of a not yet well-characterized function of
integrase during maturation and assembly of the nucleus, thus making itself “notice-
able” later in the replication cycle.
ALLINIs are still in preclinical studies but appear to be a promising new group of
integrase inhibitors. This is also illustrated by the extraordinary abundance of papers
published in recent months, where searching for suitable molecules is still on at full
speed (Review: Engelman 2019). All major HIV companies are engaged.
STP0404 is currently the most advanced ALLINI. There is no cross-resistance with
INSTIs (Maehigashi 2021). An initial study of 65 healthy volunteers showed good
tolerability, besides mostly mild headache and diarrhea (Meng 2022). Single daily
dosing is possible. According to the Korean manufacturer ST Pharm, a phase II trial
was planned in the US for the end of 2022.
GSK-1264 from ViiV Healthcare/GSK is also an allosteric inhibitor of integrase that
is still preclinical (Gupta 2014). Another compound is GSK-3839919 (Parcella 2022).
JTP-0157602 is also a potent agent well characterized preclinically (Ohata 2022).
MK-2048 was developed by MSD in 2009. It appears to have a different resistance
profile. However, in vitro data might be slightly worse than dolutegravir for specific
resistance mutations like R263K (Osman 2015). It also appears to have a short life
and is being tested in prevention as a vaginal ring, with phase I trials published in
2019 (Hoesley 2019, Liu 2019). New technologies are also being used (Tong 2022).
Stilbenavir – is a new INSTI that binds to the C-terminal domain of integrase and
thus is thought to have a different mechanism of action than the classic INSTIs.
Accordingly, there appears to be no cross-resistance, and the compound is still pre-
clinical (Aknin 2019).
Out of sight, out of mind: recently stopped integrase inhibitors
• BI-224436 – an ALLINI, stopped before Phase I
• BMS-707035, probably no advantage over raltegravir apparent
• GSK-364735 (GSK), liver toxicity in monkeys, stopped in Phase IIa in 2007
104 ART

• GS-9822, urothelial toxicity in monkeys

• L-870810 (MSD), liver toxicity in dogs
• MK-2048 (MSD), poor PK data
• S-1360 (Shionogi/GSK), probably too toxic, stopped in 2005
Literature on new integrase inhibitors
Aknin C, Smith EA, Marchand C, et al. Discovery of Novel Integrase Inhibitors Acting outside the Active Site
Through High-Throughput Screening. Molecules. 2019 Oct 12;24(20).
Amadori C, van der Velden YU, Bonnard D, et al. The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resist-
ance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus
immunoreactivity. Retrovirology 2017, 14:50.
Christ F, Voet A, Marchand A, et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase inter-
action and HIV replication. Nat Chem Biol 2010, 6:442–448.
Cook NJ, Li W, Berta D, et al. Structural basis of second-generation HIV integrase inhibitor action and viral resist-
ance. Science. 2020 Jan 30.
Engelman AN. Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition. J Biol
Chem 2019, 294:15137-57.
Gupta K, Brady T, Dyer BM, et al. Allosteric inhibition of human immunodeficiency virus integrase: late block
during viral replication and abnormal multimerization involving specific protein domains. J Biol Chem 2014,
289:20477-88.
Gupta K, Turkki V, Sherrill-Mix S, et al. Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase. PLoS
Biol 2016, 14:e1002584.
Hassounah SA, Alikhani A, Oliveira M, et al. Antiviral Activity of Bictegravir and Cabotegravir against Integrase
Inhibitor-Resistant SIVmac239 and HIV-1. Antimicrob Agents Chemother 2017, 61.
Hoesley CJ, Chen BA, Anderson PL, et al. Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc
(MK-4176)/MK-2048A Intravaginal Rings. Clin Infect Dis 2019, 68:1136-1143.
Liu AY, Zhang J, Anderson PL, et al. Phase 1 Pharmacokinetic Trial of 2 Intravaginal Rings Containing Different
Dose Strengths of Vicriviroc (MK-4176) and MK-2048. Clin Infect Dis 2019, 68:1129-1135.
Maehigashi T, Ahn S, Kim UI, et al. A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase
inhibitor targeting host LEDGF/p75-integrase interaction site. PLoS Pathog. 2021, 17, e1009671.
Ohata Y, Tomonaga M, Watanabe Y, et al. Antiviral Activity and Resistance Profile of the Novel HIV-1 Non-Catalytic
Site Integrase Inhibitor JTP-0157602. J Virol 2022, 96:e0184321.
Osman N, Mesplède T, Quashie PK, et al. Dolutegravir maintains a durable effect against HIV replication in tissue
culture even after drug washout. J Antimicrob Chemother 2015, 70:2810-5.
Parcella K, Wang T, Eastman K, et al. Discovery and Preclinical Profiling of GSK3839919, a Potent HIV-1 Allosteric
Integrase Inhibitor. ACS Med Chem Lett. 2022 May 9;13(6):972-980.
Passos DO, Li M, Jó wik IK, et al. Structural basis for strand transfer inhibitor binding to HIV intasomes. Science.
2020 Jan 30.
Singh PK, Li W, Bedwell G, et al. Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of
LEDGF/p75 and HDGFL2 Host Factors. Viruses 2022, 14, 1883.
Tong X, Patel SK, Li J, et al. Development and Evaluation of Nanoparticles-in-Film Technology to Achieve Extended
In Vivo Exposure of MK-2048 for HIV Prevention. Polymers (Basel). 2022, 14:1196.
Tsiang M, Jones GS, Niedziela-Majka A, et al. New class of HIV-1 integrase (IN) inhibitors with a dual mode of
action. J Biol Chem 2012; 287:21189–21203.
Van Bel N, van der Velden Y, Bonnard D, et al. The Allosteric HIV-1 Integrase Inhibitor BI-D Affects Virion
Maturation but Does Not Influence Packaging of a Functional RNA Genome. PLoS One 2014, 9:e103552
5.3. ART 2024+: Beyond the horizon 105

New entry inhibitors

Attachment inhibitors, coreceptor antagonists and fusion inhibitors are currently
grouped as entry inhibitors, although they are heterogeneous. Four entry inhibitors
are available: maraviroc, T-20, ibalizumab, and fostemsavir (see previous chapter).
With the new entry inhibitors, in combination with bNAbs (see below), fascinating
new possibilities could open up. On the other hand, much is still little more than
basic research – many of the compounds discussed below will disappear into obscu-
rity, and some already have done so.
Albuvirtide (Aikening®) is a fusion inhibitor with a half-life of 11–12 days (Chong
2012). Frontier Biotechnologies presented an interim analysis of a larger trial
(TALENT) in late 2016 in which 171 individuals with treatment failure on first-line
therapy received therapy consisting of weekly infusions of albuvirtide plus lopinavir/r
or standard lopinavir/r-based therapy with 2 NRTIs (Wu 2016). A full paper has since
appeared (Su 2022). After 48 weeks, more individuals with albuvirtide as second-line
therapy had achieved viral loads below 50 copies/mL (80% versus 66%). Although
numerous methodological problems were evident and data are sparse, China
approved albuvirtide for HIV in 2018. It is said that the approval will be extended
to other countries, and several studies are underway, including PrEP (Nie 2021), but
also in combination with bNAbs.
Cenicriviroc (TBR-652 or previously TAK-652) is an orally available CCR5/CCR2
antagonist sold first by Takeda to Tobira and then Allergan. Laboratory data showed
that multiple mutations in the V3 region (and in the env gene) must be present for
complete resistance. Oral bioavailability is good, and the half-life is 35–40 hours
(Martin 2012). Cenicriviroc also appears to have activity against CCR2, a receptor
on monocytes, dendritic, and memory T-cells. Nevertheless, there are no safety con-
cerns because of this activity. After ten days of monotherapy with different doses,
viral load decreased by a maximum of 1.5–1.8 log levels in 54 patients (Marier 2011).
In a phase II trial of 150 patients testing cenicriviroc as 100 mg and 200 mg against
efavirenz (all receiving TDF+FTC), 68% and 64%, respectively, were below
50 copies/mL after 48 weeks, compared with only 50% on efavirenz. However, viro-
logic treatment failure was more frequent under cenicriviroc. Tolerability was good
(Thompson 2016). However, with the overall somewhat unfavorable data on mar-
aviroc in recent years, it is unlikely that cenicriviroc will make it to market. It’s also
unclear what advantage it would have over maraviroc. The new owner, Allergan,
focuses on use in NASH, with moderate success (Ratziu 2020). Phase III trials are
ongoing. It is also being positioned against COVID-19 (Files 2022).
GSK3732394 (formerly BMS-986197), a “Combinectin”, is a new, long-acting com-
pound that inhibits HIV entry into the target cell by three different pathways.
Adnectins are small proteins that bind to gp41 and CD4, among others. Three
synergistically acting adnectins were bound to human serum albumin to stabilize
the compound. The effect could be comparable to classical ART. Favorable PK data
in the monkey model suggest that once-weekly subcutaneous injections may become
feasible (Krystal 2016). Like several other compounds, GSK3732394 was initially
developed by BMS and has since been sold to ViiV. Unfortunately, a phase 1, first-
time-in-human study on subcutaneous administrations showed unexpectedly low
levels in healthy volunteers. The study was terminated when it became clear that
the maximum planned doses would not achieve the desired therapeutic profile
(Krystal 2022). Other adnectins are being developed that bind primarily to N17, a
highly conserved site on gp41 that is not sterically accessible to antibodies (Wensel
2018). Future studies will expand on these findings to improve PK profiles for other
long-acting biologics designed as multivalent proteins.
106 ART

Leronlimab (formerly Pro-140) is a monoclonal antibody developed by Progenics

that targets human CCR5 receptors (Trkola 2001). Thus, it is not a chemokine
derivative like maraviroc, with which there even appears to be a synergistic effect
(Murga 2006). The resistance barrier is probably high (Jacobson 2010). Leronlimab
must be given parenterally. The normal function of CCR5 receptors should not be
disrupted. Under single intravenous doses ranging from 0.5 to 5.0 mg/kg, viral load
at the highest dose decreased by 1.83 log levels at nadir by day 10 (Jacobson 2008).
Weekly subcutaneous administration can also achieve comparable effects (Jacobsen
2010, Tenorio 2011). CytoDyn now owns the rights. In a long-term follow-up, viral
load remained suppressed for at least two years of maintenance therapy in some
patients with R5 viruses; participants injected themselves subcutaneously with the
antibody weekly (Dhody 2019). Tolerability has been good so far; IIb/III trials are
reportedly ongoing. Weekly or fortnightly injections are likely reasonable, at least
in patients with limited options. However, these patients often have X4-tropic
viruses, for which Leronlimab is ineffective. Therefore, there are also considerations
to use the substance as PrEP; animal studies were encouraging (Chang 2021). In
October 2022, however, CytoDyn announced that it had voluntarily withdrawn its
pending Biologics License Application. This decision was “based on various factors,
including systemic issues related to the quality of the data collection and monitor-
ing of the pivotal clinical trials by the clinical research organization contracted to
manage the trials, resulting in significant concerns with achieving a successful FDA
BLA approval”. Whatever this means. We’ll see.
Lipovurtide is a fusion inhibitor developed in China with broad activity against
HIV-1 (Lan 2021). Initial human injection studies are underway.
Mavorixafor (AMD 11070) is a CXCR4 antagonist from AnorMED. Theoretically,
blockade of the CXCR4 receptor is attractive because individuals with X4 viruses and
limited options could benefit. However, CXCR4 blockade in animal studies had far-
reaching consequences in angiogenesis, hematopoiesis, or brain development
(Review: Miao 2020). Healthy subjects tolerated AMD 070 well but often developed
leukocytosis (Stone 2004). Two pilot studies (Moyle 2007, Saag 2007) demonstrated
efficacy in the dual-tropic virus. After ten days of monotherapy, viral load decreased
by at least one log level in 7/15 individuals. However, development was temporarily
halted in 2007 due to liver toxicity. Binding to the X4 receptor is localized some-
what differently than that of the prodrug Plerixafor, giving hope that there is scope
in the development of new, more potent, and less toxic CXCR4 antagonists – with
AMD 11070 at least a start has been made and evidence of efficacy established. The
compound is currently under further investigation in oncology (Miao 2020).
Plerixafor (AMD3100, Mozobil®) is a CXCR4 antagonist (Miao 2020). Plerixafor is
now approved as a leukocyte growth factor in combination with G-CSF in certain
situations due to its side effects, leukocyte mobilization. As an antiretroviral agent,
plerixafor is too weak.
UB-421 is a new antibody from BioPharma that targets the CD4 receptor but at a
different domain than ibalizumab, namely the first. UB-421 was tested in phase II
in PLWH, whose plasma viremia was below 20 copies/mL (Wang 2019). After ART
interruption, 29 subjects received eight intravenous infusions of UB-421 at either
10 mg/kg per week or 25 mg/kg every two weeks. UB-421 maintained virologic sup-
pression in all for 8–16 weeks; however, 8 experienced passive blips below
400 copies/mL. One patient discontinued the study because of a rash. No severe
immunologic complications were observed, and CD4 T-cells remained stable – which
is noteworthy because UB-421 potentially competes with CD4 function. In August
5.3. ART 2024+: Beyond the horizon 107

2022, the FDA gave the green light for a phase II trial in patients with multidrug-
resistant viruses.
Vicriviroc (SCH-D) is an orally bioavailable CCR5 antagonist. Schering-Plough
halted development in July 2010 after analyzing two phase III trials (Gathe 2010).
Of 721 pre-treated patients who received vicriviroc or placebo to optimized therapy,
64% versus 62% were below 50 copies/mL at 48 weeks. Despite significant differ-
ences in those down to a maximum of two active drugs (70 versus 55%), the company
discontinued development. MSD has since taken up the compound and is testing it
as a PrEP option or vaginal ring under the name MK-4179 (Hoesley 2019, Liu 2019).
Virip blocks the entry of HIV-1 into the cell by interacting with the gp41 fusion
peptide. It is also known as an anchoring inhibitor. German researchers from Ulm
discovered the peptide in hemofiltrate, the fluid filtered from dialysis patients’ blood,
to replace it with an electrolyte solution. Virip is thus a “natural” entry inhibitor
whose antiretroviral activity could be significantly enhanced by slight modifications
or replacement of a few amino acids (Munch 2007). Several such Virip derivatives
are being explored, including Virip-576 and -353. Under continuous infusions of
Virip-576, viral load decreased by about one log level after ten days at the highest
dose (Forssmann 2010). Tolerability was good. However, resistance mechanisms have
been reported (González-Ortega 2011), resulting in a significant loss of fitness (Müller
2018). It seems possible that Virip will remain an academic anecdote.
Out of sight, out of mind: stopped entry inhibitors
• AMD 3100 (CXCR4A) from AnorMed, Cardiotoxicity
• Aplaviroc/GW873140/AK602 (CCR5A) from GSK, hepatotoxicity
• BMS-806, BMS-488043 (attachment inhibitor), poor pharmacokinetics
• FP-21399 (FI) from Lexigen or Merck, probably too weak
• Pro-542 (attachment inhibitor) from Progenics focuses on Pro-140
• SCH-C/Ancriviroc (CCR5A) from Schering-Plough, cardiac arrhythmias
• Sifuvirtide (FI) – from China, worse PK than Albuvirtide
• T-1249 and T-649 (FIs) from Roche/Trimeris, lack of likelihood of success
• TAK-779, TAK-220 (CCR5A) from Takeda, replaced by TAK-652
• TRI-1144, TRI-999 (FIs), probably too poor PK data

Literature on new entry inhibitors

Berkhout B, Eggink D, Sanders RW. Is there a future for antiviral fusion inhibitors? Curr Opin Virol 2012, 2:50-9.
Chang XL, Webb GM, Wu HL, et al. Antibody-based CCR5 blockade protects Macaques from mucosal SHIV trans-
mission. Nat Commun 2021, 12:3343.
Chong H, Yao X, Zhang C, et al. Biophysical Property and Broad Anti-HIV Activity of Albuvirtide, a
3-Maleimimidopropionic Acid-Modified Peptide Fusion Inhibitor. PLoS One 2012, 7:e32599.
Dhody K, Pourhassan N, Kazempour K, et al. PRO 140, a monoclonal antibody targeting CCR5, as a long-acting,
single-agent maintenance therapy for HIV-1 infection. HIV Clin Trials 2018, 19:85-93.
Files DC, Tacke F, O’Sullivan A, Dorr P, Ferguson WG, Powderly WG. Rationale of using the dual chemokine recep-
tor CCR2/CCR5 inhibitor cenicriviroc for the treatment of COVID-19. PLoS Pathog 2022, 18:e1010547.
Forssmann WG, The YH, Stoll M, et al. Short-term monotherapy in HIV-infected patients with a virus entry
inhibitor against the gp41 fusion peptide. Sci Transl Med 2010, 2:63re3.
Gathe J, R Diaz R, Fätkenheuer G, et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate
safety but not significantly superior efficacy over potent background regimens alone. Abstract 54LB, 17th CROI
2010, San Francisco.
Gonzalez E, Ballana E, Clotet B, Esté JA. Development of resistance to VIR-353 with cross-resistance to the natural
HIV-1 entry virus inhibitory peptide (VIRIP). AIDS 2011, 25:1557-83.
González-Ortega E, Ballana E, Badia R, Clotet B, Esté JA. Compensatory mutations rescue the virus replicative
capacity of VIRIP-resistant HIV-1. Antiviral Res 2011, 92:479-83.
Hoesley CJ, Chen BA, Anderson PL, et al. Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc
(MK-4176)/MK-2048A Intravaginal Rings. Clin Infect Dis 2019, 68:1136-1143.
Ingallinella P, Bianchi E, Ladwa NA, et al. Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor
dramatically increases its antiviral potency. Proc Natl Acad Sci U S A 2009 Mar 18.
108 ART

Jacobson J, Thompson M, Fischl M, et al. Phase 2a study of PRO 140 in HIV-infected adults. Abstract HG-1220,
49th ICAAC 2009, San Francisco.
Jacobson JM, Lalezari JP, Thompson MA, et al. Phase 2a study of the CCR5 monoclonal antibody PRO 140 admin-
istered intravenously to HIV-infected adults. Antimicrob Agents Chemother 2010, 54:4137-42.
Jacobson JM, Thompson MA, Lalezari JP, et al. Anti-HIV-1 activity of weekly or biweekly treatment with subcu-
taneous PRO 140, a CCR5 monoclonal antibody. J Infect Dis 2010, 201:1481-7.
Krystal M, Chabria S, Austin D, et al. A Phase 1 randomized study of GSK3732394, an investigational long-acting
biologic treatment regimen for HIV-1 infection. Antivir Ther 2022, 27:13596535221131164.
Krystal M, Wensel D, Sun YM, et al. HIV Combinectin BMS-986197: A long-acting inhibitor with multiple modes
of action. Abstract 97, 16th CROI 2016, Boston.
Lan Q, Pu J, Cai Y, et al. Lipopeptide-based pan-CoV fusion inhibitors potently inhibit HIV-1 infection. Microbes
Infect 2021, 23:104840.
Liu AY, Zhang J, Anderson PL, et al. Phase 1 Pharmacokinetic Trial of 2 Intravaginal Rings Containing Different
Dose Strengths of Vicriviroc (MK-4176) and MK-2048. Clin Infect Dis 2019, 68:1129-1135.
Marier JF, Trinh M, Pheng LH, Palleja SM, Martin DE. Pharmacokinetics and Pharmacodynamics of TBR-652, a
Novel CCR5 Antagonist, in HIV-1-Infected, Antiretroviral Treatment-Experienced and CCR5 Antagonist-Naïve
Patients. Antimicrob Agents Chemother 2011 Apr 12. [Epub ahead of print].
Martin D, Beliveau M, Marier JF, et al. Pharmacokinetics of Cenicriviroc following 100- or 200-mg Once-daily
Dosing with Open-label Emtricitabine/Tenofovir in HIV 1+ Subjects Enrolled in a Phase 2b Study. Abstract 600,
19th CROI 2012, Seattle.
Miao M, De Clercq E, Li G. Clinical significance of chemokine receptor antagonists. Expert Opin Drug Metab
Toxicol 2020, 16:11-30.
Moyle G, DeJesus E, Boffito M, et al. CXCR4 antagonism: proof of activity with AMD 11070. Abstract 511, 14th
CROI 2007, Los Angeles.
Müller JA, Glöckle A, Gawanbacht A, et al. Reduced Susceptibility to VIRIP-Based HIV-1 Entry Inhibitors Has a
High Genetic Barrier and Severe Fitness Costs. J Virol. 2018 Aug 16;92(17).
Munch J, Standker L, Adermann K, et al. Discovery and optimization of a natural HIV-1 entry inhibitor targeting
the gp41 fusion peptide. Cell 2007;129:263-75.
Murga JD, Franti M, Pevear DC, Maddon PJ, Olson WC. The potent antiviral synergy between monoclonal anti-
body and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. Antimicrob Agents
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5.3. ART 2024+: Beyond the horizon 109

Broadly neutralizing antibodies

FLOR IAN KLEI N, C H R ISTIAN HOFFMAN N

The so-called envelope proteins, or spikes, protrude from the envelope surrounding
HIV. These envelope glycoprotein complexes (Env for short) each consist of an outer
glycoprotein (gp120) and a transmembrane protein (gp41). Each envelope protein
contains three gp120/gp41 molecules, forming a trimeric structure. The HIV enve-
lope protein is directly visible to antibodies and thus forms a central target of the
human humoral immune response, hence of vaccine and antibody research. HIV
has developed a variety of very effective mechanisms for the envelope proteins or
spikes to evade the immune response (Klein 2010+2013). Given the high genetic
variance alone, this forms a moving target. In addition, only a relatively small number
of spikes are found on each virion, and their vulnerable, conserved regions are often
coated with many sugar molecules (glycan shield). Approximately 10–25% of PLWH
develop a neutralizing antibody response against various env regions sometime after
infection – rarely within the first year (Sather 2009, Stamatatos 2009, Mikell 2011).
This immune response is more commonly found in individuals exposed to high
levels of envelope protein as antigen, i.e., individuals with a plasma viral load over
a prolonged period (Doria-Rose 2010, Rusert 2016). Interestingly, it is not only the
individual immune system that favors development but also the virus itself: certain
viruses seem to induce a broader antibody response than others (Kouvos 2018).
The therapeutic potential was already looked into in the early 1990s; however, studies
showed a minimal effect (Trkola 2005) since the antibodies used were limited in their
activity. Research has been spurred in recent years by better techniques for cloning
human antibodies and the identification of so-called “elite neutralizers,” i.e., patients
who have a markedly good neutralizing antibody response against HIV in serum
(West 2014). Since about 2009, a plethora of new antibodies have been discovered
that are significantly more potent than first-generation antibodies and target mul-
tiple, vulnerable sites of env (Walker 2009, Wu 2010, Scheid 2011, Caskey 2019). The
latter include, most notably, the CD4 binding site, but also the loop-like and vari-
able regions in gp120 (“V-loops”) and various regions in the gp41 glycoprotein (see
Figure 3.1). Because they can recognize and render many HIV variants harmless,
these antibodies are called broadly neutralizing antibodies (bNAbs). In addition to
the activity against the free virus, antiviral effects of bNAbs against HIV-infected cells
have been observed, among others, by blocking the release of HIV (Duflo 2022).

Figure 3.1: The ENV glycoprotein and binding sites of broadly neutralizing antibodies.
110 ART

Although “broad” remains poorly defined, most bNAbs can neutralize approximately
60% to over 97% of circulating HIV isolates (Wu 2010, Scheid 2011, Klein 2013,
Schommers 2020). In 2015, encouraging antiretroviral effects were shown for the
first time in humans (Caskey 2015, Lynch 2015), further boosting development.
Many clinical trials have already been conducted, testing different bNAbs. In addi-
tion to studies for use in prevention, numerous bNAb studies are underway for HIV
therapy. Common approaches here are to achieve long-term viral control with a
combination of different bNAbs or to eliminate infected cells and reduce the viral
reservoir by combining them with ART and drugs for immune activation (current
reviews: Caskey 2019, Julg 2021, Gruell 2022). Meanwhile, major companies have
also become active in the field of HIV therapy. Here, we will briefly touch upon the
clinical experience of the major bNAbs. Given the rapid development in recent years,
only a snapshot (as of the beginning of 2023) can be given.

CD4 binding site

One group of bNAbs attacks the CD4 binding site, a protected area surrounded by
glycans. They are also abbreviated as “CD4bs bNAbs”. Many have broad and partic-
ularly potent activity and were the first new-generation bNAbs to be clinically tested.
VRC01 is one of the prototypes of this group. Healthy subjects tolerated various
doses well (Ledgerwood 2015). In 6/8 PLWH, viral load decreased by 1.1–1.8 logs,
although pre-existing resistance was detectable in two subjects (Lynch 2015).
Unfortunately, in two pilot studies, monotherapy showed little effect on viral
rebound during analytic therapy breaks despite drug levels still being present (Bar
2016). VRC01-resistant isolates were found during therapy breaks; they were pre-
existing and newly selected. Also, in a small, double-blind, randomized trial from
Thailand in men with acute HIV, VRC01 remained without effect on viral setpoint
during analytic therapy breaks (Crowell 2019). VRC01 has also been studied in two
large Phase II trials (HVTN 704 and HPTN 085) as transmission prophylaxis in indi-
viduals at high risk for HIV infection. Again, the expected protective effect did not
occur: among the 2,699 participants, 32 infections occurred in the low-dose group,
28 in the high-dose group, and 38 in the placebo group (Corey 2021). However, a
sub-analysis showed that infections with sensitive viral strains with an IC80 of less
than 1 µg per milliliter were effectively prevented by VRC01 (efficacy of approxi-
mately 75%). Thus, it can be inferred that passive immunization with highly potent
bNAbs may well be able to confer protection from HIV infection. However, the neu-
tralizing activity of VRC01 alone was insufficient to produce a significant effect across
the study population. Better bNAbs, preferably combined, would need to be used for
a successful outcome.
VRC07-523LS is about 5–8 times as potent as VRC01 and can neutralize up to 96%
of all HIV-1 variants tested (Rudicell 2014). In addition, the antibody has a muta-
tion in the Fc portion (LS mutation), resulting in a significantly longer half-life, about
33 days intravenously and about 29 days subcutaneously (Mahomed 2022). This
mutation is now incorporated in almost all other bNAbs. Single subcutaneous doses
of VRC01-523LS were also well tolerated in a Phase I study in healthy individuals
(Gaudinski 2019). In a small pilot study in viremic adults, VRC07-523 was shown to
have better antiviral activity than VRC01 (both had the LS mutation incorporated).
In 3/7 subjects, viral load dropped > 0.5 log under VRC01LS; under VRC07-523LS,
8/9 showed a drop of > 1.2 log (Chen 2019). A study by the IMPAACT pediatric
network recently presented PK data as PrEP in 22 HIV-exposed but uninfected infants
supporting three months of administration (Cunningham 2022).
Teropavimab (3BNC117 or GS-5423) also targets the binding site for human CD4.
A single infusion of 30 mg/kg reduced viral load by 0.8–2.5 logs, and viral load
5.3. ART 2024+: Beyond the horizon 111

remained partially reduced for 28 days (Caskey 2015). It is possible that adminis-
tration also enhances the HIV-specific immune response (Schoofs 2016). During
analytic therapy breaks, viral rebound took several weeks longer after 2–4 infusions
than in historical controls (Scheid 2016). In monkeys, administration during acute
infection resulted in durable control of SIV infection (Nishimura 2017). The immune
activation mediated by bNAbs (so-called ‘vaccinal effect’) of the autologous immune
response is currently under further investigation (Tipoe 2022). The cause could be
bNAb/HIV immune complexes, which lead to an additional amplification of the
immune response. Combination with romidepsin did not affect the latent reservoir
(Gruell 2022). Teropavimab is currently being tested mainly in combination with
other Gilead bNAbs, such as 10-1074 (see below).

V1/V2 and V3 Loop of gp120

Some bNAbs do not bind to the CD4 binding site but to the V1/V2 loop, a variable
glycan-containing region of gp120. These antibodies also interact with the glycan
shield, among others. Representatives are PGDM1400 and CAP256. Another criti-
cal target is at the base of the V3 loop and surrounding glycans. Representative agents
include zinlirvimab and PGT121. The bNAbs directed against the V-loops are partly
more potent but usually less broad (about 60–80%) than the antibodies directed
against the CD4bs (Gama 2018). Bispecific bNAbs that simultaneously bind multi-
ple epitopes on V1/V2 and V3 are already being investigated and thus maybe even
more broadly effective and potent (Davis-Gardner 2020).
Zinlirvimab (10-1074, GS-2872) binds to the stem of the V3 loop at the env protein.
In an initial monotherapy study, the highest dose reduced viral load by 1.5 logs
(Caskey 2017). However, viral load did not decrease in all individuals. Instead, on
monotherapy, resistance was selected in almost everyone. Resistance was much less
common when combined with 3BNC117 (Bar-On 2018, Mendoza 2019). This anti-
body is used by Gilead in various combinations (see below).
PGT121 is a monoclonal antibody isolated from an African “elite neutralizer” in
2011. Like 10-1074, PGT121 targets the base of the V3 loop. In a pilot study, viral
load decreased by 1.77 logs, with a median viral load reaching nadir after 8.5 days.
Two individuals with low baseline viral loads experienced ART-free viral suppression
for more than 168 days (Stephenson 2021). Long-acting versions such as
PGT121,414LS are being tested in combination with other bNAbs or drugs.
Elipovimab (GS-9722) is a further development of PGT121 and is designed to be
particularly effective in targeting and eliminating HIV-infected cells, thereby reduc-
ing the reservoir (Thomsen 2019). It is currently in Phase Ib. Manufacturer Gilead
Sciences plans to study GS-9722 in combination with other bNAbs and other
immunomodulatory agents.

Regions of gp41
MPER stands for “membrane proximal external region”, a binding site on the gp41
transmembrane protein. bNAbs have now also been isolated for this site and for
another glycan-rich region on gp41 that arises shortly before fusion and is located
at the junction between gp120 and gp41 (Falkowska 2014). PGT151 targets this
“gp120/gp41 interphase”.
10E8 binds to the conserved region in MPER of gp41, neutralizing more than 95%
of all HIV-1 variants, making it the bNAb with the broadest activity ever (Huang
2012, Kwon 2016). However, subcutaneous application was associated with skin reac-
tions at the injection site, including grade 3 erythema associated with fever and
feeling sick. This led to a halt to ongoing studies (Caskey 2019).
112 ART

Prediction, pre-existing resistances

Many HIV isolates may be resistant to bNAbs or develop mutations relatively quickly.
How well and with what methods can possible resistance or the development of
resistance be predicted? Numerous studies are addressing these questions. Genotypic
analysis of the env gene is a relatively simple method for a possible prediction. For
some antibodies, e.g., V3-loop bNAbs like zinlirvimab or PGT121, there is a very
good correlation to the actual (phenotypic) susceptibility. This is more difficult for
other antibodies like CD4bs bNAbs (Moldt 2021, Pabus 2022). Also, the escape
dynamics of HIV-1 during antibody treatment can now be robustly predicted (Meijers
2021).
In a rather large study from the UK, 48% of 147 individuals were found to be resist-
ant to one or both of the bNAbs tested, with 29% resistant to zinlirvimab and 13%
resistant to teropavimab. A total of 3.4% were resistant to both bNAbs. Phylogenetic
analyses revealed evidence of both transmitted resistance and evolution in the host
(Zacharopoulou 2022). In another study, 41/54 (76%) were sensitive to teropavimab,
37/54 (69%) to zinlirvimab and 30/54 (56%) to both bNAbs (Montaner 2022).

Combinations of bNAbs, new approaches

Given the development of resistance to individual bNAbs, combinations are increas-
ingly being tested. In animal models, this has prevented resistance (Klein 2012). In
addition, combinations of two to four bNAbs can neutralize up to 100% of the viruses
in a panel (Kong 2015). Combining multiple attachment sites on a single molecule
has also become possible with newer technologies. In monkey models, such bi- or
tri-specific antibodies are highly protective (Gautam 2016, Xu 2017). Human studies
with the tri-specific antibody SAR441236 are currently underway. A synergistic effect
of some bNAbs also appears to exist when combined with the attachment inhibitor
fostemsavir, a small molecule that also binds to gp120, approved in 2021. Thus,
bNAb-resistant isolates remain sensitive to fostemsavir and vice versa (Zhang 2019).
Teropavimab (3BNC117) plus zinlirvimab (10-1074, GS-2872) shows good toler-
ability and antiviral activity and is already more commonly used (Cohen 2019, Gruell
2022). In a Phase 1b study, PLWH were given both antibodies at a dose of 30 mg/kg
each at weeks 0, 3, and 6. The nine subjects with sensitive virus maintained
suppression without classical ART for a median of 21 weeks (in some cases
significantly longer). Viral rebound was detected only when antibodies fell below
their therapeutic levels. As long as the drug levels were sufficiently high, resistant
viruses did not develop (Mendoza 2018). Global licensing rights for both bNAbs were
purchased by Gilead Sciences in 2020. In a recently published study, virologic
suppression could be maintained for at least 20 weeks without ART in 13/17
individuals with seven administrations of the bNAb combination (Gaebler 2022). In
two subjects, viral suppression persisted for one year. There was also a positive effect
on the viral reservoir during bNAb administration (Gaebler 2022) and possibly on
the T cell response (Niessl 2020). In the monkey model, the combination was pro-
tective (Garber 2021). In another study in which both bNAbs were combined with
pegylated interferon, 10/14 remained below the detection limit after 26 weeks (Tebas
2022).
Long-acting preparations of the antibodies in which the Fc receptor was modified
are being studied (Lee 2022). Initial clinical data were presented at CROI 2022 (Caskey
2022). The modified bNAbs (with half-lives of approximately 62 and 80 days, respec-
tively) were infused into six untreated male PLWH. Two patients with baseline viral
loads below 10,000 copies/mL showed long-lasting viral suppression, while four
showed transient suppression. The combination is currently also being tested with
the long-acting capsid inhibitor lenacapavir.
5.3. ART 2024+: Beyond the horizon 113

VRC01-LS plus zinlirvimab (10-1074, GS-2872): The Tatelo study tested this
combination in infected infants as an alternative to daily oral ART (Shapiro 2022).
In this proof-of-concept study, viral load remained below 40 copies/mL in 11/28
children (44%) by week 24. However, in 14/28 children, the median viral load
increased again to > 400 copies/mL after four weeks.
VRC07-523LS plus PGDM1400 plus PGT121: What happens when three bNAbs are
combined? In a pilot study, five viremic adults received the CD4 binding site anti-
body VRC07-523LS and two V2/V3 loop-specific antibodies (Julg 2022). Viral load
decreased maximally by a mean of 2.04 log10 copies/mL; however, viral rebound
occurred in all participants within an average of 20 days after nadir. Rebound viruses
showed partial to complete resistance to PGDM1400 and PGT121 in vitro while main-
taining sensitivity to VRC07-523LS.
Is it possible to let patients produce the bNAbs themselves? Recently, a study was
presented in which the transfer of DNA encoding VRC07 was tested using a vector
(Casazza 2022). For this, an adeno-associated virus (AAV8) vector encoding both the
light and heavy chains of VRC07 was administered to eight adults living with HIV
(Casazza 2022). New approaches in which mRNA technologies are also used could
further advance this pathway (Naranayan 2022).
Broadly neutralizing antibodies could change antiretroviral therapy as we under-
stand it. The real potential is not yet foreseeable and is not limited to the treatment
of HIV infection. Essential roles in prevention and even functional cures are also
conceivable. The problems that have come to light – especially resistance and cost
– do not seem insoluble. If it were possible to administer such maintenance therapy
every 6–12 months with a short infusion (a few minutes), many people with HIV
would opt for it. Still, there are other hurdles to overcome. For example, greater
neutralizing efficacy and breadth are needed to avoid and overcome resistance. But
there is no doubt: this chapter will continue to grow in future issues.

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Stephenson KE, Julg B, Tan CS, et al. Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neu-
tralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial. Nat Med
2021, 27:1718-1724.
Sung JA, Pickeral J, Liu L, et al. Dual-affinity re-targeting proteins direct T cell-mediated cytolysis of latently HIV-
infected cells. J Clin Invest 2015, 125:4077-90.
Tebas P, Azzoni L, Papasavvas E, et al. BEAT2: PEG-IFN-α2B + 3BNC117 and 10-1074 keeps HIV at <20 c/µl during
26 week ATI. Abstract 352, CROI 2022.
Thomsen N, Balakrishnan M, Pace C, et al. GS-9722: First-in-Class, Effector-Enhanced, Broadly Neutralizing
Antibody for HIV Cure. Abstract 356, CROI 2019, Seattle.
Tipoe T, Fidler S, Frater J. An exploration of how broadly neutralizing antibodies might induce HIV remission:
the ‘vaccinal’ effect. Curr Opin HIV AIDS 2022, 17:162-170.
Trkola A, Kuster H, Rusert P, et al. Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive
transfer of human neutralizing antibodies. Nat Med 2005, 11:615-22.
Walker LM, Phogat SK, Chan-Hui PY, et al. Broad and potent neutralizing antibodies from an African donor reveal
a new HIV-1 vaccine target. Science 2009, 326:285-9.
West AP Jr, Scharf L, Scheid JF, Klein F, Bjorkman PJ, Nussenzweig MC. Structural insights on the role of anti-
bodies in HIV-1 vaccine and therapy. Cell 2014, 156:633-48.
Wibmer CK, Moore PL, Morris L. HIV broadly neutralizing antibody targets. Curr Opin HIV AIDS 2015;10:135–143.
Wu X, Yang ZY, Li Y, et al. Rational design of envelope identifies broadly neutralizing human monoclonal anti-
bodies to HIV-1. Science 2010;329:856–861.
Xu L, Pegu A, Rao E, et al. Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in
macaques. Science 2017, 358: 85-90.
Zacharopoulou P, Nogueira L, Oliveira T, et al. Mutational landscape of 10-1074 and 3BNC117 sensitivity in a UK
population with PHI. Abstract 505, CROI 2022.
Zhang Y, Chapman JH, Ulcay A, Sutton RE. Neutralization Synergy between HIV-1 Attachment Inhibitor
Fostemsavir and Anti-CD4 Binding Site Broadly Neutralizing Antibodies against HIV. J Virol 2019, 93.
Zhou P, Wang H, Fang M. Broadly resistant HIV-1 against CD4-binding site neutralizing antibodies. PLoS Pathog.
2019, Jun 13;15(6):e1007819.
116 ART

Maturation inhibitors and other mechanisms of action

Maturation inhibitors (MIs) inhibit HIV replication at a later stage, namely when
new virions are budding. As with INSTIs, antiviral activity was first demonstrated
in vivo in 2005. MIs are, thus, undoubtedly an exciting class of compounds. With
the development of bevirimat, the pioneer compound, some problems have become
apparent, but they are probably surmountable (Review: Reguireo-Ren 2019).
Bevirimat (MPC 4326, formerly also PA-457) is a derivative of betulinic acid that
can be isolated from a plant-derived natural product. It inhibits the budding or mat-
uration of new virions (Li 2003), specifically, the conversion of the capsid precursor
protein p25 to the mature capsid protein p24, resulting in non-infectious viruses.
The long half-life allows once-daily oral administration (Smith 2007). To date,
bevirimat, tested in over 650 people, has been well tolerated. In an initial placebo-
controlled Phase IIa study (Beatty 2005), viral load decreased by a median of 1.03
logs after ten days at 200 mg. However, no effects on viral load were detectable in
some subjects, likely due to “natural” polymorphisms in the gag gene (Lu 2011).
Without polymorphisms, the effect was more than one log, with polymorphisms
only 0.2 log (Bloch 2009). With no gag polymorphisms, only about 50–70% of patients
appear to be without polymorphisms overall. PI resistance also affects efficacy
(Verheyen 2010, Fun 2011). Given these problems, Myriad declared in June 2010
that it would not pursue further development. Second-generation MIs are expected
to overcome the problem of gag polymorphisms (Urano 2019).
GSK-3532795 (formerly BMS-955176) is a second-generation MI that demonstrated
efficacy in 2015. In a Phase II study, viral load decreased by up to 1.64 log levels after
ten days of monotherapy, independent of most known gag polymorphisms and PI
resistance. However, after purchasing the BMS pipeline, ViiV decided to terminate
development in 2016, primarily due to rapid resistance (Morales-Ramirez 2018).
GSK-2838232 is another second-generation MI. In a Phase II trial, 33 PLWH received
different doses boosted with cobicistat. After ten days of monotherapy, the maximum
viral load was as high as 1.7 log levels; there was a nice dose-response relationship
(DeJesus 2019).
Fipravirimat (GSK-3640254, GSK-254) has been among the most promising
candidates and was the first after bevirimat to be given a proper name. Its effect
seems to be largely independent of gag polymorphisms. Phase II showed a decrease
of up to 2 logs and a dose-response relationship (Spinner 2022). Concurrent food
intake increases absorption (Johnson 2022). A larger Phase II trial (Dynamic) in
combination with dolutegravir has been fully enrolled since June 2022. However, it
currently seems that ViiV has decided not to progress. The move to cull fipravirimat
was made because the drug was “not differentiated enough in the daily oral HIV
market”. Meaning: not good enough.

Other mechanisms of action

Obefazimod (ABX464) is also a substance with a completely new mechanism of
action. It inhibits the activity of rev – this protein mediates, among other things, the
nuclear export of unspliced viral RNA into the cytoplasm. In a pilot study in Thailand,
the viral load fell by more than half a log in 4/6 patients after oral administration
of 150 mg for 12 days – not much, but still proof of concept. The substance has been
well tolerated so far (Steens 2017). In another small study conducted in Europe,
proviral DNA was reduced in some subjects (Rutsaert 2019). However, the company
currently seems to be focusing more on other indications, including rheumatoid
arthritis and ulcerative colitis, where it is already in Phase III (Vermeire 2022).
5.3. ART 2024+: Beyond the horizon 117

Literature on Maturation Inhibitors and Other Agents

Beatty G, Jacobson J, Lalezari J, et al. Safety and Antiviral Activity of PA-457, the First-In-Class Maturation Inhibitor,
in a 10-Day Monotherapy Study in HIV-1 Infected Patients. Abstract Abstract H-416D, 45th ICAAC 2005,
Washington.
Bloch M, Bodsworth N, Fidler M, et al. Efficacy, safety, and pharmacokinetics of MPC-4326 (bevirimat dimeglu-
mine) 200mg BID and 300mg BID monotherapy administered for 14 days in subjects with HIV-1 infection. Abstract
H-1230, 49th ICAAC 2009, San Francisco.
DeJesus E, Harward S, Jewell RC, et al. A Phase IIa Study Evaluating Safety, Pharmacokinetics, and Antiviral Activity
of GSK2838232, a Novel, Second-generation Maturation Inhibitor, in Participants With Human Immunodeficiency
Virus Type 1 Infection. Clin Infect Dis 2019 Nov 26.
Fun A, van Maarseveen NM, Pokorná J, et al. HIV-1 protease inhibitor mutations affect the development of HIV-1
resistance to the maturation inhibitor bevirimat. Retrovirology 2011, 8:70.
Johnson M, Pene Dumitrescu T, Joshi SR, et al. Relative Bioavailability and Food Effect of GSK3640254 Tablet and
Capsule Formulations in Healthy Participants. Clin Pharmacol Drug Dev 2022, 11:632-639.
Lalezari J, Richmond G, Thompson M, et al. Pharmacokinetics and safety of a novel 100 mg tablet formulation
of MPC-4326 in subjects with HIV-1 infection. Abstract H-1309/42, 49th ICAAC 2009, San Francisco.
Li F, Goila-Gaur R, Salzwedel K, et al. PA-457: a potent HIV inhibitor that disrupts core condensation by target-
ing a late step in Gag processing. Proc Natl Acad Sci U S A 2003, 100:13555-60.
Lu W, Salzwedel K, Wang D, Chakravarty S, Freed EO, Wild CT, Li F.A Single Polymorphism in HIV-1 Subtype C
SP1 is Sufficient to Confer Natural Resistance to the Maturation Inhibitor, Bevirimat. Antimicrob Agents
Chemother. 2011 Apr 18.
Martin DE, Galbraith H, Schettler J, Ellis C, Doto J. Pharmacokinetic properties and tolerability of bevirimat and
atazanavir in healthy volunteers: an open-label, parallel-group study. Clin Ther 2008, 30:1794-805.
Morales-Ramirez J, Bogner JR, Molina JM, et al. Safety, efficacy, and dose-response of the maturation inhibitor
GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive
HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial. PLoS One 2018, 13:e0205368.
Regueiro-Ren A, Dicker IB, Hanumegowda U, Meanwell NA. Second Generation Inhibitors of HIV-1 Maturation.
ACS Med Chem Lett 2019, 10:287-294.
Regueiro-Ren A, Sit SY, Chen Y, et al. The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1
Maturation. J Med Chem 2022, 65:11927-11948.
Rutsaert S, Steens JM, Gineste P, et al. Safety, tolerability and impact on viral reservoirs of the addition to anti-
retroviral therapy of ABX464, an investigational antiviral drug, in individuals living with HIV-1: a Phase IIa ran-
domised controlled study. J Virus Erad 2019, 5:10-22.
Smith PF, Ogundele A, Forrest A, et al. Phase I and II study of the safety, virologic effect, and PKs/pharmacody-
namics of single-dose 3-o-(3’,3’-dimethylsuccinyl)betulinic acid (bevirimat) against HIV infection. Antim Ag
Chemoth 2007;51:3574-81.
Spinner CD, Felizarta F, Rizzardini G, et al. Phase IIa Proof-of-Concept Evaluation of the Antiviral Efficacy, Safety,
Tolerability, and Pharmacokinetics of the Next-Generation Maturation Inhibitor GSK3640254. Clin Infect Dis
2022, 75:786-794.
Steens JM, Scherrer D, Gineste P, et al. Safety, Pharmacokinetics, and Antiviral Activity of a Novel HIV Antiviral,
ABX464, in Treatment-Naive HIV-Infected Subjects in a Phase 2 Randomized, Controlled Study. Antimicrob Agents
Chemother 2017 Jun 27;61(7).
Urano E, Timilsina U, Kaplan JA, et al. Resistance to Second-Generation HIV-1 Maturation Inhibitors. J Virol 2019, 93.
Verheyen J, Verhofstede C, Knops E, et al. High prevalence of bevirimat resistance mutations in protease inhibitor-
resistant HIV isolates. AIDS 2010, 24:669-73.
Vermeire S, Sands BE, Tilg H, et al. ABX464 (obefazimod) for moderate-to-severe, active ulcerative colitis: a phase
2b, double-blind, randomised, placebo-controlled induction trial and 48 week, open-label extension. Lancet
Gastroenterol Hepatol 2022, S2468-1253(22)00233-3.
118 ART

Immunomodulatory therapies
In addition to antiretroviral therapies, immunomodulatory therapy strategies are
also tested in HIV. Although they are repeatedly discussed as alternatives or supple-
ments, all therapies have failed to provide proof of clear clinical benefit. Nevertheless,
some approaches will be briefly outlined below in alphabetical order. Except for
checkpoint inhibitors, none of these are in active investigation.
Checkpoint inhibitors: To prevent excessive T cell responses, many cells, including
tumor cells, carry T cell inhibitory receptors such as PD-1 (programmed cell death
receptor 1). These receptors and their ligands are targeted by antibody-based thera-
peutics known as checkpoint inhibitors. CPIs are arguably one of the most exciting
drugs in oncology at present. Still, they could also play a role in HIV therapy because
it may be possible to reach latently infected cells via these checkpoints (review:
Gubser 2022). Because of the immunomodulatory properties of CPIs, people with
HIV were long excluded from trials. This is now changing. However, the immuno-
logical results were moderate in the first pilot study with the anti-PD-1 antibody
BMS-936559 (Gay 2017). Also, another study in 32 PLWH with various cancers treated
with the already approved CPIs, nivolumab, pembrolizumab, and cemiplimab
showed only minimal effects on the reservoir (Baron 2022). Data are still very limited,
and it is becoming apparent that combinations will likely be necessary (Gubser 2022).
Corticosteroids have been discussed repeatedly. Results from randomized trials have
not been encouraging (McComsey 2001, Wallis 2003). In a study of 236 patients, a
slightly increased CD4 T-cell count was matched by an approximately threefold
increase in viremia (Kasang 2016).
Cyclosporin A (Sandimmun®), otherwise used as prophylaxis for transplant rejection,
could inactivate the immune system and thus reduce the replication possibilities of
HIV. However, this did not work in clinical trials in chronically or acutely infected
individuals (Markovitz 2010).
G-CSF (granulocyte colony-stimulating factor) is approved, among other things, for
persistent neutropenia in advanced HIV infection to prevent bacterial infections.
In a randomized trial of 258 PLWH with CD4 T-cells below 200/µl, rates of severe
neutropenia and bacterial infections decreased (Kuritzkes 1998). There was no appar-
ent effect on HIV viral load. In CMV retinitis, G-CSF was even shown to have a sur-
vival benefit (Davidson 2002). Although severe neutropenia has become rare with
ART, G-CSF may be useful today, especially with chemotherapy, interferon, or other
myelosuppressive drugs such as valganciclovir.
GM-CSF (granulocyte-macrophage colony-stimulating factor) is available as
molgramostim (Leucomax®) or sargramostim (Prokine®). Three double-blind,
randomized studies showed a slight decrease in HIV viral load (Angel 2000, Skowron
1999, Brites 2000), but one study in uncontrolled infection showed a slight increase
(Jacobson 2003). It is not recommended outside of clinical trials – it is not approved
in Europe. Currently, some projects with vaccines are ongoing, as GM-CSF enhances
vaccine responses (Yu 2016).
Hydroxyurea (HU, Litalir®) is an old chemotherapeutic agent leading to an intra-
cellular deoxynucleoside triphosphate deficiency. After the case of the original
“Berlin patient” who took HU in addition to indinavir+ddI during acute infection
and later remained off ART and had no plasma viremia (Lisziewicz 1999), HU came
into vogue temporarily – until several studies showed no effects except toxicity
(Swindells 2005). Even in a study on primary infection, the Berlin patient could not
be “reproduced” (Zala 2002).
5.3. ART 2024+: Beyond the horizon 119

Interferons have an antiretroviral effect, about 0.5–1 logs with pegylated interferon
(Asmuth 2010). In one study of 20 people who discontinued ART, 9 remained below
400 copies/mL at 12 weeks on pegylated interferon (Azzoni 2013). Given the side
effects, interferons are admittedly of more academic interest today. They may help
to eradicate latent reservoirs (Review: Bourke 2017).
Interleukin-2 (IL-2, Aldesleukin, Proleukin®) is a cytokine that stimulates prolif-
eration and cytokine production of T, B, and NK cells. This results in sustained CD4
and CD8 T-cell increases. Randomized trials such as ESPRIT and SILCAAT showed no
clinical benefit (Abrams 2009). Despite better CD4 T-cells, this did not lead to less
opportunistic infections. There was also no reduction in mortality. The effects of
IL-2 are laboratory cosmetics, nothing more.
Interleukin-7 plays a fundamental role in T cell homeostasis and influences CD4
T-cell formation and maturation. In Phase II studies, good CD4 T-cell increases were
observed with different subcutaneous doses (Thiébaut 2016). Whether this has a clinical
effect is doubtful after the experience with IL-2. This is also true for interleukin-12
(Jacobson 2002), IL-10 (Angel 2000) and IL-15 (Ahmad 2005).
Murabutide can induce anti-inflammatory cytokines and growth factors and enhance
the antiviral effects of cytokines such as IL-2 or interferon. In HIV, it has been used
as an immunomodulator, especially in France, but with moderate effect (Bahr 2003).
Mycophenolate (Cellcept®) inhibits inosine monophosphate (IMP) dehydrogenase
and is used to prevent acute transplant rejection and autoimmune diseases. Inhibition
of lymphocyte proliferation is thought to reduce target cells and thus inhibit HIV
replication. No effect was seen in randomized trials (Sankatsing 2004, Kaur 2006).
Remune®, as a prototype of a therapeutic vaccination, suffered shipwreck years ago.
This vaccine, which consists of a virus deprived of its envelope proteins (gp120) and
can induce an HIV immune response, does not seem to provide any clinical bene-
fits. A trial involving more than 2,500 patients was terminated prematurely in May
1999 for lack of effect (Kahn 2000).
THC (cannabinoids) do not affect the immune system, as a randomized study
showed (Bredt 2002). However, THC, which is degraded via the cytochrome p450
system, did not cause harm in terms of viral load and plasma levels (Abrams 2003).
THC might help in sensitive polyneuropathy – a small randomized trial showed pain-
relieving effects (Abrams 2007). It may also be useful in wasting syndrome (see AIDS).
Vitamins do nothing and may even harm. In a double-blind, randomized African
trial, 3,418 patients received a high-dose combination of vitamin B complex, vitamin
C, and E or standard doses in parallel with ART initiation. The trial was terminated
because there was no effect on clinical events, CD4 T-cells, viral load, BMI, or hemo-
globin. In addition, liver elevations were more common with high-dose vitamin
administration (Isanaka 2012). Other randomized studies showed immunological
benefits (Baum 2013, Guwatudde 2015).

Literature on immunotherapies
Abrams D, Lévy Y, Losso MH, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med 2009,
361:1548-59.
Abrams DI, Hilton JF, Leiser RJ, et al. Short-term effects of cannabinoids in patients with HIV-1 infection: a ran-
domized, placebo-controlled clinical trial. Ann Intern Med 2003; 139:258-66.
Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-
controlled trial. Neurology 2007; 68:515-21.
Ahmad A, Ahmad R, Iannello A, et al. IL-15 and HIV infection: lessons for immunotherapy and vaccination. Curr
HIV Res 2005, 3:261-70.
Angel JB, High K, Rhame F, et al. Phase III study of granulocyte-macrophage colony-stimulating factor in advanced
HIV disease: effect on infections, CD4 cell counts and HIV suppression. Leukine/HIV Study Group. AIDS 2000,
14:387-95.
120 ART

Angel JB, Jacobson MA, Skolnik PR, A multicenter, randomized, double-blind, placebo-controlled trial of recom-
binant human interleukin-10 in HIV-infected subjects. AIDS 2000; 14:2503-8.
Asmuth DM, Murphy RL, Rosenkranz SL, et al. Safety, tolerability, and mechanisms of antiretroviral activity of
pegylated interferon Alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial. J Infect Dis 2010,
201:1686-96.
Azzoni L, Foulkes AS, Papasavvas E, et al. Pegylated Interferon alfa-2a monotherapy results in suppression of HIV
type 1 replication and decreased cell-associated HIV DNA integration. J Infect Dis 2013, 207:213-22.
Bahr GM, De La Tribonniere X, et al. Clinical and immunological effects of a 6 week immunotherapy cycle with
murabutide in HIV-1 patients with unsuccessful long-term antiretroviral treatment. J Antimicrob Chemother
2003, 51:1377-88.
Baron M, Soulié C, Lavolé A, et al. Impact of Anti PD-1 Immunotherapy on HIV Reservoir and Anti-Viral Immune
Responses in People Living with HIV and Cancer. Cells. 2022, 11:1015.
Baum MK, Campa A, Lai S, et al. Effect of micronutrient supplementation on disease progression in asympto-
matic, antiretroviral-naive, HIV-infected adults in Botswana: a randomized clinical trial. JAMA 2013, 310:2154-63.
Bourke NM, Napoletano S, Bannan C, et al. Control of HIV infection by IFN-α: implications for latency and a
cure. Cell Mol Life Sci. 2017 Oct 7.
Bredt BM, Higuera-Alhino D, Shade SB, et al. Short-term effects of cannabinoids on immune phenotype and func-
tion in HIV-1-infected patients. J Clin Pharmacol 2002; 42:82S-89S.
Brites C, Gilbert MJ, Pedral-Sampaio D, et al. A randomized, placebo-controlled trial of granulocyte-macrophage
colony-stimulating factor and nucleoside analogue therapy in AIDS. J Infect Dis 2000, 182: 1531-5.
Davey RT JR, Murphy RL, Graziano FM, et al. Immunologic and virologic effects of subcutaneous interleukin 2
in combination with ART: A randomized controlled trial. JAMA 2000, 284: 183-9.
Davidson M, Min YI, Holbrook JT, et al. Use of filgrastim as adjuvant therapy in patients with AIDS-related CMV
retinitis. AIDS 2002, 16: 757-65.
Gay CL, Bosch RJ, Ritz J, et al. Clinical Trial of the Anti-PD-L1 Antibody BMS-936559 in HIV-1 Infected Participants
on Suppressive Antiretroviral Therapy. J Infect Dis 2017, 215:1725-1733.
Gubser C, Chiu C, Lewin SR, et al. Immune checkpoint blockade in HIV. EBioMedicine 2022, 76:103840
Guwatudde D, Wang M, Ezeamama AE, et al. The effect of standard-dose multivitamin supplementation on disease
progression in HIV-infected adults initiating HAART: a randomized double-blind placebo-controlled trial in
Uganda. BMC Infect Dis 2015, 15:348.
Isanaka S, Mugusi F, Hawkins C, et al. Effect of high-dose vs standard-dose multivitamin supplementation at the
initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial. JAMA
2012, 308:1535-44.
Jacobson JM, Lederman MM, Spritzler J, et al. GM CSF induces modest increases in plasma HIV type 1 RNA levels
and cd4+ lymphocyte counts in patients with uncontrolled HIV infection. J Infect Dis 2003; 188: 1804-14.
Jacobson MA, Spritzler J, Landay A, et al. A Phase I, placebo-controlled trial of multi-dose recombinant human
interleukin-12 in patients with HIV infection. AIDS 2002; 16:1147-54.
Kahn JO, Cherng DW, Mayer K, et al. Evaluation of HIV-1 immunogen, an immunologic modifier, administered
to patients infected with HIV having 300 to 549 x 10(6)/L CD4 cell counts: A randomized controlled trial. JAMA
2000, 284:2193-202.
Kasang C, Kalluvya S, Majinge C, et al. Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated
HIV Infection: A 2-Year Randomized, Double-Blind Placebo-Controlled Clinical Trial. PLoS One 2016, 11:e0146678.
Kaur R, Bedimo R, Kvanli MB, et al. A placebo-controlled pilot study of intensification of antiretroviral therapy
with mycophenolate mofetil. AIDS Res Ther 2006 May 26;3:16.
Kuritzkes DR, Parenti D, Ward DJ, et al. Filgrastim prevents severe neutropenia and reduces infective morbidity
in patients with advanced HIV infection: results of a randomized, multicenter, controlled trial. AIDS 1998, 12:65-74.
Lisziewicz J, Rosenberg E, Lieberman J, et al. Control of HIV despite the discontinuation of antiretroviral therapy.
NEJM 1999, 340:1683-4.
Markowitz M, Vaida F, Hare CB, Boden D, et al. The virologic and immunologic effects of cyclosporine as an
adjunct to antiretroviral therapy in patients treated during acute and early HIV-1 Infection. J Infect Dis 2010
Mar 17. [Epub ahead of print].
Marra A, Scognamiglio G, Peluso I, et al. Immune Checkpoint Inhibitors in Melanoma and HIV Infection. Open
AIDS J 2017, 11:91-100.
McComsey GA, Whalen CC, Mawhorter SD, et al. Placebo-controlled trial of prednisone in advanced HIV-1 infec-
tion. AIDS 2001;15:321-7.
Sankatsing SU, Jurriaans S, van Swieten P, et al. Highly active antiretroviral therapy with or without mycophe-
nolate mofetil in treatment-naive HIV-1 patients. AIDS 2004, 18:1925-31.
Skowron G, Stein D, Drusano G, et al. The safety and efficacy of granulocyte-macrophage colony-stimulating
factor (Sargramostim) added to indinavir- or ritonavir-based antiretroviral therapy: a randomized double-blind,
placebo-controlled trial. J Infect Dis 1999, 180:1064-71.
Swindells S, Cohen CJ, Berger DS, et al. Abacavir, efavirenz, didanosine, with or without hydroxyurea, in HIV-
infected adults failing initial nucleoside/protease inhibitor-containing regimens. BMC Infect Dis 2005, 5:23.
Thiébaut R, Jarne A, Routy JP, et al. Repeated Cycles of Recombinant Human Interleukin 7 in HIV-Infected Patients
With Low CD4 T-Cell Reconstitution on Antiretroviral Therapy: Results of 2 Phase II Multicenter Studies. Clin
Infect Dis 2016, 62:1178-85.
Wallis RS, Kalayjian R, Jacobson JM, et al. A Study of the immunology, virology, and safety of prednisone in HIV-1-
infected subjects with CD4 cell counts of 200 to 700 mm-3. J AIDS 2003; 32: 281-6.
Yu TW, Chueh HY, Tsai CC. Novel GM-CSF-based vaccines: One small step in GM-CSF gene optimization, one
giant leap for human vaccines. Hum Vaccin Immunother 2016, 12:3020-3028.
Zala C, Salomon H, Ochoa C, et al. Higher rate of toxicity with no increased efficacy when hydroxyurea is added
to a regimen of stavudine plus didanosine and nevirapine in primary HIV infection. J Acquir Immune Defic Syndr
2002, 29: 368-73.
5.4. Goals and principles of therapy 121

5.4. Goals and principles of therapy

Given the increasingly louder debate about potential cure strategies for HIV infection,
fueled by some exciting case reports in recent years (much has been put into
perspective again), this chapter will be divided into two parts. The first part deals
with the goals and principles of lifelong treatment. The second part will discuss the
treatment goal of “HIV cure” and the problems on the way there.

5.4.1. Lifelong treatment

C H R ISTIAN HOFFMAN N

With the currently available antiretroviral therapies, eradication of HIV (explained

in more detail in the second part below) has not yet been achieved. It also remains
questionable whether it will ever be achievable for many people with HIV. Right
now, this means that ART has to be taken for life. And lifelong can mean several
decades because there is much to suggest that – given an otherwise healthy lifestyle
– life expectancy for PLWH is now close to normal. This has become evident in indus-
trialized countries, even if there is still a difference of several years compared to the
general population, at least in specific sub-populations (Marcus 2016, Wandeler 2016,
Gueler 2017, Xia 2022). So, we will have to continue to deal with long-term treat-
ment (and its side effects) for decades. The most important goal remains to prolong
the lives of PLWH with as good health and a high quality of life as possible. A treat-
ment that only aims to improve laboratory values and ignores the physical and
mental well-being of the person with HIV is not good. Let’s treat people, not viral
load or CD4 T-cells.

Success and failure of lifelong treatment

Virologic, immunologic, and clinical criteria can evaluate treatment success and
failure. Although these are often strongly associated with each other, they should be
kept apart. The virological success or failure of therapy is usually the first seen. This
usually means a drop or lack of drop or even an increase in viral load. This is followed,
often with a bit of a delay, by immunological therapy success, measured by CD4 T-cells,
or immunological therapy failure. The clinical therapy failure, if any, usually becomes
visible much later – first, the values deteriorate, then the patient. The clinical success
of therapy in asymptomatic persons is often not perceived. There is little glory in
prevention – although the risk of opportunistic infections is reduced to half after
only three months of ART (Ledergerber 1999), the individual may not realize what
was avoided by therapy.

Virological treatment success and failure

Virological treatment success is usually understood as reducing viral load below the
detection limit (usually 50 copies/mL). This is based on early experience that the
faster and, above all, the lower the viral load falls, the more durable the effect of
therapy (Raboud 1998, Powderly 1999). The viral load decreases biphasically under
therapy. A very rapid drop during the first few weeks is followed by a more extended
phase in which plasma viremia decreases only gradually. A value below the detec-
tion limit should be reached after 2–4 months, depending on the therapy (see below).
This decline may take longer if the viral load is initially very high. A viral load above
the detection limit after six months, on the other hand, is almost always to be
considered a failure. The same applies to a viral load that is rising again, in which
case – after a short-term check – consideration should be given to what can be
improved about the therapy (absorption, resistance, compliance?).
122 ART

Figure 1: Viral load values in the first 250 days on ART. Gray: Values are from 10 patients who achieved
durable viral suppression. Black: 3 patients in whom resistance developed on first-line therapy.

Virological therapy failure can be recognized quite early. A check after four weeks is
helpful for psychological reasons (“the virus is going down nicely” is good motivation)
and indicates further success. If the viral load is not at least below 5,000 copies/mL
after four weeks, later treatment failure is likely (Maggiolo 2000). However, the pre-
dictive value of a single absolute measurement, especially at the beginning, remains
limited (Brima 2017). This is illustrated by the following figure, which compares
cases with and without the development of resistance.
ART regimens also have an impact on viral kinetics. Viral load decreases significantly
faster with INSTI-based regimens than others (Murray 2007, Cardozo 2017). In GS-
1490, comparing the two INSTIs, bictegravir, and dolutegravir, each combined with
TAF+FTC, more than 75% were already below the detection limit by week 4 (Sax
2017). In the DRIVE-FORWARD trial, a comparison of the NNRTI doravirine and the
PI darunavir/r, the rates were only 20%. Nevertheless, even in the latter study, more
than 80% ultimately achieved a viral load below the limit of detection, and by
week 16, the rate was approximately 75% (Molina 2018).
This observation has less to do with potency and more with the mode of action of
INSTIs. This implies that clinicians must be more worried about INSTI-based thera-
pies if the viral load is not below 50 copies/mL after two months.

Just above the detection limit: Low-Level Viremia

The cut-off point of 20 or 50 copies/mL as a criterion for success is somewhat arbi-
trary. It is based on the currently available viral load assays. Whether 60 copies/mL
is worse than 30 copies/mL and indicates a lower treatment success has not been
proven. In the case of a persistent low-level viremia (LLV) between 20 and 50 copies/mL,
the risk of virological failure seems not to be increased for at least one year
(Charpentier 2012). Other studies found an association between viral load and
subsequent virological failure, even at such low levels (Maggiolo 2012, Pugliese 2013,
Elvstam 2022).
LLV was considered predictive of subsequent virologic failure only when above
200 copies/mL (Navarro 2016). This value was also an essential cut-off in the Swiss
cohort. If there is a viral load of 21–400 copies/mL at least three times, the risk of
virologic failure increases above 200 copies/mL by up to 12% within one year. In
5.4. Goals and principles of therapy 123

contrast, no virological failure occurred in 26 cases with LLV at 21–49 copies/mL

(Boillat-Blanco 2015). These findings are supported by a Swedish study in which an
LLV between 200–999 over a 4.5-year period was associated with a threefold increased
risk of treatment failure, but an LLV of 51–199 copies/mL was not (Elvstam 2017).
With low values, measurement inaccuracies must always be taken into account, as
well as methodological problems (Mortier 2017). A viral load that has risen to low
values only once (“blip”) is often not relevant (see below) and should be distin-
guished from LLV. However, some studies suggest that resistance may already be
detectable in the case of LLV (Elvstam 2022). Replication, and thus the formation of
new resistance, may continue to occur even at such low levels of viral replication
(Gunthard 1998, Nettles 2004, Taiwo 2012). However, some studies do not back this
up (Vancoillie 2017). Whether immune activation and inflammatory parameters are
increased in LLV is also controversial. At least two studies found no unfavorable effect
from LLV (Eastburn 2011, Taiwo 2012), while one did (Reus 2013).
In summary, the lower the viremia, the less relevant it is; a critical limit may be
around 200 copies/mL. While a low LLV tends to imply no need for action, higher
levels should be evaluated for reasons for virological treatment failure. The most
critical risk factors are antiretroviral pre-treatment (existing resistance) and poor
adherence or sub-optimal drug levels. Resistance testing is often possible with a viral
load above 200 copies/mL. Drug level measurement (therapeutic drug monitoring,
TDM, see below) of PIs, INSTIs, or NNRTIs is also an option and should preferably
be unannounced.
Any LLV should be an opportunity to talk to the patient about potential problems
with ART. There is nothing wrong with going over the current treatment plan again.
Are medications being taken regularly, or is a dose sometimes skipped? Are intake
requirements (fasting or with food) being followed? What additional therapies (PPIs?)
are being taken that are not in the chart? All of this should be considered before
changing a therapy.
Even with all this said, morbidity and mortality can be significantly reduced even
when the virological success of therapy is not reduced below the limit of detection
(Grabar 2000, Deeks 2002). Many patients also remain immunologically stable for
a relatively long time despite insufficient viral suppression. In a cohort study
from Switzerland, CD4 T-cells did not drop as long as the viral load remained below
10,000 copies/mL or at least 1.5 logs below the individual setpoint (Lederberger 2004).
Even in intensively pre-treated patients, efforts should be made to reduce the viral
load below the detection limit, i.e., with new agents and/or drug classes. Below
50 copies/mL is desirable, and below 200 copies/mL is the minimum goal.

Blips – do they mean virological failure?

Viral blips are transient (and almost always low-level) increases in viral load – pro-
vided the viral load was below the detection limit of 50 copies/mL before and after
each blip. Therefore, identifying a blip takes at least three viral load measurements.
Blips should be distinguished from LLV. They are a common phenomenon under
ART and can be observed in up to 20–40% of cases (Sungkanuparph 2005). The more
often one looks, the more likely one is to find one. Biological or statistical
coincidences are quite possible, at least up to 200 copies/mL (Nettles 2005). Another
possibility, as with LLV, is measurement problems with samples left unprocessed for
too long. Plasma separation should occur by 24 hours, ideally by 8 hours. Otherwise,
viral loads above 400 copies/mL are frequently seen (Portman 2012).
Nevertheless, there is often uncertainty with blips. Is this a sign of treatment failure?
The data situation is not clear. While previous studies suggest that this is not the
case in the medium term (Sungkanuparph 2005, Dijkstra 2022), the risk of virologic
124 ART

failure in a recent European cohort with blips was lower than with LLV. Still, it
increased overall by about 1.7 (95% confidence interval 1.3–2.2) compared with indi-
viduals with constant viral suppression (Elvstam 2022). Little is known about the
causes of the blips. Probably many things play a role.
For example, whether there is an association with adherence is unclear. Some studies
found no association between adherence and blip frequency (Di Mascio 2003, Miller
2004), while others did (Podsadecki 2007). Immunological mechanisms may also
play a role. The earlier in the course of the infection treatment is given or the higher
the CD4 T-cells are at the beginning of therapy, the less frequently blips seem to
occur (Di Mascio 2003+2004, Sungkanuparph 2005). In our study of 853 successfully
treated patients with viral suppression and at least five years of ART experience, the
blip rate was high and strongly associated with baseline viral load, even after many
years of ART (Erdbeer 2014). In patients with a pre-treatment viremia of more than
100,000, 50,000–100,000, and less than 50,000 copies/mL, the proportions of people
with blips during the previous five years were 39.5%, 30.5%, and 21.8% (p=0.007),
respectively. The blip level was relatively low in most cases (68%) at 51–200
copies/mL. However, these findings indicate that blips are not always coincidental but
probably reflect the individual immunological situation.
Is there an association with specific antiretrovirals? In a large cohort (Sungkanuparph
2005), the blip rates were 34% with NNRTIs and 33% with PIs, occurring at the same
levels (median 140 and 144 copies/mL, respectively). In both groups, the risk of viro-
logic failure was approximately 8% at two years. An important finding was that blips
did not increase risk even with NNRTIs, which had been theorized, given the rapid
development of resistance to NNRTIs. These findings were since confirmed (Martinez
2005). However, a more recent study from the Netherlands indicated that blips are
less frequent on INSTIs than with other combinations. Among 1,661 PLWH,
compared with an NNRTI anchor, blip incidence was higher for PIs (incidence rate
ratio 1.37) and lower for INSTIs (0.64). Again, blips were associated with a higher
zenith viral load, higher test frequency, and shorter time since antiretroviral therapy
initiation (Dijkstra 2022).
Finally, other factors may be responsible for intermittent viremia. For example,
immune activation induced by other infections could increase the risk of blips simply
by releasing viruses from latently infected reservoirs (Jones 2007). In a large retro-
spective analysis, intercurrent infections were the cause of transient viremia in 26%
(Easterbrook 2002). Thus, during active syphilis, viral load can increase significantly,
and CD4 T-cells can drop (Buchacz 2004). The viral load can also rise temporarily
during vaccinations (Kolber 2002).
Overall, ART should not be changed even in case of repeated blips. However, high
blips (> 200–500 copies/mL) should be controlled cautiously.

How long does virological treatment success last?

Little is known about how long treatments remain effective. The belief that treat-
ment success is limited to only a few years is widespread. It originated during the
early years of ART. Many patients at the time were inadequately pre-treated with
mono- or dual-therapy and had thus developed extensive resistance. In such patients,
the effect of treatment was often limited, as even a single point mutation was often
enough to topple a whole regimen.
In the modern era, things are different. The risk of treatment failure has become
much lower. Even more, the risk of virologic failure decreases significantly over time.
This is confirmed by cohort studies in which virological therapy failure due to resist-
ance has become significantly less frequent in recent years.
5.4. Goals and principles of therapy 125

Viral resistance, especially multiple resistance mutations, now almost exclusively

affects individuals who have received antiretroviral treatment since the 1990s. This
may be illustrated by the Swiss cohort, in which 11,084 PLWH were analyzed.
At least one resistance mutation was found in almost 29%. The by far most relevant
risk factor was the time at which therapy was started. Of those with three-class resist-
ance (n=471), only 1.7% had started ART after 2006; for two-class resistance
(n=1,198), the figure was just 5.0%. Of the 14 individuals with four-class resistance,
none had started ART after 2006 (Scherrer 2016). In our evaluation of over
200 patients with resistance to at least three classes, virological suppression was still
90%. Thus, long-term virologic treatment failure is rarely due to resistance – lack of
adherence is likely to be the leading cause of lack of virologic control.
Overall, data and experience show that the viral load can remain below the detec-
tion limit for decades in most PLWH – provided that therapy does not have to be
interrupted. Resistance is by no means inevitable.
Antiretroviral therapy continues to improve, and clinicians are learning as well. In
the German ClinSurv cohort (n > 24,000), virologic treatment success (< 50 copies/mL)
among treatment-naïve individuals increased from 56.4% in 1999 to 94.1% in 2014
(Schmidt 2017). Thus, most PLWH consistently have a viral load below 50 copies/mL.
And it looks like it will stay that way.
However, treatment success must benefit everyone, not only those in therapy.
UNAIDS set a goal of “90-90-90” for 2020, meaning that at least 90% of all PLWH
would be diagnosed with HIV. Of these, at least 90% would receive antiretroviral
therapy, followed by 90% having a viral load below the detection limit. In December
2020, UNAIDS declared a new global target of “95-95-95” for 2025–2030. According
to a recent report, many countries have already achieved the “95-95-95” targets,
including Botswana, Rwanda, and Zimbabwe. Modeling studies showed that achiev-
ing the 2025 targets would reduce new annual infections by 83% (71% to 86% across
regions) and AIDS-related deaths by 78% (67% to 81% across regions) by 2025 com-
pared to 2010 (Glover 2021). However, there are many voices now calling for the
introduction of a fourth “90” or “95” – meaning that 90% or 95% of all PLWH should
have a good quality of life (Popping 2021).

Immunological therapy success and failure

The success of immunological therapy is understood as an increase in CD4 T-cells.
However, it is not defined more precisely; a systematic review found 14 different
definitions in 20 studies on this topic (Kelly 2016). Depending on the study, increases
of 50, 100, or 200/µl or increases to over 200, 500, or 750/µl are considered as immuno-
logical treatment success. Failure is usually described as a lack of increase or a decrease
in CD4 T-cells.
It is difficult to individually predict the immunologic success of therapy for patients
on ART, as it varies significantly from one person to another. As with the decrease
in viral load, the increase in CD4 T-cells also seems to have two phases. After a first,
usually rapid increase over the first three to four months, further increases are con-
siderably less pronounced. In EuroSIDA, the greatest mean increase in CD4 count of
100 cells/µl per year was seen in the year after starting ART. Significant, but lower,
increases, around 50 CD4 T-cells/µl per year, were seen even five years after starting
ART (Mocroft 2007). The COHERE group has published reference curves for the CD4
increase from nearly 30,000 patients. Median CD4 T-cells increase by 133/µl in the
first six months (strongly dependent on initial count) and by 38/µl in the following
six months (Bouteloup 2017).
The most critical factor predicting immune reconstitution is the CD4 T-cell count
before starting therapy (Bouteloup 2017). The lower the CD4 T-cells were, the less
126 ART

likely normalization becomes. In the Swiss cohort, of 2,235 individuals who started
ART in 1996–97, only 39% achieved CD4 T-cells above 500/µl (Kaufmann 2003). The
adverse effects of late ART initiation often remain apparent for a long time. For
example, about 25% of individuals who started ART with low CD4 T-cells still did
not normalize to 500/µl even after 7–10 years despite sustained and good viral
suppression (Kelley 2009, Lok 2010). It is unclear whether the immune system
continues to restore itself continuously after prolonged viral suppression or whether
a plateau is reached after three to seven years (Smith 2004, Mocroft 2007, Lok 2010).
In our experience, there may be both: people whose CD4 T-cells continue to rise
slowly even after five or six years, but also those whose CD4 T-cells stagnate at a
level after a relatively short time.
Immunological treatment success is not necessarily linked to maximal viral
suppression. Even with partial suppression, CD4 T-cells can recover (Kaufmann 1998,
Ledergerber 2004). The crucial factor seems to be that the viral load remains lower
than before therapy (Deeks 2002, Ledergerber 2004). Given the many factors that
can influence the regenerative capacity of the immune system (see below), it is usually
not beneficial to use CD4 T-cells as a decisive criterion for treatment success.
Virological success is better suited for this purpose. Once CD4 T-cells have normalized,
significant decline is rare as long as the viral load remains below the detection limit
(Phillips 2002). The likelihood of CD4 T-cell counts remaining above the relevant cut-
off of 200/µl is over 99% over four years in patients who have once reached 300/µl
and who then suppress their viral load to below 200 copies/mL (Gale 2013). Immuno-
logical therapy success does not need to be continually monitored if the immune
status is good. In the US, the quarterly measurement of CD4 T-cells is no longer manda-
tory for successfully treated patients. In other countries (such as Spain), it’s annual.

Discordant response
A discordant response occurs when the treatment goals – immunological and viro-
logical – are not achieved (Table 4.1). Thus, treatment may be successful virologi-
cally without showing immunological effects; despite undetectable viral load, CD4
T-cells bobble around (Grabar 2000, Moore 2005, Tan 2007). Conversely, ART can
produce substantial CD4 T-cell increases even though viral load remains detectable.
Even today, despite ever-improving therapies, discordant responses are still present
in about a quarter of all treatment-naïve patients. Particularly in those individuals
in whom therapy is successful virologically but not immunologically, it is often
unclear how to continue.
Mortality seems slightly higher in patients with discordant responses, but this is
probably not only due to AIDS (Gilson 2010, Kelly 2016). In a study of 835 patients
who had not reached 200 CD4 T-cells even after three years with viral suppression,
this was associated with a 2.6-fold increase in mortality (Engsig 2014).

Table 4.1: Treatment response in prospective cohort studies.

ART response Grabar 2000 Moore 2005 Tan 2008
n=2,236 n=1,527 n=404
Virological and immunological 48% 56% 71%
Discordant: Immunological only 19% 12% 16%
Discordant: virological only 17% 15% 9%
No therapeutic success 16% 17% 5%
The immunological response was defined as CD4 T-cell increase > 50/μl after six months (Grabar 2000)
or at least once during follow-up (Moore 2005, Tan 2007). Virologic response was defined as a viral
load < 1,000 (Grabar 2000), < 500 (Moore 2005), or < 50 copies/mL (Tan 2008).
5.4. Goals and principles of therapy 127

Another study found an increased risk of AIDS only in the first six months in those
patients with poor immunological response (Zoufaly 2011).
Different courses over time are shown in the following figure. The risk factors for a
lack of immunological success are mostly not heterogeneous (review: Aiuti 2006).
Low CD4 T-cells and a low viral load before therapy are only two factors (Kaufmann
2005, Moore 2005, Kelly 2009). Age also plays a role. In older patients, immuno-
logical success is often moderate. The immune system’s regenerative capacity
decreases with age, probably due to thymic degeneration (Lederman 2000, Grabar
2004, Engsig 2016). Several studies showed that the older the patients and the smaller
the thymus in CT, the more often immunological success fails (Goetz 2001, Piketty
2001, Teixeira 2001). Regulatory T cells also seem to play a role (Saison 2014).
Other causes may be concomitant immunosuppressive or myelosuppressive thera-
pies. We have seen people who remained below 50/µl for years despite suppressed
viral load. In Figure 2, it took about 15 years for the patient (in the upper left) to
reach 200/µl! Interestingly, a plateau still does not seem to have been reached here.
Sometimes, it may make sense to discontinue potentially myelosuppressive
prophylaxis such as cotrimoxazole. Autoimmune diseases (Crohn’s disease, lupus
erythematosus) or liver cirrhosis may also have a negative impact on immunologi-
cal success.
In addition, there is evidence that certain antiretroviral drugs are unfavorable. For
example, significant CD4 T-cell declines were observed in patients who switched to
nevirapine plus TDF+ddI (Negredo 2004), probably due to unfavorable interactions

Figure 2: CD4 T-cell trajectories in four patients with sustained viral suppression on ART. Absolute
CD4 T-cells/μl (primary axis left, dark), relative CD4 T-cells in % (secondary axis right, gray). Upper left,
poor (but still continuous?) immune reconstitution with initially very poor immune status (discordant
response). Top right moderate immune reconstitution with a plateau below 500 CD4 T-cells with a very
poor immune status initially. Below are two patients with very good immune reconstitution. At the
bottom right, however, there was a significant drop during a therapy break of only three months.
128 ART

between ddI and tenofovir. In two other studies, CD4 T-cells increased more signif-
icantly under ABC+3TC and TDF+FTC than AZT+3TC despite comparable virologic
success (DeJesus 2004, Pozniak 2006). In the Swiss cohort, individuals on AZT-
containing regimens had gained about 60 fewer CD4 T-cells after two years than
those without AZT (Huttner 2007). It is doubtful whether, apart from AZT, a therapy
change makes sense in case of poor immunological success. There are no differences
in the extent of immune reconstitution between NNRTIs and PIs; a switch remains
without effect (Torti 2011).
What about INSTIs? Data from the large RESPOND cohort show that better immune
reconstitution is observed with INSTIs (Neesgard 2020), and manufacturers always
like to emphasize a better immunological response with their drug (when seen!).
And yet, a clear trend, at least one that influences therapy selection, has not been
shown. Particularly with cohort analyses such as RESPOND, great caution is required,
as too many confounding variables are hard to factor out. PIs and NNRTIs are used
in different patients than INSTIs.
The same is valid with maraviroc. Early observations of particularly good CD4 T-cell
increases with maraviroc led to various randomized trials investigating additional
maraviroc administration. The results were consistently sobering. In ANRS 146
(OPTIMAL), a study of 409 late presenters with AIDS or low helper cells, this strategy
resulted in no immunologic, virologic, or clinical benefits (Lelievre 2017).
Overall, in the era of modern ART regimens, switching due to a lack of immune
reconstitution is not reasonable. Experiments with additional immunostimulants
such as St. John’s wort, which was popular in the past, or even interleukin-2 (see
above, Immunotherapies) should be avoided. It is individual factors that influence
immune reconstitution. It is not the therapy.

Practical considerations when dealing with viral load and CD4 T-cells
• The viral load is the most critical parameter for therapy monitoring – it can be
influenced directly!
• Stay with one measurement method (in the same laboratory) if possible – take
method-related fluctuations (up to half a log) into account!
• After one month of new or switched ART, virologic success should be reviewed.
• After 3–4 months (after six months in case of high viral load), the viral load must
be below 50 copies/mL during initial therapy – if not, look for the causes!
• The viral load decreases faster with INSTIs than with NNRTIs or PIs.
• Minor viral load increases (blips or LLV) up to 200 copies/mL usually have no
relevance.
• Values above this should be checked in the short term (after 4–6 weeks).
• The higher the age, the more likely a discordant immunological response (viral
load well suppressed, CD4 T-cells without relevant increase).
• In contrast to the viral load, the increase in CD4 T-cells, i.e., the immunological
success, can hardly be influenced – a change in ART in cases of insufficient CD4
response is useless.
• With good values, CD4 T-cells can be measured less frequently. The higher the
CD4 T-cells, the greater the fluctuations.

Clinical therapy success and failure

Clinical treatment success is dependent on virologic and immunologic therapeutic
success. In individual patients, clinical response is not always easy to assess. After
all, there is no way to show what might have occurred if treatment had not been
5.4. Goals and principles of therapy 129

started. As an asymptomatic patient cannot feel much better, it may be challenging

to find good arguments to continue treatment in the presence of side effects, which,
at least temporarily, may affect quality of life.
Clinical success is almost always evaluated via clinical endpoints (AIDS-defining
illnesses, death). However, improving ART in a person with considerable constitu-
tional symptoms should also be considered a clinical success. With regard to the risk
of disease progression, the immunologic response is at least as critical as the virologic
response. However, the extent of virologic success is of great significance. In the Swiss
Cohort, in those with a constantly undetectable viral load, the proportion of patients
who developed AIDS or died was 6.6% after 30 months. In contrast, this was 9% in
patients with viral rebound and up to 20% if the viral load was never suppressed to
undetectable levels (Ledergerber 1999). The importance of sustained virological treat-
ment success for clinical benefit has also been reported from other cohorts (Thiebaud
2000, Lohse 2006).

Table 4.2: Morbidity and mortality related to virological and immunological therapy success, respecti-
vely. See Table 4.1 for the definition—95% confidence interval in parentheses.
Grabar 2000 Piketty 2001 Moore 2005
Median CD4 T-cells at baseline 150 73 180–250
Treatment success:
Complete = Reference 1 1 1
Immunological only, RR 1.6 (1.0–2.5) 6.5 (1.2–35.8) 1.9 (1.1–3.0)
Virological only, RR 2.0 (1.3–3.1) 9.7 (1.6–58.4) 2.5 (1.5–4.0)
No therapeutic success, RR 3.4 (2.3–5.0) 51.0 (11.3–229.8) 3.5 (2.3–5.3)
RR = relative risk.
Clinical endpoints: Progression/death (Grabar 2000, Piketty 2001), death (Moore 2005).

However, even a reasonably effective therapy is still better than none. Even in viremic
patients, taking ART is still associated with a significant reduction in morbidity
(Mocroft 2012).
Clinical treatment failure is usually understood to mean that the patient develops
AIDS or even dies. A distinction must be made between clinical failure that results
from ART failure and clinical failure that results from simply starting ART too late.
This applies, for example, to immune reconstitution syndromes in which preexist-
ing, subclinical infections manifest in the first few weeks after initiating antiretro-
viral therapy (see AIDS). Therefore, an OI in the presence of rising CD4 T-cells does
not necessarily mean ART failure but rather that the immune system is simply resum-
ing its work. On the other hand, the case in which the patient develops severe side
effects or even dies is a treatment failure. Fortunately, this is very rarely the case.
Finally, other causes must also be taken into account.

Table 4.3: Causes of death among PLWH in France (Morlat 2014). For 2020/21, the analysis was
restricted to the Paris area (Sellier 2023).
2000 (n=964) 2005 (n=1,042) 2010 (n=728) 2020/21 (n=202)*
AIDS-defining diseases 47% 36% 25% 13%
Non-AIDS-defining tumors 11% 17% 22% 31%
Liver disease 13% 15% 11% 4%
Cardiovascular diseases 7% 8% 10% 12%
Suicide 4% 5% 3% 4%
* COVID-19 accounted for more than half of the mortality related to non-AIDS infections over the
period (14% of all cases with known causes of death).
130 ART

Many of the events today on ART are neither ART- nor AIDS-associated but hepatic
or cardiovascular. The following table shows the causes of death among deceased
PLWH from France from 2000 to 2010. More recently, an update was given for the
Paris area only (Sellier 2023). According to this data, less than one in four deaths is
AIDS-related. Other diseases, such as tumors or (mostly hepatitis-related) liver
diseases, are gaining importance.
As in the case of immunological treatment success, attempts are repeatedly made to
evaluate differences between agents or drug classes in the case of clinical success.
Given extremely low event rates, this is inevitably done using cohort studies.
Sometimes differences are found, as in a recent association of large cohorts from the
US and Europe, where higher mortality was observed under INSTI raltegravir than
under other agents. This has led to much speculation (Trickey 2022) but could ulti-
mately be because raltegravir is a drug with few side effects and interactions, which
is often used in the case of concurrent malignancies and is explicitly recommended
there. Overall, there is no clear evidence that there are class-specific differences with
regard to clinical treatment success.

What can be achieved?

We should not forget what has been and is being achieved via ART. The success is
self-evident; AIDS has become rare. Some diseases that occur only in the most severe
immunodeficiencies are practically non-existent today. CMV retinitis or MAC infec-
tions are now rare. Today, AIDS almost only affects people who have not received
antiretroviral treatment beforehand – because they did not know or did not want to
know about their infection. These so-called “late presenters” now account for many
AIDS cases (see below).
Table 4.4: Case study (woman, 41 years) showing what ART has made possible*.
CD4 T-cells/μl Viral load
Feb 95 AZT+ddC 23 (4%) NA
Nov 96 AIDS: toxoplasmosis, MAC, candida esophagitis 12 (1%) 815,000
Feb 97 d4T+3TC+SQV 35 (8%) 500
Jun 97 STOP ART due to polyneuropathy
Jul 97 AZT+3TC+IDV 17 (4%) 141,000
Mar 98 147 (22%) < 50
Mar 99 AZT+3TC+IDV/r+NVP 558 (24%) 100
Mar 00 942 (31%) < 50
Apr 05 AZT+3TC+LPV/r+NVP 744 (30%) 130
Jan 12 TDF+FTC+DRV/r 817 (32%) < 50
Nov 19 TDF+FTC+DRV/c (STR) 715 (27%) < 50
* Very good immune reconstitution despite severe immunodeficiency and several AIDS-defining disea-
ses. All prophylaxis (MAC, Toxo, PCP) has since been discontinued. Since 2019, the patient has been
taking a single-tablet regimen.

In ART-CC, a collaboration of several large cohorts, the average life expectancy of a

20-year-old person living with HIV increased from 36.1 to 49.4 years between 1996–
1999 and 2003–2005 (ART-CC 2008). There is little doubt now that the life expectancy
of an otherwise healthy PLWH is thus beginning to converge more and more with
that of the general population, as has been impressively demonstrated by a flood of
analyses from various regions of the world in recent years (review: Wandeler 2016).
A more recent analysis from ART-CC showed that for PLWH on ART and with high
CD4 T-cell counts who survived to 2015 or started ART after 2015, life expectancy
5.4. Goals and principles of therapy 131

was only a few years lower than that in the general population, irrespective of when
ART was started. However, life expectancy estimates were substantially lower for
people with low CD4 counts at the start of follow-up, emphasizing the continuing
importance of early diagnosis and sustained treatment of HIV (Trickey 2023).
Even today, there are certain groups for whom there is still a gap compared to the
general population. These are not only individuals with hepatitis co-infection or
active drug use but also black patients or those with low CD4 T-cells at ART initia-
tion. Comorbidities and alcohol use also worsen the prognosis. Late initiation of
therapy also has an unfavorable impact on life expectancy (Marcus 2016). One of
the most important negative factors is still often forgotten today: smoking! In a study
from Denmark, 2,921 PLWH (only non-IVDUs were included) were examined; this
was impressively shown – PLWH today lose more years of life through smoking than
HIV-related diseases (Helleberg 2013). There also continue to be marked regional
differences. For example, mortality remains significantly higher in North America
than Europe, likely due to a higher proportion of socially marginalized people
(Wandeler 2016).
However, prospective, controlled studies of the dramatically improved life expectancy
are rare. Only a few randomized studies have clinical endpoints (Hammer 1997,
Cameron 1998, Stellbrink 2000). Moreover, due to design, the successes in these trials
have been comparatively modest. In the ABT-247 trial, in which 1,090 clinically
advanced patients received either ritonavir juice or placebo on top of ongoing
therapy, the probability of AIDS and death after 29 weeks was 21.9% in the ritonavir
arm and 37.5% in the placebo arm – about half as high (Cameron 1998).

Table 4.5: Decline in mortality and morbidity in large cohorts.

Region Patients Mortality Morbidity
(n) (period) (/100 PY) (/100 PY)
Palella USA (1,255) <100 CD4 T-cells/μl 29.4 → 8.8 21.9 → 3.7*
1998 (1/94–6/97)
Mocroft Europe (7,331) All (94–98) k.A. 30.7 → 2.5
2000
Mocroft Europe (8,556) All (94–01) 15.6 → 2.7 n.a.
2002
D’Arminio Worldwide (12,574) The first 3 months versus n.a. 12.9 → 1.3
2005 3rd year after ART
[Link] 2010 Worldwide (33,308) All (99–07) 1.7 → 1.0 n.a.
May 2016 Worldwide (37,496) The first 6 months versus 3.3 → 1.4 n.a.
10 years after ART
initiation (96-01)
*MAC, PCP, CMV. Mortality/morbidity each per 100 PY = patient-years

Fortunately, the number of clinical endpoints that occur is now extremely low. As a
result, the duration of any contemporary study to prove the clinical benefit of one
combination over another would have to be extended over a long period.
Unrealistically large study populations are now required given the extremely low
probability of progression –rarely will such investigations be undertaken in the future
(Raffi 2001). Two of the few trials that could confirm the benefits of ART on clini-
cal endpoints were SMART (see chapter 5.11. on Treatment Interruption below) and
START (see next section).
132 ART

In the Swiss cohort, the effect of ART still increased with duration – after more than
two years of ART, the risk of progression was only 4% of the risk without ART (Sterne
2005). However, several large cohorts (over 20,000 patients) showed that, especially
in recent years, AIDS and death rates have not continued to decline – in both 1997
and 2003, the AIDS risk was about 6%. It is possible that, in many cases, ART is now
started too late. In recent years, for example, one in two had fewer than 200 CD4
T-cells at the start of therapy (May 2016). The effect of ART on the incidence of indi-
vidual AIDS cases is likely to be variable. Viral OIs show the most marked decline
but are less pronounced than fungal OIs (D’Arminio 2005).
At least as apparent as the effect on incidence is the effect of ART on its course.
Diseases such as cryptosporidiosis or PML can resolve heal without specific therapy,
and Kaposi’s sarcoma can disappear entirely without specific therapy. Prophylaxis
can usually be safely discontinued. These effects are discussed in more detail in the
corresponding chapters.

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136 ART

5.4.2. Therapeutic goal: HIV cure

GEORG B EH R ENS, C H R ISTIAN HOFFMAN N

The cure for people living with HIV remains the holy grail of HIV medicine. With
the introduction of the first ART combinations, it was calculated that 70 years of
therapy should lead to the viral eradication of all reservoirs. Thus, it is clear that we
must develop strategies beyond ART to drive HIV and the latently infected cells out
of the body. An international group of researchers defined the goals and strategies
for the next five years at the end of 2021 (Deeks 2021).
The case of the “Berlin patient” Timothy Brown, published in 2009, shows that it is
possible to eradicate HIV infection. Brown had acute myeloid leukemia, and there
was an indication for an allogeneic stem cell transplant (allo-SCT). One of the poten-
tial stem cell donors was homozygous for the delta 32 mutation in the CCR5 gene.
This otherwise harmless gene defect lacks an important co-receptor on the target
cells that HIV requires for entry. After two successful transplants using stem cells
from the donor, Brown, who had had a very high viral load before starting ART,
remained undetectable for many years, even without ART (Hütter 2009). The virus
could not be detected in the blood, lymph nodes, or intestinal mucosa (Yukl 2013).
Unfortunately, Brown died of leukemia in September 2020, 13 years after trans-
plantation. Other cases of successful remission after transplantation of homozygous
deficient stem cells have since been published (Gupta 2020, Jensen 2023), but the
observation periods are shorter. A cure (at least for 14 months) was also recently
reported with resistant stem cells from umbilical cord blood in one woman (Hsu
2023). These cases have provided essential insights on the way to a cure. Such
approaches are generally impractical, given the effort involved and especially the
considerable risks (Duarte 2015, Koelsch 2017). There is also an important case in
which an allo-SCT was unsuccessful (not able to eradicate HIV), indicating that, at
least in some cases, HIV that uses CCR5 receptors can persist and continue to spread
(Rubinstein 2023).

What is meant by “cure”?

Eradication of all replication-capable viruses would be the surest path to a cure. But
perhaps less is enough – we would already achieve a lot if the body could control
HIV without the aid of drugs – like other viral infections, i.e., herpes, where low
levels of virus persist throughout life. A distinction is therefore made today between
“Sterilizing Cure” and “Functional Cure” (note: the term “sterilizing” terminology
has been criticized for being potentially derogatory in its connotations to disinfec-
tion and eugenics).
A “functional” cure is achieved in so-called “Post Treatment Controllers”, which can
maintain viral replication at low or undetectable levels after stopping ART. At least
four strategies are currently being pursued or combined to achieve this. These are
(1) elimination of latently infected cells, (2) control of residual replication, (3)
enhancement of the HIV-specific immune response, and (4) attempts to make cells
resistant to HIV infection ultimately.
Some patients succeed at least in the “functional cure” without any therapy. These
so-called “elite controllers” (ECs) make up less than 1% of all PLWH. The CD4
T-cells remain normal for many years, and the viral load is, more impressively, below
the limit of detection (primarily constant) even without therapy. Responsible for this
are usually favorable HLA constellations (especially HLA B57*, B58*, and B27*) and/or
other gene variants like heterozygosity for the Δ32 deletion (see Basics). In particu-
lar, it is from those ECs who lack protective alleles and where control of HIV likely
5.4. Goals and principles of therapy 137

occurs via CD8 cytotoxic cells that future learning is needed to better understand
the immune system (Moyano 2021).
ECs are not a homogeneous group; attenuated viruses can also be the cause, although
rarely (review: Lopez-Galindez 2019). There are also at least two case reports in which
no intact provirus was found even with extremely sensitive methods – in both cases
of such “spontaneous cure”, interestingly, women were affected (Jiang 2020, Turk
2022). Using CRISPR/Cas9, a wealth of other potential genes or functional host factors
have now been discovered, which will help to understand individual variability in
HIV control better (Hiatt 2022).
Despite normal CD4 T-cells and an undetectable viral load, ECs exhibit differences
compared to healthy controls. There is evidence for increased systemic inflamma-
tion and immune activation. Compared with PLWH, who controlled their infection
with ART, ECs had a significantly increased risk of hospitalization even after adjust-
ment for demographics, primarily related to cardiovascular events (Crowell 2015).
However, one study found no increased risk of sub-clinical cardiovascular disease in
ECs (Brusca 2019).
In a prospective pilot study, 16 ECs received antiretroviral therapy (Hatano 2013).
Signs of T cell activation and dysfunction in the lymph node and intestinal mucosa
regressed after 24 weeks on ART, even in patients with an undetectable viral load
below 40 copies/mL before ART initiation. Thus, it is likely that even extremely low
residual replication can result in adverse effects or chronic immune stimulation. If
it can be assumed that residual replication is also present in “post-treatment con-
trollers,” the question arises whether such a functional cure is desirable. Apart from
the fact that no treatments need to be taken, is this equivalent to well-tolerated and
cost-effective ART?

Can (very) early ART lead to a cure?

In 2013, the case of the perinatal infected “Mississippi Baby” gained worldwide atten-
tion. This infant had been antiretrovirally treated only 31 hours after birth (Persaud
2013). The baseline viral load of 19,812 copies/mL fell to 265 copies/mL at day 19
and was undetectable for 18 months. The baby was then lost to the healthcare system
for six months. Unexpectedly, the viral suppression remained undetectable when
tested for HIV upon return. For more than two years, this girl had no signs of the
virus in her blood despite cessation of treatment. An ultrasensitive assay revealed 4
copies of HIV DNA/million PBMCs but no HIV-specific immune responses. Protective
HLA types, as seen in elite controllers, were not observed. The finding encouraged
scientists hoping to find a way to save children from a lifetime of ART. However, the
virus resurfaced in the patient 27 months after stopping ART (Ledford 2014). It
became apparent that the “post-treatment control” had only been transient. It
remains unclear what led to the abrupt rebound.
Meanwhile, similar pediatric cases have been published where viral rebound later
occurred within a few days after treatment interruption despite immediate ART after
birth, with only a few exceptions (Butler 2015, Frange 2016, Vieira 2019).
Before the Mississippi baby case, several PCT cases had been presented from France
(Sáez-Cirión 2013). In the so-called VISCONTI cohort (Viro-Immunological Sustained
CONtrol after Treatment Interruption), 14 PLWH who had received antiretroviral
treatment within 35–70 days of infection and for a median of 3 years showed no
viral load rebound during multi-year treatment interruptions, which lasted 7.5 years
(48 to 113 months). In all 14 people, the viral load was below 500 copies, and provi-
ral DNA remained detectable in PBMC. In no case were favorable genetic defects or
protective alleles detectable, and the patients had worse CD8 responses than “elite
controllers”. Further French and Thai studies suggested that early therapy could limit
138 ART

viral reservoirs (Hocqueloux 2013, Crowell 2016). In contrast, in other studies, the
effect on the reservoir remained independent of the Fiebig stage of acute HIV infec-
tion (Kroon 2018). Even when therapy was started very early (Fiebig 1), HIV RNA
increased again after ART was discontinued (Colby 2018). Overall, a clear statement
about the potential of a so-called PCT with immediate ART during acute infection
is impossible. The probability seems to be low. In an analysis of 14 studies, post-
treatment controllers (individuals who underwent treatment interruption with viral
loads ≤ 400 copies/mL at two-thirds or more of time points for ≥ 24 weeks) were
more frequently identified in those treated during early vs. chronic infection (13%
versus 4%). The durability of PCT was heterogeneous. Of post-treatment controllers,
55% maintained HIV control for two years, with approximately 20% maintaining
control for ≥ 5 years (Namazi 2018).
Similarly, SPARTAC, a large randomized trial in which 366 people with early HIV
infection (less than six months) received ART for 12–48 weeks or remained untreated,
showed a slight but only transient benefit in favor of earlier therapy (SPARTAC 2013,
Martin 2017). It also remains unclear, especially in acutely treated patients, whether
and how long control persists after treatment. Attempts are being made to predict
this based on the breadth of the CTL response (Conway 2015), but there is admittedly
no reliable predictor. Despite these uncertainties and the overall low probability of
achieving something like PTC with immediate ART and favorably influencing the
individual natural history of HIV infection, there is nevertheless much to be said for
immediate treatment in acute HIV infection. In times of well-tolerated regimens,
given the START study, which showed a clinical advantage in early therapy initiation
(see chapter 5.5. When to start with ART?) and reduced infectivity, there are barely
any strong arguments against immediate initiation.

A cure in chronically infected patients?

Acute HIV infection is rarely diagnosed. The main question is what can be achieved
in chronic infection. Several barriers to a cure in these patients must be overcome,
such as the intrinsic stability of the viral genome in latently infected CD4s and other
cells and persistent low-level replication in different compartments. It remains an
open question whether surrogate markers and methods can reliably measure the
latent reservoir (Crooks 2015, Massanella 2016, Wang 2018). Measuring proviral DNA
from lymphocytes by PCR is not sufficient – it leads to values that are significantly
(300-fold) higher than the quantifications of so-called viral outgrowth assays (VOA),
in which latently infected cells in culture are stimulated to produce HIV. This sug-
gests that many cells are infected with defective viruses. In addition, residual viremia
does not correlate with VOA, perhaps putting the importance of low viremia into
perspective. According to VOA studies, the frequency of latently infected cells in
antiretroviral-treated patients is approximately 1/106. Although many cells are
infected with defective viruses, researchers have been able to isolate intact viruses
from cells in 12% after maximal in vitro stimulation (Ho 2013). These non-induced
proviruses possessed unmethylated promoters and were integrated into active
transcription units. In short, we cannot rule out the possibility of these viruses being
activated in vivo. Thus, quantification of the viral reservoir is technically complex
(Bruner 2019). Interpretation of these methods for prospective use in clinical trials
will remain a major challenge. In the end, there will be no way around so-called
analytical antiretroviral therapy breaks to validate measurement methods of latent
reservoirs (Julg 2019). However, the timing of viral rebounds and the viral setpoint
are subject to numerous influences. In any case, it is good to start ART as early as
possible. In the START trial, starting therapy when there were more than 800 CD4
T-cells was associated with a smaller reservoir (Rasmussen 2022).
5.4. Goals and principles of therapy 139

The latent reservoirs

At this point, eradication of HIV, i.e., the removal of all viruses from the body, is
somewhat unrealistic. The main reason is that HIV-infected cells comprise a lifelong
reservoir. The reservoir consists of very heterogeneous cell populations, including
long-lived CD4-positive memory T cells and their progenitors, stem cells, macro-
phages, and others, whose stability is probably independent of residual viral repli-
cation (McManus 2018).
The reservoir is quickly established after infection. Moreover, viral transcription can
still be detected in them even after years of sufficient suppression (Finzi 1999, Furtado
1999, Sigal 2011, Einkauf 2022). This is especially true for cells in the blood; however,
replication also occurs in lymph nodes and the gastrointestinal tract, even when
nothing is detectable in the blood. Latently infected reservoirs persist even after
myeloablative chemotherapy and autologous stem cell transplantation (Cillo 2013,
Henrich 2014).
Theoretically, how long does it take until the last latently infected cells are removed?
In a study of 62 patients whose viral load had been successfully suppressed for seven
years on ART, the half-life was 44.2 months for the latently infected cell reservoir
(Siliciano 2003). The calculated time to eradication of these reservoirs was 73.4 years.
Even in those patients in whom not a single blip was measurable during at least
three years of stable ART and where an overall trend for somewhat faster decline was
observed, the eradication time was still 51.2 years. Even after almost nine years on
ART, the virus remains in resting CD4 memory cells, with minimal evolution. It is
possible that the latently infected cell reservoir is much larger than previously
thought (Dolgin 2013) and that the latently infected cells are particularly resistant
to immune challenge (Huang 2018). A recent calculation showed that even with
effective ART, a total of 108 cells with HIV DNA remain (Estes 2017), containing
replicable viruses. Controversy continues to surround whether residual replication
of HIV, in particular, keeps “filling” the reservoir or whether the homeostatic pro-
liferation of latently infected cells keeps the size of the reservoir from diminishing
(Hosmane 2017, Lee 2017, McManus 2018). It has become clear that the reservoir is
much more complex and dynamic than initially thought (Cho 2022).
Various strategies are being tested to combat the latent reservoir: the “shock (or kick)
and kill” strategy, in which cells are activated and subsequently eliminated, the reduc-
tion of the reservoir (by intensification or/and antibodies), the excision of HIV by
gene therapies, and “block and lock” approaches, in which latently infected cells are
prevented from activation. These approaches often read very promisingly in theory
but, in practice – at least so far – have not lived up to their claims.

Intensification studies
Several studies addressed whether viral load reduction can be accelerated by inten-
sive therapy or anything changes at all. Can the remaining viral replication and
latent reservoirs be further reduced? Does activation of the latently infected cells
make sense? Various strategies have been pursued, including additional administra-
tion of integrase and entry inhibitors and agents to help empty latent reservoirs.
These are briefly discussed below.

Mega-HAART, entry, and/or integrase inhibitors

In a study of patients with good viral suppression who still intensified their ART
with PIs or NNRTIs, ultrasensitive single-copy assays showed no further viral load
reduction (Dinoso 2009). The viral load level on ART depends less on the regimen
used than on the pre-therapeutic setpoint (Maldarelli 2007). This is also true for
maraviroc, which was evaluated as a potential immunomodulatory CCR5 antago-
140 ART

nist in a prospective study of 40 people with acute HIV infection. In any case, five-
drug ART with maraviroc and raltegravir remained without any advantage over
classical triple therapy regarding residual viremia, the extent of immune reconstitution,
or immune activation (Markowitz 2014). Several prospective studies in which the
INSTIs raltegravir or dolutegravir were added to ART showed neither an additional
antiviral effect nor an effect on proviral DNA with ultrasensitive viral load assays
(Buzon 2010, Chege 2012, Rasmussen 2018). It is not a question of how many ARVs.
However, some studies observed an increase in episomal DNA on raltegravir. This
DNA, also called “2-long terminal repeat (2-LTR) circular”, is formed when INSTIs
prevent DNA from being integrated into chromatin. The detection of this episomal
DNA (“2 LTR circles”) in some patients who added raltegravir to effective ART perhaps
means that active viral replication was inhibited in these cases (Buzon 2010, Llibre
2012, Hatano 2013). However, there are also studies where this phenomenon was
not found (Besson 2012, Rasmussen 2018).

“Shock and Kill”

According to the studies described above, it is highly doubtful that eradication will
be achievable with the current classes of active agents (Shen 2008). Intensification
or expansion has not had meaningful results. For this reason, the old “shock and
kill” strategy is currently being resumed, in which infected cells are activated and
then (hopefully) killed by the immune system (Zerbato 2019).
Valproic acid, an antiepileptic drug that is an inhibitor of histone deacetylases
(HDACs) and is thought to lead to flushing of HIV from resting T cells, showed
encouraging effects in a pilot study (Lehrman 2005). However, a more extensive
study showed no effects (Routy 2012). Romidepsin, which may be more effective, as
well as vorinostat (Fidler 2020), panobinostat, and other HDAC inhibitors (Edelstein
2009, Rasmussen 2013) are being studied but appear to lead to HIV reactivation in
only some cells (Winckelmann 2017). In particular, Romidepsin was expected to be
very effective after in vitro studies (Søgaard 2015). In clinical studies, the substance
has failed to provide proof (MacMahon 2021), even in combination with vaccines.
In a small pilot study, HIV DNA decreased by 40%, and in 8/17 cases, there was an
increase in viral load in the sense of a “washout” – but this did not affect the rebound
during a therapy break (Leth 2016). The same was true for the combination of
romidepsin and monoclonal antibodies (Gruell 2022). Other chemical classes
thought to activate latently infected cells include quinoline derivatives or disulfiram.
Likely, the “kill” part will also require activation of HIV-specific CTLs, perhaps with
therapeutic vaccines (review: Board 2021).
Immune checkpoint inhibitors, which are increasingly used in oncology and are very
effective in abrogating negative signals for T cells, could also play a role (review:
Gubser 2022). Combinations of different checkpoint inhibitors are probably necessary
(Baron 2022).
Approaches using broadly neutralizing antibodies (bNAbs) are also repeatedly pos-
tulated. Since 2009, many such antibodies have been discovered that target not only
the CD4 binding site, such as VRC01 but also other vulnerable sites of the env
glycoprotein of HIV (for an updated overview, see ART). Numerous clinical trials are
planned or underway, both as prevention and with a therapeutic goal, not only
complementary to ART but also with the potential to eliminate infected cells and
reduce the viral reservoir. In a few people, this approach does seem to be able to reduce
the reservoir, but larger controlled studies are lacking (Gaebler 2022). Intriguingly,
the still very new field of bifunctional antibodies (BITEs or DARTs) that bind not
only to HIV but also to CD3/CD8 could theoretically help empty the viral reservoir.
Pre-clinical studies have been published (Pegu 2015, Sung 2015, Ramadoss 2020).
5.4. Goals and principles of therapy 141

Gene therapy approaches are also being pursued, but CRISPR-based approaches have
not yet worked. These involve attempts to modify hematopoietic stem cells so they
no longer express CCR5, making them resistant to HIV infection and then prefer-
entially spreading after reinfusion into the donor (Tebas 2014, Xu 2019). It is also
likely to be challenging to remove latent reservoirs with “gene scissors”, in which
specific enzymes are introduced into host cells that seek out the viral genome in the
nucleus and selectively excise it from human DNA (Karpinski 2016). What works in
animal models (Hauber 2013) is being tested in humans.
Another innovation from oncology, CAR-T cell therapy, is also being discussed as a
possibility. This involves taking T cells from patients and genetically modifying them
outside the body so that they better recognize tumor cells when returned. Numerous
studies are underway on HIV (review: York 2022).
Other approaches
1. enzymatic excision of HIV from latently infected cells via “zinc finger nucleases”
or with CRISPR/Cas9 (Zhu 2015).
2. Artificially engineered T cell receptors to enhance the function of HIV-specific
lymphocytes (Sahu 2013, Yang 2014).
3. Vector-based vaccination to induce broadly neutralizing antibodies to HIV that
then suppress HIV even without ART (Horwitz 2013, Jardine 2015).

Safety
Many PLWH repeatedly ask about the chances of a cure and express their willing-
ness to participate in experimental studies. Especially given the still very present
stigmatization and discrimination, many are willing to take considerable risks. A
controversy has erupted over the question of what risks are acceptable and reason-
able today in times of almost normal life expectancy. There are increasing calls to
proceed with great caution; studies must ultimately withstand regulatory and ethical
scrutiny (Dubé 2020). Transplantation, checkpoint inhibitors, or CAR-T cells carry
significant risks. But even well-known drugs are not without dangers: in a small
study, the first two patients recently developed severe (fortunately reversible)
neurotoxicity from the combination of high-dose disulfiram and vorinostat; the
study was stopped (McMahon 2022). However, it is not only toxicities that need to
be considered; the analytic treatment interruption that usually follows curative trials
also poses risks, especially in the era of COVID-19 (Fidler 2021). The safety of PLWH
is paramount. Open communication about the risks is required; no unrealistic expec-
tations should be raised (Deeks 2021).

Conclusion
The cure is not around the corner. However, we may expect some people to be called
PTC or functionally cured in the next few years. Also, in the long run, only partic-
ular patients will be considered for cure strategies, i.e., those with well-preserved
immune systems (another reason to start ART as early as possible!). Latently infected
cells differ from non-infected cells only by a minuteness that is hardly detectable
with current means and cannot be specifically targeted. Washing out the reservoirs
or eliminating all infected memory cells has been either unsuccessful or too toxic.
The excision of the HIV genome from infected cells using special recombinases has
been successful in laboratory and animal models; however, clinical application is
still a long way off. This also applies to the CRISPR/Cas9 system, which is currently
the subject of much discussion. Given the immune system’s complexity, which is
only gradually beginning to be understood, a solution still seems a long way off.
142 ART

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5.5. When to start with ART? 145

5.5. When to start with ART?

C H R ISTIAN HOFFMAN N

The optimal time point to start ART has been debated for many years. Possible side
effects of antiretroviral agents had to be weighed against the potential risk of
evolution to AIDS without ART. CD4 T-cells and viral load were essential decision-
making tools. Finally, the results of the START study published in 2015 changed this.
What used to be “the most important question in HIV medicine” (Anthony Fauci)
has since become easy to answer – all PLWH, even those without symptoms, should
be offered ART regardless of CD4 T-cells or viral load. The European guidelines
still allow an exception for individuals with high and stable CD4 T-cells and a low
viral load of less than 1,000 copies/mL (EACS 2022). However, this is rarely seen.
Today, the main decisive factor is the patient’s willingness to start ART. Even today,
some persuasion is still necessary. There are still people with considerable reserva-
tions about antiretroviral therapy.

The risk of progression

It is pretty simple – the higher the viral load, the faster the CD4 T-cells decline
(COHERE 2014). The higher the viral load, the higher the risk of AIDS (Mellors 1997,
Lyles 2000). It may be helpful to know about the current AIDS risk if ART is not
started. Table 5.1 lists (selected) risks; the data are from over 3000 individuals in the
“pre-HAART era” (Phillips 2004). The range of risk of progression, calculated based
on age, CD4 T-cell count, and viral load, is high.

Table 5.1: Probability (%) of developing AIDS within six months without therapy, by age, viral load
level, and CD4 T-cells (data from the "pre-HAART era").
100 CD4/μl 200 CD4/μl 350 CD4/μl
35 years old
HIV-RNA 10,000 copies/mL 5.3 2.0 1.1
HIV-RNA 100,000 copies/mL 10.6 4.1 2.3
55 years old
HIV-RNA 10,000 copies/mL 10.7 4.6 1.8
HIV-RNA 100,000 copies/mL 20.5 9.2 3.6
From: Phillips A, CASCADE Collaboration. AIDS 2004, 18:51-8.

However, different risks remain even after ART initiation, as shown in Table 5.2 for
different age groups. Data for these calculations were generated from 12 cohorts in
Europe and North America in which over 20,000 individuals had started ART between
1995–2003 (May 2007).
It should be noted that the risks apply only to asymptomatic non-IVDU patients;
otherwise, the risks of progression may increase, in some cases, significantly. On the
other hand, given the data from the early days of ART, it is conceivable that the risks
are lower today, thanks to modern treatments. The fact that ART interruptions were
not considered could also lead to an overestimation of the risk of progression. Thus,
the risks are only rough guidelines but can aid any discussion. At the same time, we
don’t want to frighten patients or put them under pressure.
Nevertheless, it is still essential that all asymptomatic patients with good values are
monitored regularly – especially if they decide not to start ART. Data from the
COHERE database of 34,384 treatment-naïve individuals describe the course of
untreated HIV infection. The mean CD4 T-cell drop was 78 (95% confidence interval,
146 ART

Table 5.2: Probability (%) of AIDS or death in the year after starting ART (in parentheses: in the next
five years). The risk applies to non-IVDU patients without AIDS.
<25 25–49 50–99 100–199 200–350 >350
CD4/μl CD4/μl CD4/μl CD4/μl CD4/μl CD4/μl
16–29 years
VL<100,000 10 (19) 8 (17) 7 (16) 5 (11) 2 (7) 2 (6)
VL>100,000 12 (23) 10 (21) 9 (19) 6 (13) 3 (8) 2 (7)
30–39 years
VL<100,000 12 (22) 10 (19) 8 (18) 5 (12) 3 (8) 2 (6)
VL>100,000 14 (26) 12 (23) 10 (22) 6 (15) 3 (10) 2 (8)
40–49 years
VL<100,000 13 (25) 11 (22) 10 (20) 6 (14) 3 (9) 2 (7)
VL>100,000 16 (29) 13 (26) 12 (24) 7 (17) 4 (11) 3 (9)
>50 years
VL<100,000 16 (29) 13 (26) 12 (24) 7 (17) 4 (11) 3 (9)
VL>100,000 19 (35) 16 (31) 14 (29) 9 (21) 5 (13) 3 (11)
VL = viral load (HIV RNA copies/mL). From: [Link]

–80 to –76) cells/µl per year. It is closely associated with viral load. With every
additional log of viral load, 38 CD4 T-cells/µl per year are added (COHERE 2014).
No association exists with gender, ethnicity, drug use, or transmission route.
Incidentally, the viral load increased slightly over the years.
Interestingly, an unusual viral variant (the VB variant) was described in early 2022
and has been circulating in the Netherlands for years (Wymant 2022). CD4 T-cell
counts dropped twice as fast as expected in more than one hundred individuals. This
subtype B virus line, which emerged de novo at the turn of the millennium, has exten-
sive changes in the genome. According to the authors, these findings “emphasize
the importance of access to frequent testing for at-risk individuals and adherence to
recommendations for immediate treatment initiation for every PLWH”. No more,
no less.

Practical experiences, rapid start

Treatment practice has changed significantly in recent years. In Europe, the median
CD4 count at ART initiation was around 200/µl for many years, having been as high
as 270/µl in 1998 (May 2006). In recent years, an opposite trend has been seen; the
pendulum is swinging back – given the increasingly better, more tolerable drugs,
people are starting earlier. In the German PROPHET study, which enrolled nearly
450 treatment-naïve PLWH from almost 30 priority centers in 2014/15, median CD4
T-cells at therapy initiation were already slightly above 350/µl. In resource-poor coun-
tries, however, most patients have well below 200 CD4 T-cells/µl at therapy initiation
(Mugglin 2012). In Europe, male immigrants, in particular, start ART later (COHERE
2017).
In recent years, initiating ART as early as the day of HIV diagnosis has become a
strategy for increasing global interest in controlling the HIV epidemic and optimizing
the health of PLWH. No detrimental effects of rapid-start ART have been identified
in randomized controlled trials undertaken in low- or middle-income countries or
cohort studies performed in high-income countries (review Boyd 2019). However,
there is insufficient evidence for guidelines to recommend universal test-and-treat
strategies for all people, in all settings, on HIV diagnosis.
5.5. When to start with ART? 147

Before starting any ART, whether the person concerned is ready should be clarified.
Assessment for readiness is critical. Sometimes, the decision is made hastily, often
prematurely. The risk of AIDS is often low. Prescribing ART to a person with HIV at
the first presentation can be unwise. Clinicians should get a picture of the person’s
situation and learn about lifestyle and motives, why they went to the doctor, and
what is expected. It also often happens that patients harbor misconceptions. Not
everyone knows that ART has to be taken for life. A few weeks is not enough. This
is often difficult to convey to people from other cultures in particular. The question
of sexual partners is essential, and any wish for parenthood should also be discussed.
Is there a negative partner? The fact that ART offers the best protection for others
motivates many people more than anything else to start with ART (see TasP in chapter
Prevention). Treatment as prevention has been included in almost all guidelines.
If a vacation is imminent, it is possible to wait, provided the values are decent since
the success of the therapy and side effects cannot be monitored from afar. On the
other hand, patients sometimes give new reasons (job stress, exams, job change).
Many are afraid of AIDS, but often just as afraid of the therapy (“the pills are the
beginning of the end!”). This may lead to irrational and false expectations of ART
and its consequences – the beginning of a therapy does not mean that one will be
subjected to daily infusions and unable to work. Therefore, it should be made clear
to every person with HIV what ART means in daily routine, nothing more, nothing
less.
Defining individual thresholds from the beginning is also helpful, especially with
hesitant people. It is good to convey to many people that immediate ART is also a
strategic decision. Often, there are concerns about potential long-term toxicity. But
what is gained in terms of quality of life in waiting? The CD4 T-cell drop is between
50 and 100 cells/µl annually, even at an average viral load. What is saved in long-
term toxicities over the next twenty or thirty years by one, two, or three therapy-
free years? Will it still be relevant in 2040 or 2050, whether therapy started in 2023
or 2025? Probably not. This makes sense to many.

Practical tips for starting therapy

Below 500 CD4 T-cells/µl and in AIDS patients
• Start as soon as possible with ART. The lower the CD4 T-cells, the sooner!
• Assess readiness: Take time to get to know the person (why did they wait so long?),
examine, educate, and start prophylaxis if CD4 T-cells are very poor (< 200/µl).
• Address all fears and reservations about therapy.
• With > 200/µl, there is a little more time, but talk about timelines for decision-
making (vacation, etc.).
Above 500 CD4 T-cells/µl if the patient is hesitant
• Talk about ART early (and repeatedly), and explain administration (number of
tablets).
• Set thresholds for onset (according to older guidelines, e.g., at 350 CD4/µl).
• Don’t just evaluate absolute CD4 T-cells; look at other factors. Clinical progres-
sion? Rapid decline? Any co-infection? Age > 50? Malignancies? Pregnancy?
Starting ART is more important!
• Is there an HIV-negative partner? A hope for parenthood? Talk about the decreas-
ing infectivity on ART – this can be a good reason for many.
• Check on any clinical studies that may be interesting and/or relevant!
148 ART

Patients should be involved in the decision-making process. It may be useful to see

patients several times to prepare them for ART. Only two situations are an exception:
acute HIV infection (see Acute HIV Infection) and severe immunodeficiency (see
below). But even then, it is not a matter of one or two visits; therapy must be discussed
and chosen. Will the person come back at all? In these cases, we start with PCP
prophylaxis and use the first days for examinations (funduscopy! X-ray thorax,
sonography) and informational talks about maybe a clinical study. A picture of the
psychosocial situation should also be obtained. Needs regarding the number of pills
and their modalities should be addressed. ART is not started until these issues have
been clarified.

Asymptomatic patients below 500 CD4 T-cells/μl

For this group, all guidelines strongly recommend starting therapy. Even though the
overall risk of disease is relatively low, at least above 350 CD4 T-cells/µl, one should
not be complacent above these limits. We have seen patients who developed Kaposi’s
sarcoma, PML, or lymphoma at almost normal levels. In the START study, some AIDS
events occurred with high CD4 T-cells.
A look at the calculator described above (May 2007) gives a rough idea about the
individual risk. A 45-year-old, asymptomatic patient with 200–350 CD4 T-cells/µl, a
viral load below 100,000 copies/mL, and no drug use has a combined AIDS/death
risk after five years of ART initiation of 8.7%. With more than 350 CD4 T-cells/µl at
ART initiation, the risks decrease to 7.3%. If the patient is over 50 years old and the
viral load is over 100,000 copies/mL, the five-year risk is reduced from 13.1% to
11.0%. This “reduction” of 1–2% may seem marginal at first glance. And yet, in
today’s era of well-tolerated ART, such a risk of developing AIDS or death has become
relevant. The 1–2% has become avoidable and unnecessary.
Before START, essential data were provided by HTPN-052, a study of 1,763 HIV-
discordant couples in the US, Africa, and Asia. The HIV-positive partners had to be
antiretroviral naïve and have CD4 T-cells between 350 and 550/µl. They were
randomized to start ART immediately or only when CD4 T-cells fell below 250/µl or
at the onset of AIDS (Cohen 2011, Grinsztejn 2014). Although HIV transmission was
the primary endpoint, in an interim evaluation, severe illness, and death were
decreased in the immediate ART group (57 versus 77, p=0.07). The difference was
significant for AIDS cases (40 versus 61, p=0.03). However, this difference was
primarily caused by extrapulmonary tuberculosis (17 versus 34), which was also
mainly observed in India.

Asymptomatic patients over 500 CD4 T-cells/μl

The WHO or US guidelines always recommend starting ART even if the immune
status is normal (above 500 CD4 T-cells/µl in most cases). Some guidelines, however,
keep a backdoor open for those with low viremia. However, the following additional
criteria make the indication clearer even in those with no evidence of any immune
defect:
• Viral load above 100,000 copies/mL
• HCV or HBV coinfection
• Pregnancy
• Age over 50
• Framingham score above 20% within the next ten years
• Rapidly decreasing CD4 T-cell count
• Patient’s wish or need for reduction of infectivity
5.5. When to start with ART? 149

There appears to be a risk of AIDS or death closely related to CD4 T-cells, even above
500/µl. In a large British cohort of therapy-naïve individuals, the risk per 1,000
person-years was 24.9 at 350–499/µl, compared with 15.4 at 500–649/µl and 9.6 at
more than 650/µl. Nevertheless, there has long been an emotional debate about the
optimal initiation of therapy at normal immune status, even in the face of con-
flicting data from cohort studies. In contrast to a US study (Kitahata 2009), European
studies had shown no benefit of ART above 450–500/µl (Sterling 2003, Sterne 2009).

START Study
Rarely has a study had such an impact on HIV therapy. Since 2009, START, or Strategic
Timing of Antiretroviral Therapy, has followed 4,685 otherwise healthy PLWH with
more than 500 CD4 T-cells/µl in two strategy arms. One-half immediately began
ART, which was selected by the treating physician (regimens included TDF in 89%
and efavirenz in 62%), and the other half waited until CD4 T-cells fell below the pre-
viously accepted threshold of 350/µl. The primary clinical endpoint was defined as
not only all deaths and severe AIDS events (excluding herpes infections and thrush
esophagitis, but scoring Hodgkin’s lymphoma) but also non-AIDS events such as car-
diovascular disease, renal and hepatic decompensation, and cancer.
The results were surprising in their clarity: patients in the delayed therapy arm devel-
oped more AIDS and more serious non-AIDS-defining events; the hazard ratios in
favor of early ART were 0.28 and 0.61, respectively. Despite the low incidence rates,
the differences were so stark that the randomized phase was terminated early in May
2015 after only three years of observation. The Data Safety Monitoring Board found
that the original question of the study had been clearly answered in these three years
and recommended ART for all PLWH in the future.
Regardless of whether male or female, young or old, black or white – all participants
benefited from early ART. Interestingly, the benefit was seen even at very high CD4
T-cell counts and low viral loads (below 5,000 copies/mL). In a more recent sub-
analysis, however, the benefit did disappear at viral loads below 3,000 copies/mL.
These patients also had significantly higher CD4 T-cell counts (Sereti 2019).

Table 5.3: Clinical endpoints in START, each per 100 patient-years (INSIGHT 2015).
Immediate ART Delayed ART Hazard ratio (95% CI),
n=2,326 n=2,359 p-values
Primary endpoints (see text) 0.60 (n=42) 1.38 (n=96) 0.43 (0.30–0.62), p < 0.001
Serious AIDS events 0.20 (n=14) 0.72 (n=50) 0.28 (0.15–0.50), p < 0.001
Serious non-AIDS events 0.42 (n=29) 0.67 (n=47) 0.61 (0.38–0.97), p=0.04
Deaths 0.17 (n=12) 0.30 (n=21) 0.58 (0.28–1.17), p=0.13
CI, confidence interval.

AIDS events were rare but occurred in both arms, even those with very high CD4s.
Most events were lymphoma, Kaposi’s sarcoma, and tuberculosis (41/50 in the
delayed arm versus 10/14 in the immediate arm). 16/26 (62%) of the TB cases were
observed in Africa. Tumor diseases accounted for a relevant proportion of non-AIDS
events (18/47 versus 9/29). In total, 22/27 (81%) of these tumors were observed in
Australia, Europe, and the United States, as were 19/26 (73%) of the cardiovascular
diseases. However, these events did not differ between the two strategy arms, likely
due in part to the young age of the participants (36 years at baseline). Mortality
overall, as well as severe grade IV outcomes, were equally common in both arms.
150 ART

Given the impressive trial size, START holds a wealth of exciting data examining
early ART’s benefit in other aspects. Many sub-analyses are ongoing, and prelimi-
nary data showed a benefit in quality of life (Lifson 2017), bacterial infections, and
infection-associated tumors. No benefit was seen in other cancers or concerning
cardiovascular risk scores (Baker 2017) or neurocognitive testing. Some disadvantage
of immediate therapy was instead seen in increased bone density decline during the
first year of ART (Hoy 2017).
Initial sub-analyses suggest that the positive effect of ART may have been signifi-
cantly underestimated in the first publication (Sharma 2019). START was known to
have included many long-term stable patients, which implies selection (clinically
stable people without ART). A detailed analysis of the delayed arm showed that newly
infected patients (less than six months) had more clinical events than those infected
for more than two years. Longer follow-up of START also revealed that serious AIDS
and non-AIDS risks were diminished after ART initiation, but the persistent excess
risk remained evident even for years (Lundgren 2023).
In summary, the START data do not mean that every patient MUST receive ART
immediately. However, it is recommended to all since there is some clinical benefit
even with high CD4 T-cells, and one can now at least be sure not to do any harm.

Practical tips for untreated patients

• Are the CD4 T-cells falling, and if so, how fast? → Always note relative values
(percentages) and CD4/8 ratio; absolute values often fluctuate.
• How high is the viral load? Does the picture fit together? → at low viral loads
(< 1,000 copies/mL), “true” CD4 T-cell count drops are rather unusual.
• What kind of values does the affected person come from? → if the CD4 T-cells
were always 1,000 and have now dropped to 350, the immunodeficiency is prob-
ably more pronounced than in someone who comes from 450 CD4 T-cells.
• How ready is the person for ART, how well informed, and how adherent is she
or he? → the more negative and fearful the person is, the more time must be
allowed, and the better the start of therapy must be prepared in discussions.
• How old is the patient? The immunological regeneration capacity decreases with
age → the older the person, the earlier the onset.
• Are there any symptoms that have gone unnoticed so far → regular physical exam-
ination! OHL, oral thrush, mycoses, etc.?
• A drop of more than 50–100 CD4 T-cells/µl per year is too much! Do not wait
too long! Talk with the patient.

Late presenters: AIDS and/or below 350 CD4 T-cells/μl

Despite dramatically improved treatment options, many people present still late in
the course of their HIV infection. Although not yet clearly defined, the term “late
presenter” has also become established in many countries. In most cases, a CD4
T-cell count below 350/µl and/or manifest AIDS disease at HIV diagnosis is considered
a criterion (Antinori 2011). However, what “at HIV diagnosis” means varies in scope,
ranging from three months to three years. In addition, some studies distinguish
between “late testers” and also “very late presenters” or “long-term non-presenters”.
In the US and Europe, and probably in other countries, about half of patients are
still late presenters. In COHERE, an association of European cohorts, 84,524 PLWH
were followed between 2000 and 2011. The proportion with less than 350 CD4
T-cells at initial presentation declined slowly, from 57% in 2000 to 52% in 2010/2011
(Mocroft 2013). In a more recent evaluation, the rate remained broadly stable
between 2010 and 2013, most recently at 49% (Mocroft 2015).
5.5. When to start with ART? 151

The cut-off value of 350 CD4 T-cells sometimes raises problems, as heterogeneous
groups are thus pooled. Due to the often very low CD4 T-cells during acute HIV infec-
tion, the numbers are probably somewhat overestimated (Sasse 2016); on the other
hand, the consequences of the very late onset tend to be underestimated by this
high value. In the following, the term “late presenter” is therefore primarily restricted
to persons with AIDS or with less than 200 CD4 T-cells/µl.

Incidence and risk factors for late HIV diagnosis

How common are true late presenters? Without a uniform definition, 10–44% rates
are reported in Europe and the US, with a recent slight downward trend, at least in
some countries (Table 5.4). With the FindHIV study, data for Germany have also
recently become available (Valbert 2022). Of 706 people diagnosed as HIV-positive
for the first time (within the last six months) in 40 study centers between January
2019 and May 2020, 55% had a CD4 T-cell count below 350/µl, and 20% even had
an AIDS diagnosis.
The risk factors for late diagnosis (Table 5.5) are similar worldwide: older age, immi-
gration, and heterosexual transmission route. These observations suggest that the
reasons for late presentation are complex. Presumably, both patients (reduced access
to the health care system, lack of education, fear of stigmatization) and healthcare
professionals (i.e., reduced “HIV-awareness” among some) contribute to this.
Several studies have shown that even in people at high risk for HIV infection, many
missed opportunities exist to diagnose HIV earlier (Duffus 2009, Jenness 2009). For
example, of 263 African patients in London, 76% had visited their GP the year before
their initial HIV diagnosis. As many as 38% and 15% had been treated in an outpa-
tient clinic and as inpatients, respectively (Burns 2008).
Table 5.4: Frequency of (very) late diagnoses in Western countries.
Country Period Definition of % (AIDS) Trend over time
(n) late diagnosis
France 1996–2006 CD4 < 200 cells/μl 38 (17) Decline from
(Delpierre 2008) (6,805) or AIDS < 1 year 43 to 32
USA 1996–2005 CD4 < 200 cells/μl 38 Decline from
(CDC 2009) (281,421) or AIDS < 1 year 43 to 36
Great Britain 1996–2006 CD4 < 200 cells/μl 27 (10) n.a.
(UK Chic 2010) (15,775)
Italy 1985–2013 CD4 < 200 cells/μl 38 Slight decrease
(Rafetti 2016) (19,391) or AIDS < 6 mo
Netherlands 1996–2014 CD4 < 200 cells/μl 35 Decline from
(Coul 2016) (20,965) or AIDS < 3 mo 46 to 26
Spain 2004–2018 CD4 < 200 cells/μl 26 Decline from
(Rava 2021) (14,876) or AIDS < 6 mo 34 to 24
Switzerland 2009–2012 CD4 < 200 cells/μl 25 No clear trend
(Hachfeld 2016) (1,366)
AIDS = AIDS-defining disease. Mo = months.
Of 270 late presenters admitted to a Berlin Hospital in 2009–2013, 21% had previ-
ously presented with indicator illnesses at other facilities without being tested for
HIV (Tominski 2017). In the FindHIV study, 45% of study physicians saw at least
one opportunity in the healthcare system where the initial HIV diagnosis could have
been made earlier (Valbert 2022).
152 ART

Table 5.5: Risk factors for late diagnosis in Western countries.

Country (reference) Risk factors
USA (CDC 2009) Male sex, older age, ethnicity non-white
Germany (Zoufaly 2011) Older age, heterosexual transmission, migration
France (Wilson 2014) Migration, heterosexual transmission route, older age
Italy (Rafetti 2016) Male sex, older age, heterosexual transmission route, migration
Netherlands (Coul 2016) Male sex, older age, heterosexual transmission route,
foreign origin
Spain (Rava 2021) Male sex, older age, IVDU, or heterosexual transmission
Switzerland (Hachfeld 2016) Female gender, origin sub-Saharan Africa. Protective:
high school education, MSM
Belgium (Darcis 2018) Male sex, sub-Saharan African origin, age, heterosexual
transmission

A primary focus of prevention is, therefore, on earlier identification of people who

are not yet aware of their infection – especially about the first 95 of the 95-95-95
UNAIDS goals; there is room for improvement.

Morbidity, mortality – consequences of late HIV diagnosis

Up to 90% of AIDS-defining diseases today occur in viremic – i.e., primarily untreated
– PLWH. This is especially true for classical opportunistic infections such as PCP or
CMV retinitis, but also, although less strictly, for tuberculosis or non-Hodgkin lym-
phomas (ART CC 2009). About two-thirds of patients with newly diagnosed NHL in
our lymphoma cohort had not received ART previously. Nearly 40% were diagnosed
with NHL and HIV infection simultaneously (Hoffmann 2015). In a UK analysis of
387 deaths in 2004/2005, late HIV diagnosis accounted for as many as 24% of all
deaths and 35% of all HIV/AIDS-related deaths (Lucas 2008). In a cost analysis,
treatment costs increased by 200% with fewer than 200 CD4 T-cells at the time of
HIV diagnosis (Krentz 2004). This is also likely due to immune reconstitution
syndrome (IRIS), common among late presenters (see AIDS).
There is no doubt that late HIV diagnosis is associated with an increased mortality
risk and morbidity. The worse the CD4 T-cells or CD4/CD8 ratio at therapy initiation,
the higher the risk (Sterne 2009, Mocroft 2013, Domínguez-Domínguez 2022). In
individuals with less than 350 CD4 T-cells, mortality increased 10-fold in the first
year, with no significant differences observed until after four years (Sobrino-Vegas
2016). However, there is no question that the prognosis of late presenters has
improved in recent years. In an Italian study, the 1- and 5-year survival rates of indi-
viduals with fewer than 200 CD4 T-cells and/or AIDS increased from 63% and 17%
in 1985–1991 to 95% and 91% in 2004–2009 (Raffetti 2016). Even in the severely
ill, everything should be tried. For most people, ART will be timely! Of 270 late pre-
senters with AIDS from 2009–2013 in a Berlin hospital, only 6 died as inpatients
(Tominski 2017). However, when CD4 T-cells are very low, mortality remains elevated
for many years (ART CC 2007, Lanoy 2007).
Moreover, immune reconstitution rarely remains complete in the case of severe
immune deficiency. The worse the immune system, the less likely complete restora-
tion. Even long-term viral suppression for decades does not change this. In a study
of individuals who had achieved a consistently low viral load of less than 1,000
copies/mL over at least four years on ART, 44% of patients with less than 100/µl at
ART initiation failed to achieve the average value of 500 CD4 T-cells/µl even after
5.5. When to start with ART? 153

7.5 years. For 100–200 CD4 T-cells/µl, the rate was still 25% (Kelley 2009). In addi-
tion to low CD4 T-cells, older age, often observed in late presenters, is a risk factor.
With increasing age, the regenerative capacity of the immune system decreases,
probably due to thymic degeneration (Lederman 2000, Grabar 2004). A late start
may also result in poor antigen-specific immune reconstitution, both against HIV
and opportunistic pathogens. Many studies have suggested that qualitative immune
reconstitution often fails to keep pace with quantitative immune reconstitution
(Gorochov 1998, Lange 2002). But why then does the AIDS risk decrease so signifi-
cantly and so rapidly with increasing CD4 T-cells? Why can even severely immuno-
suppressed patients discontinue their prophylaxis relatively safely as soon as CD4
T-cells have risen above 200/µl? Clinical observations seem to show otherwise, and
the relevance of impaired immune reconstitution in the long term is unclear. A large
cohort study showed that discordant response (despite good viral suppression and
low CD4s) is associated with an increased risk of AIDS only in the first months. In
virally well-suppressed individuals, CD4 T-cells are no longer an excellent surrogate
marker for AIDS risk (Zoufaly 2012).
In contrast to the immunological response, the virological response of late presenters
is usually no worse (Rava 2021). Of 760 patients with AIDS at the time of HIV
diagnosis, 89% achieved a viral load of less than 500 copies/mL (Mussini 2008).

Start with ART – always immediately?

PLWH with poor immune status and/or symptoms should start ART as soon as
possible. For a long time, many treatment providers preferred to focus initially only
on OIs and to wait a few weeks before starting ART to avoid risk therapeutic options
given the high complication potential of OI therapies. The first large randomized
trial on this made this strategy questionable (Zolopa 2009). In ACTG A5164,
282 patients with an acute OI (63% PCP, TB cases were excluded) were randomized
to start ART immediately or at the earliest after completion of OI therapy. On median,
the “immediately” treated group started ART 12 days after initiation of OI therapy,
and the “delayed” treated group started ART after 45 days. Despite this short period,
significant differences emerged after 48 weeks: significantly fewer deaths or new AIDS
cases occurred in the immediately treated group. The risk of switching ART was
slightly increased, but not the number of serious adverse events, hospitalizations, or
IRIS cases. The authors concluded that ART should be initiated immediately in
persons with acute OIs (at least PCP). Another smaller study found no relevant
differences in PCP and toxoplasmosis, but case numbers were too small, given slow
recruitment (Schäfer 2019).
In tuberculosis, at least five randomized trials have addressed the optimal timing of
ART (Abdool 2011, Blanc 2011, Havlir 2011, Török 2011, Wondwossen 2012). The
main results are that immediate therapy does not significantly improve mortality or
AIDS-related morbidity. The only exception seems to be in individuals whose CD4
T-cells are below 50 cells/µl at TB diagnosis. In these cases, immediate initiation is
strongly recommended. Of note, immediate initiation always carries the risk of par-
adoxical TB exacerbation in the setting of IRIS, which reached up to 30% in some
studies.
Adverse effects on survival were seen with immediate ART initiation in tuberculous
meningitis (Török 2012). This is also true for cryptococcal meningitis (Makadzange
2010) – it may be necessary to differentiate the OI (Lawn 2011). Another contro-
versial issue is whether to start ART in patients with malignant lymphomas
immediately or only after completion of chemotherapy (see Malignant Lymphomas).
154 ART

Which ART to start with for late presenters?

Active OI is often an exclusion criterion for clinical trials. People with OIs are thus
chronically underrepresented. Therefore, optimal therapy is an individual decision
(Manzardo 2007) (see chapter 5.6. First-line Therapy). Regarding immunological
success, no relevant differences between NNRTI- and PI-based regimens are seen in
late presenters (Samri 2007). In addition to the low interaction potential and good
tolerability, the main argument favoring INSTIs is the rapid reduction in viral load.
However, some cohort studies showed clinical benefits with INSTIs (Martin-Iguacel
2022), while others showed just the opposite (Rava 2021). Controlled, prospective
studies are lacking. The LAPTOP trial, ongoing in various European countries, ran-
domizing between bictegravir and darunavir/c in advanced immunodeficiency or
AIDS, will hopefully clarify this issue shortly. There have been some reports of
increased risk among INSTIs regarding possible immune reconstitution syndromes.
However, a large meta-analysis recently concluded that the overall IRIS risk is not
higher than in other drug classes (Zhao 2022).
Intensification with an INSTI such as raltegravir has no effect. The African REALITY
study impressively proved this in 1,805 patients with severe immunodeficiency of
less than 100 CD4 T-cells (Kityo 2018). Through 48 weeks, there was no evidence of
differences in mortality, serious adverse events, or events judged compatible with
IRIS or in hospitalizations. There is also no evidence supporting the additional admin-
istration of maraviroc; this has neither an effect on IRIS nor immune reconstitution
(Sierra-Madera 2014, Belaunzarán-Zamudio 2017 (See Chapter 5.4).
In summary, no evidence exists that late presenters require a specific ART regimen.
ART selection should be guided by factors that affect other patients (see next chapter).

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5.6. The optimal first-line therapy 157

5.6. The optimal first-line therapy

C H R ISTIAN HOFFMAN N

Given the more than thirty drugs, the number of possible combinations in first-line
therapy hardly seems manageable at first glance. Moreover, different guidelines such
as those of the International AIDS Society (IAS, Gandhi 2023), US Department of
Health and Human Services (DHHS 2022), European AIDS Society (EACS 2022) or
German-Austrian AIDS Society (GAAS 2021) – all recommend different regimens.
However, INSTI-based regimens are recommended first-line for all PLWH worldwide
(where they are available). These include BIC/TAF/FTC and DOL-containing regimens
plus TDF/FTC or TAF/FTC. Beyond these regimens, some critical differences are still
evident. For example, DHHS and EACS (but not IAS) also recommend dolutegravir
plus ABC/3TC for individuals who are HLA-B*5701 negative and without chronic
hepatitis B virus (HBV) co-infection. EACS is the only international guideline to
recommend NNRTI-based regimens (doravirine). According to DHHS, boosted
darunavir plus (TAF or TDF) plus (FTC or 3TC) is possible – “pending the results of
the genotype test”.
In the German-Austrian recommendations, at least ten therapies (based on INSTIs,
NNRTIs, and PIs) are recommended as equivalent, and others are considered
alternatives. In contrast, WHO states that only “DTG in combination with an NRTI
backbone is recommended as the preferred first-line regimen”. Due to this recom-
mendation in 2021, and thanks to access-oriented voluntary licensing agreements
worldwide, the combination of TDF/3TC/dolutegravir (“TLD”) has become the most
widely used HIV regimen globally.
However, this may not always be the best choice (and is unavailable in Western
Europe). There are other options. And there is still space for improvement. For this
reason alone, it remains sensible for therapy-naïve people to participate in clinical
trials: this is the only way to improve therapy further. But sometimes studies are not
possible. For these cases, we summarize the data situation (beyond availability).

Recommended first-line therapies

Assuming a few things, the seemingly complex situation quickly becomes clearer.
Let us assume that in first-line therapy
1. So-called single-tablet regimes (STRs) are to be preferred
2. 3TC and FTC are equivalent
3. Abacavir is more and more likely to be avoided because of cardiovascular risk
4. Food restrictions are somewhat unfavorable
Only a few combinations remain (Table 6.1). They consist of a backbone with one
or two NRTIs and a third compound and are discussed in detail below. The third
substance is either a boosted PI with darunavir, an NNRTI with doravirine, or a
second-generation integrase inhibitor, namely dolutegravir or bictegravir.
Table 6.1: Useful STR combinations in first-line therapy (no ranking).
NRTIs plus Third (or second) agent Brand name
TAF + FTC PI: Darunavir/c Symtuza®
TAF + FTC INSTI: Bictegravir Biktarvy®
3TC INSTI: Dolutegravir Dovato®1
TDF + 3TC NNRTI: Doravirine Delstrigo®
1only if viral load is below 500,000 copies/mL, if there are more than 200 CD4 T-cells, and in the
absence of hepatitis B
158 ART

These four STRs can be used in almost all clinically conceivable situations. In addi-
tion, many other therapies or agents are possible (some of which are approved),
although they are only used in exceptional cases in practice. These include agents
that have been recommended for many years, such as rilpivirine, but also elvite-
gravir or raltegravir, whose resistance barriers are probably lower than those of
doravirine, dolutegravir and bictegravir. Abacavir, which used to be widely used,
should also be avoided because of the cardiovascular risk, especially in first-line
therapy.

First-line therapy: practical and important aspects

A compelling virological superiority of a specific combination has not been shown
even in recent years; there is no gold standard. Therefore, other things often play a
role in the choice: individual adherence, concomitant diseases, concomitant med-
ication, and individual needs should be considered. Even tablet size or restrictions
regarding food intake can influence the decision.
The right first-line therapy is vital and must be well-prepared. Especially in highly
viremic patients, there is a relevant risk of resistance in the first few weeks, as it takes
several weeks for replication to be slowed down. It should not be forgotten that for
many people, the start of therapy is a drastic event: the realization that from now
on, they will probably be treated for life makes them nervous and uncertain.
Reservations can, therefore, often be great. It is not uncommon for people to have
unclear ideas about what antiretroviral therapy means nowadays.

Practical tips for first-line therapy

• The first shot should be successful, i.e., the viral load must be below the detec-
tion limit – at the latest, after 3–6 months!
• Is the patient motivated? Will they come back at all? An immediate start makes
sense in principle but is rarely necessary. In case of doubt, it may be better to wait
and check the values further.
• Be sure to address likely adherence and work and eating habits (shift work?).
• Pros and cons (side effects!) of different combinations can be discussed openly –
there is almost always time for this. Each patient may learn why the particular
therapy was chosen.
• Ask about concomitant medication (and drug use; see below) – are relevant inter-
actions to be expected?
• Check concomitant diseases – what about liver (hepatitis?), kidney?
• Is a resistance test available? Caution: Transmitted resistances are possible.
• Check if participation in a clinical trial is possible!

What should be clarified first?

It is often the little things that influence the decision. Patients should be involved
as far as possible. It has proven beneficial to ask openly, “What is important to you?
How regularly do you eat? Do you have a particular diet? Does taking pills daily
cause you problems in principle, or do you not care whether it is one or three pills
daily? Do you trust yourself to take them regularly, or are you someone who might
forget to do so? When would taking it during the day be optimal for you? Would
mild and/or temporary diarrhea be a big problem?”
5.6. The optimal first-line therapy 159

Table 6.2: Factors influencing the choice of first-line therapy, differences between drug classes. The
choice of backbone may also play a role.
NNRTI PI INSTIs
DOR DRV DTG, BIC
Number of tablets per day 1 1 1
Once-daily dose yes yes yes
Food restrictions no partly no
Viral load reduction medium often slow quickly
Interaction potential medium high low
Resistance risk during first-line 1–2% 0% 0%
Main side effect of the class allergies diarrhea weight gain
Preferred NRTI backbone TDF+3TC TAF+FTC TAF+FTC/3TC
Long-term experience (class) > 20 years > 20 years 5–10 years

People living with HIV have become more demanding. And rightly so. There are
many alternatives. As in the early days of ART, multiple daily doses are obsolete; the
once-daily administration of an STR is the rule. Lifelong ART must fit as perfectly as
possible into everyday life. And cause little disruption. It is not about a few months,
but about years, about decades. Of the combinations listed below, only the PI should
be taken with a meal; with the other three, it does not matter.

Adherence
Compliance is defined as a patient’s consent and acceptance of therapy. In the mid-
’90s, a new term, “compliance”, was adopted. Since then, the more politically correct
term – “adherence” is frequently used. This term refers to the physician and patient
working together to set up a treatment concept acceptable to both parties. It empha-
sizes that responsibility for the failure of the therapy is not automatically the patient’s
fault. Adherence includes all factors that influence staying on a regimen in terms of
acceptability under these three buckets:
1. The success of a treatment is endangered if medication is taken irregularly
2. Clinicians tend to overestimate a patient’s adherence
3. Adherence diminishes with the complexity of the treatment
Is the patient able to take the therapy on his own? Do they understand that ART is
a life-long treatment that should not be stopped when they feel better? Do they
realize that there is no need to tolerate severe side effects? What is realistic, given
their private and social background?
No doubt, adherence is the Achilles’ heel of every antiretroviral therapy. Poor adher-
ence is the main if not the primary, factor for developing resistance and treatment
failure (Turner 2002). However, adherence can be improved! Resistance is virtually
bred by only partial viral suppression and insufficient drug levels. ART should be
taken consistently. All or nothing: Regarding the development of resistance, some-
times it is better not to take any therapy. The reasons for poor adherence are complex.
They range from being overwhelmed with the intake (number of tablets, timing of
intake, food intake) to side effects or concerns about them. A poor doctor-patient
relationship also plays a role. Sometimes, it is just the hurdle of keeping regular
doctor’s appointments and getting prescriptions. Not everyone ensures that there is
always enough medication in the house.
Patients at risk for poor adherence are not only drug users, alcoholics, or those with
side effects. Depressed people, people living alone, and younger people have also
been identified as problem groups in many studies (Glass 2006). Favorable factors,
on the other hand, are the physician’s experience, the understanding of ART, and
160 ART

Figure 6.1: Two cases with adherence problems, CD4 T-cells/μl (dark, primary axis left, cells/μl), and
viral load (dashed, primary axis right, RNA copies/mL). In both, initially, inconsistent ART use for many
years, as indicated by high viral loads. In both cases, several HIV-associated problems and resistance
mutations occurred over time.

social support. In contrast, ethnicity, gender, or stage of disease do not seem to play
a role. Further factors include the individual worldview of disease and health, the
acceptance of conventional medicine, or the fear of side effects. However, there is a
large variance. Ultimately, adherence is difficult to predict in individual cases;
experience and intuition are essential factors.
Countless studies have shown that it is crucial to take medication regularly. However,
the previously propagated need for at least 95% adherence (95% of doses taken) can
no longer be proven. Modern agents with a high resistance barrier, such as darunavir,
dolutegravir, or bictegravir, probably have a high forgiveness – they “forgive”
significantly more “non-compliance” (Nelson 2010, Bezabhe 2016). Recent studies
investigating regular treatment interruptions also show that absolute adherence is
not always required, especially in patients treated for many years. In the French
QUATUOR trial (ANRS 170), 647 successfully treated patients were randomized to
continue taking their ART daily or only on 4/7 days (every Friday to Sunday off).
After 48 weeks, 96% remained below the limit of detection in the experimental arm,
and resistance had occurred in only 3/318 patients (Landman 2022). Although one
can argue about the ethical aspects of such a human experiment – it shows that
repeated treatment interruptions can remain without consequences for most indi-
viduals over a longer period. Concepts of Directly-Observed-Therapy (DOT) or
DAART (directly administered antiretroviral therapy) discussed in the past are mostly
obsolete today. Moreover, the effect of DOT usually disappears as soon as the patients
are left to themselves (Berg 2011).
Poor adherence does not only mean virological failure. It also has immunological
consequences and clinical consequences beyond surrogate markers. In a Spanish
study, patients who failed to take more than 10% of their medications had an almost
4-fold increased risk of mortality (Garcia 2002). Increased mortality and more
hospitalizations were also found in other studies (Wood 2004). It is likely that non-
adherence also increases the risk that resistant viruses will be transmitted.
The essential features of developing resistance should be explained to the patients.
Education is key! A large randomized study in 400 PLWH proved that intensive early
adherence counseling at ART initiation (three counseling sessions) had a sustained,
significant impact on adherence, and virologic treatment failure during the
18-month follow-up while using an alarm device had no effect (Chung 2011)!
Participants who received counseling were 29% less likely to have monthly adherence
< 80% (hazard ratio 0.71, p=0.055) and 59% less likely to experience viral failure
(HR 0,41; p=0.01) compared to those who received no counseling.
5.6. The optimal first-line therapy 161

It is crucial to explain that once resistance has been generated, it does not disappear
but is likely to persist for life. And that this is an essential difference from other
chronic diseases. The comparison with diabetes or hypertension has proven itself –
while it is forgivable to skip a tablet in these diseases, it is different with HIV. Blood
sugar or blood pressure can be lowered again easily the next day, but this is not
certain with HIV. “Sloppiness” can have irreversible consequences, and the therapy
becomes more complicated with each resistance mutation. The reminder should be
repeated occasionally and be a part of routine care. Diverse adherence-promoting
strategies range from additional nurses and the community to regular text messages
or even phone calls. The effect of such strategies depends heavily on individual
factors; on the other hand, social media interventions can be useful, especially for
younger people (reviews: Locher 2019, Shah 2019). However, often, this is not
practical – and with a good education, it is mostly unnecessary. The effects of these
interventions are limited.

Twelve steps to improve adherence

• Every patient receives a written (comprehensible) treatment plan, which is
reviewed at the end of the visit. The plan contains a telephone number (or email)
for queries.
• Patient and physician agree on the treatment plan. The patient’s concerns and
questions have been discussed.
• It is clear to the patients that the therapy was not chosen arbitrarily but tailored
to their needs.
• Explaining a new therapy or a change takes time and should not happen
haphazardly – all questions must be answered.
• The patient has learned in broad terms why adherence is essential – not only
when starting or when or why changing therapy! Repeated discussions about
adherence are part of routine care.
• It should be explained what side effects can be expected and how to deal with
them. Support Groups and local associations have been mentioned or referred.
• It is essential to note that the individual can and should come in immediately if
there are problems with the ART.
• It has been discussed that the therapy should never be partially reduced (“I left
out the big pills last month...”).
• Irregularities in prescriptions should be addressed openly.
• Just at the beginning, when viral load is dropping, and CD4 T-cells are rising,
communicating this success can be motivating.
• Treat depression!

If adherence remains poor

Despite all efforts, some patients will fail to improve adherence. Physicians and other
healthcare providers should not take this personally or feel offended. Although
accepting the patient’s views on life, disease, and treatment may be difficult, health-
care providers must keep tolerance and acceptance as key components in their inter-
actions with patients. Some providers, especially those who treat selective patient
populations in university settings, tend to forget the reality of routine medical
practice. Rigidly upholding the principles of modern medicine usually does not help
here, and putting patients under pressure will achieve even less. It is essential to
clearly outline and explain, advise, help, question, and listen.
162 ART

One’s positions must be clearly represented and well justified. Whether non-com-
pliant patients should continue to be treated with antiretroviral therapy can be chal-
lenging to address. On the one hand, some patients benefit even from sub-optimal
therapy; on the other hand, drugs are expensive and should not be prescribed too
readily. Restraint should be applied until the reason for poor compliance is under-
stood. A referral to counseling (peer support?) may be needed.
Clinicians should also be aware of criminal schemes – there are always reports of
deals with pharmacies in which those involved procured other drugs (methadone,
etc.) or money. Prescriptions issued should be documented. If there are reasonable
doubts about compliance or honesty, one can also arrange for plasma levels to be
measured (TDM, preferably without notice).

The Duesberg Sect

Patients who refuse antiretroviral treatment on principle are a special case. These
patients are frequently not on treatment thanks to (shockingly misdirected) doctors,
who call themselves “Duesbergians” (after the US virologist and AIDS dissident Peter
Duesberg, who denies any association between AIDS and illness). In such cases,
leaving patients to their fate can be very difficult. Informative consultations should
be as detailed as possible and preferably documented in writing.
An example: an approximately 40-year-old patient with a long history of untreated
HIV, 30 CD4 T-cells/µl, and cerebral toxoplasmosis (TE), which improved signifi-
cantly after four weeks of acute treatment (the last MRI still showed scattered lesions)
introduced his case to the HIV outpatient department. Clinically, he was relatively
well and fully oriented and due for discharge that day. In a conversation, the patient
categorically refused to start the urgently recommended antiretroviral therapy. His
Duesbergian physician had advised him against HIV therapy (“You can die from AZT,
and the other drugs are not much better, etc.”). He refused antibiotics on principle
as well. This was why the patient would not continue the TE maintenance therapy,
which had made him suffer from diarrhea (NB, probably cryptosporidiosis), skin
problems (seborrhoeic dermatitis, thrush), and extreme loss of weight (MAC?) since
his first day in hospital. It was imperative for him to have a break from all medica-
tion.
In such cases, we make sure the patients sign the information sheets. Every patient
is allowed to and should decide for himself (if fully cognizant and capable) – they
must be fully informed about what they are doing. It is vital to give the patient
control: if they change their mind, they may return! In our experience, arguing with
medical Duesbergians leads nowhere. This sect has a very restricted view of the world
and sticks to its repetitive mantra-like arguments. Discussing with them is time-con-
suming and a waste of energy. Fortunately, these cases have become rarer. The initial
widespread skepticism towards ART has decreased significantly due to its over-
whelming success in recent years. Concerning Peter Duesberg, he is relatively quiet
as far as his HIV activities go. The sect is in decline.

Pre-existing (transmitted) resistance

At least one genotypic resistance test should be available before ART initiation. In
Europe, pre-existing resistance mutations that have been transmitted and are there-
fore present even though the affected person has not yet taken ART can be expected
to be constant at about 10–15% (see Resistance). These resistance mutations must be
considered in any treatment decisions. A single resistance mutation such as K103N,
found in just under 2% in Europe among untreated individuals, can throw an NNRTI
regimen into disarray, with the threat of further mutations. Since some mutations,
such as M184V, that reduce viral replication fitness may disappear over time, old
5.6. The optimal first-line therapy 163

tests should also be considered. If no test has been available to date, it should be
performed. Suppose ART needs to be started urgently, for example, in cases of
advanced immunodeficiency or initial diagnosis in pregnancy. In that case, waiting
for the result may be optional, often taking 7–14 days. It may be better to start a
high resistance barrier ART regimen with, for example, darunavir and adjust it if
necessary (Huhn 2020).

Concurrent illnesses
Before starting therapy, all concurrent illnesses should be known (medical history,
examination). This is important: someone with consistent diarrhea is likelier not to
be given a boosted PI. Latent diabetes mellitus may become insulin-dependent with
PIs. Is obesity present? In these cases, remember that significant weight gain has
been described in some studies under both INSTIs and TAF (Sax 2019, Venter 2019,
see next chapter). Caution is advised with TDF in renal disease or osteoporosis, espe-
cially with boosted PIs. Caution with abacavir is warranted in the presence of high
cardiovascular risk (Behrens 2010). Liver disease or chronic hepatitis should also be
considered. The risk of severe hepatotoxicity with nevirapine or ritonavir increases
(Sulkowski 2000). However, our co-infected patients have not seen an increased risk
(Mauelshagen 2012).
Table 6.3: Concurrent illnesses where specific agents may be problematic (not limited to first-line the-
rapies) exist.
Disease Caution with
Active hepatitis B Nevirapine, boosted PIs
(instead, favorable: TDF or TAF plus FTC!)
Active hepatitis C Nevirapine, boosted PIs
Active drug use, substitution NNRTIs, ritonavir (possibly favorable: raltegravir)
Anemia AZT
Chronic diarrhea, intestinal diseases All PIs
Diabetes mellitus All PIs
Myocardial infarction Abacavir, darunavir, lopinavir
Kidney diseases TDF, atazanavir, cobicistat
Psychoses, other CNS disorders Efavirenz, possibly dolutegravir, bictegravir
Osteoporosis TDF

In case of an active hepatitis B co-infection, the high anti-HBV potency of TDF and
TAF (and also FTC and 3TC) should be used. Long-term control of hepatitis B over
many years is possible with tenofovir (de Vries-Sluijs 2010). However, we always
recommend combining it with a cytidine analog such as 3TC or FTC. In contrast,
the weakly effective, resistance-prone 3TC alone (in Kivexa®, Dovato®, Triumeq®)
should be avoided in patients with hepatitis B. In all PLWH, the current hepatitis B
status should be known and well documented. It is common for the rebound to
occur with 3TC alone or an NRTI-free regimen.
Finally, the desire to have children must also be considered, and women of child-
bearing potential should refrain from taking efavirenz. With INSTIs such as bicte-
gravir and doravirine, experience during pregnancy is still limited. Even if the neural
tube defects described in a 2018 cohort on dolutegravir have not been confirmed
(Zash 2019), it still seems advisable to use proven agents (see chapter ART in children).
However, this is in flux, and more pregnant women are likely to be below detection
at term on dolutegravir in particular than on other therapies (Lockman 2021, Patel
2022).
164 ART

Interactions with medications and drugs

Interactions also play an essential role when choosing individual regimens
(see Interactions). Knowledge of these is often limited. How strong interactions can
be may be illustrated by a study in which ritonavir increased the plasma levels
of simvastatin by 3059% in healthy individuals (Fichtenbaum 2002). Severe
rhabdomyolysis with statins and PIs has been described (review: Chauvin 2013).
Severe side effects have also been described with chemotherapies, especially with
vinca alkaloids. They should not be combined with boosters such as ritonavir or
cobicistat. The same applies to some hepatitis drugs and some DAAs (see chapter 11).
Many other agents should not be combined with ART because of the potential for
unpredictable interactions. These also include certain contraceptives. Even prepara-
tions with which one would not have suspected any problems at first glance can be
unfavorable: for example, Cushing’s syndromes have been observed with steroid-
containing asthma sprays and PIs (Saberi 2013). Cumarins can also be problematic;
ritonavir significantly lowers levels (Llibre 2002). Some NOAKs should also be used
cautiously; severe bleeding has been described with rivaroxaban and boosted PIs
(Egan 2014, Lakatos 2014).
Even professionals make mistakes, and interactions are common (Lopes 2020). In
the Swiss cohort, the proportion of boosted regimens decreased significantly between
2008–2018, but simultaneously, the number of co-medications increased. Poly-
pharmacy is a growing problem. Concomitant use of five or more non-HIV
medications was observed in 14%, with older individuals more frequently affected
(6%, 18%, and 33% in the 18–49, 50–64, and ≥ 65 age groups). The proportion of
unfavorable interactions was 29%, and the proportion of critical interactions was
2% (Deutschmann 2021). The most common errors were the combination of boosted
ART with steroids (fluticasone, mometasone, triamcinolone: Cushing’s syndrome),
quetiapine, and domperidone (QT prolongations in each case). Also common were
combinations of PPIs with unboosted atazanavir or rilpivirine. Typical problematic
medications included migraine medications, prokinetics, and sedatives/hypnotics.
One death has been described with ergotamine and ritonavir (Pardo 2003).
Simultaneous administration of ART and PDE-5 inhibitors also has issues (see Sexual
Dysfunction). At this point, it is not possible to refer to every substance. Many can
be found in the Drugs section and the Interactions chapter. However, it is always advis-
able to also look at the drug information. The start of ART is always an excellent
opportunity to reflect on the existing co-medication. If interactions are imminent
and co-medication is mandatory, unboosted, TDF-free INSTI regimens may be the
best choice (Lopes 2020).
However, the best way to check possible interactions with ART is the Liverpool Drug
Interactions website, established in 1999 by members of the Department of
Pharmacology at the University of Liverpool. This is a clinically useful, reliable, com-
prehensive, up-to-date, evidence-based drug-drug interaction resource that is freely
available to everybody. It can be found at [Link]
checker.

Interactions with drugs

Drugs or alcohol also interact with ART (review: Kumar 2015), party drugs, especially
with boosted regimens, and NNRTIs (review: Bracchi 2015). “Chemsex” is now
integral to many patients’ lives; it describes sexual contact under psychoactive agents
such as mephedrone, crystal methamphetamine, and gamma-hydroxybutyrate (see
Sexual Dysfunction). Adherence is often impaired. Patterns of use range from
occasional use to complete loss of control with social decline. Counseling services
are rare, and there is often no awareness of the problem (“I’m not a junkie”). Drug
5.6. The optimal first-line therapy 165

use is associated with higher educational attainment, a steady seropositive partner,

younger age, and poor ART adherence. In a survey of 2,248 HIV-infected MSM in
London, 51% had used party drugs in the previous three months (Daskalopoulou
2015). These figures will likely be transferable to other local metropolitan areas in
Western countries. Of 453 PLWH (22% female, mean age 46 years) in Germany, 56%
reported recreational drug use in the previous six months: nitrite inhalants
(“poppers”), cannabis, and PDE-5 inhibitors were common in all age groups; ecstasy,
methamphetamine, and gamma-hydroxybutyrate were predominantly reported by
younger people (Funke 2021). Only 7% considered drug use combined with ART a
problem. Strikingly, 44% and 42% had received medical treatment or were hospi-
talized for drug use.
Clinicians should know about these drugs in basic terms. Before starting ART, one
should talk openly about drugs. The patient does not always desire this. However, it
is crucial to know the indicators of the hidden use of party drugs (see box).

Indicators for (hidden) use of party drugs

• Frequent missed doctor’s appointments, frequent appearances without appoint-
ments.
• Frequent incapacity to work, especially after the weekend.
• Congested noses and nosebleeds, “funny” stories.
• Frequently occurring STDs (especially hepatitis C!).
• Recurrent thrombophlebitis, abscesses (for example, see picture section).
• Desire for sleeping pills

Interactions can have dangerous consequences. Several deaths following concomitant

use of ritonavir and amphetamines or MDMA/ecstasy or gamma hydroxybutyrate
have been published (Henry 1998, Harrington 1999, Hales 2000). In particular,
ritonavir and cobicistat inhibit the metabolism of amphetamines (speed or
MDMA/ecstasy), ketamines, or LSD (Bracchi 2015). ART regimens with boosters
(ritonavir, cobicistat) should be avoided for people who use party drugs. Compared
with party drugs, marijuana, and THC probably have little interaction potential
(Kosel 2002). For methadone-substituted individuals, nevirapine and efavirenz may
significantly increase the need for methadone. This is also true to a weaker extent
for ritonavir. Data are inconsistent for lopinavir, but dose adjustments may also be
required. In contrast, raltegravir and dolutegravir do not affect methadone levels
(Anderson 2010, Song 2013).

Additive toxicities
Additive toxicities should also be considered when selecting therapy. In the case of
potentially nephrotoxic agents, caution is advised, especially with TDF; in these cases,
TAF is preferable. Cobicistat or even dolutegravir, although not nephrotoxic, may
provide falsely low GFR values by inhibiting tubular secretion of creatinine, and
monitoring may become difficult. If myelotoxic agents (valganciclovir, cotrimoxa-
zole) are necessary simultaneously, AZT should generally no longer be used.
Finally, potentially allergenic agents are unfavorable in first-line therapy if anti-infective
prophylaxis with cotrimoxazole or other sulfonamides is required simultaneously.
These include all NNRTIs, abacavir, as well as darunavir. Otherwise, it may be
challenging to identify the causative agent without doubt in the case of drug exan-
thema.
Overall, the toxicity of the newer antiretroviral agents is significantly reduced
compared to the past. Discontinuation rates have decreased (see Side Effects).
166 ART

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168 ART

Which drug classes should be used?

Once all practical aspects have been considered and the options remain unlimited,
the appropriate first-line therapy must be selected. Currently, recommended
combinations include two NRTIs plus either the PI darunavir, the NNRTI doravirine,
or one of the two integrase inhibitors (INSTIs), dolutegravir and bictegravir. They
are discussed in more detail here.
The German-Austrian guidelines recommend a total of 18 different combinations at
the end of 2021, including some multiple-tablet regimens. Much of this appears
dispensable. However, guidelines focusing on INSTIs only may unnecessarily limit
treatment decisions. For rilpivirine or elvitegravir, it is increasingly difficult to identify
situations in which they might still be useful or justifiable. TAF/FTC (Descovy®)
should be avoided because of the high costs. Large randomized trials directly com-
paring different drug classes in treatment-naïve patients can be found in Table 6.4.
Table 6.4: Randomized, cross-drug class comparisons in first-line therapy.
Study Drugs (n) Results on virological failure (VF) and
adverse events (AEs)
NNRTIs versus PIs
ACTG 5142 EFV versus LPV/r VF less with EFV, severe AEs same
(Riddler 2008) (250 + 253) (but more lipoatrophy with EFV)
ACTG 5202 EFV versus ATV/r VF same, more severe AEs with EFV
(Daar 2011) (929 + 928) (with ABC+3TC), but better lipid profile
ARTEN NVP versus ATV/r VF same, but more severe AEs and resistance
(Soriano 2011) (376 + 193) with NVP, better lipid profile
DRIVE-FORWARD DOR versus DRV/r VF slightly less with DOR (but overall high
(Molina 2020) (385 + 384) drop-out rates), better lipid profile
NNRTIs versus INSTIs
STARTMRK EFV versus RAL VF same, more total AEs with EFV
(Rockstroh 2011) (282 + 281)
GS 236-102 EFV versus EVG/c VF and tolerability same (more CNS AEs,
(Wohl 2014) (352 + 348) less nausea with EFV)
SINGLE EFV versus DTG VF less with DTG, more AEs, and disconti-
(Walmsley 2013) (419 + 411) nuations with EFV
ADVANCE EFV versus DTG VF less with DTG, more AEs and discon-
(Venter 2019) (351 + 702) tinuations with EFV, weight gain with DTG
NAMSAL EFV 400 versus DTG VF and tolerability same; more weight gain
(Calmy 2020) (303 + 310) with DTG
INIs versus PIs
ACTG 5257 RAL versus ATV/DRV/r VF similar, tolerability better with RAL than
(Lennox 2014) (603 + 1206) with both PIs
GS 236-103 EVG/c versus ATV/r VF and tolerability same
(Clumeck 2014) (353 + 355)
FLAMINGO DTG versus DRVr VF low (no resistances!), tolerability slightly
(Clotet 2014) (217 + 200) worse with DRV/r
ARIA DTG versus ATV/r VF less with DTG, more AE-related
(Orrell 2017) (250 + 249, women only) discontinuations with ATV/r
Notes: Different NRTI backbones (some randomized) were used; some had additional study arms.
VF = Virological Failure, AEs = Adverse Events.
5.6. The optimal first-line therapy 169

It is striking that the currently recommended (and broadly used) therapies are under-
represented. For bictegravir and rilpivirine, large, valid cross-class comparisons still
need to be made. Most studies used agents that are no longer first-line today, includ-
ing efavirenz, atazanavir, or lopinavir. In most class-comparative studies, antiviral
potency was broadly comparable, at least as measured by the proportion of patients
with viral loads below the detection limit. Although some differences emerged,
especially regarding tolerability (and risk of resistance), the results are not likely to
compromise any of the three classes. In a review of 29 studies involving 9047 PLWH,
no differences were found between NNRTIs and boosted PIs in terms of clinical and
immunological-virological success (Borges 2016).

NNRTIs versus PI/s

In various studies such as ACTG 5142/5202, FIRST, ARTEN, or DRIVE-FORWARD, the
NNRTI was at least as effective as the respective PI. In some cases, even more patients
achieved a viral load below the detection limit, primarily due to better tolerability
of the NNRTIs. Some patients discontinued PIs due to gastrointestinal side effects.
However, resistance occurs more rapidly and frequently with NNRTIs than with PIs,
probably due to the lower resistance barrier. A meta-analysis of 20 studies involving
7,940 subjects found comparably frequent virologic failure among NNRTIs (4,9%)
and PIs (5.3%) among PIs. Where genotypic resistance testing was successful,
resistance was observed significantly more frequently among NNRTIs. This was true
not only for resistance mutations to NNRTIs or PIs but also for NRTI key mutations
such as M184V and K65R (Gupta 2008). This phenomenon was particularly evident
in the ARTEN study (Soriano 2011). While not a single resistance occurred under the
PI atazanavir/r, 6% developed two-class resistance while on nevirapine. With
doravirine, the risk of resistance is likely lower (Molina 2020). In two studies (DRIVE-
FORWARD and -AHEAD), only 9/747 developed resistance (1.2%), less than is usually
seen with NNRTIs.

INSTIs versus NNRTIs

In three large randomized trials, STRTMRK, GS102, and SINGLE, the three INSTIs
raltegravir, elvitegravir/c, and dolutegravir each measured up against the standard
of care, namely efavirenz (Rockstroh 2011, Walmsley 2013, Wohl 2014). All three
INSTIs were better tolerated. Efavirenz tended to be inferior or, in the case of
dolutegravir in SINGLE, significantly inferior in each case, primarily due to increased
discontinuations due to CNS side effects. Admittedly, tolerability was also dependent
on the particular setting. For example, the discontinuation rate of efavirenz due to
CNS side effects increased in recent studies, and in SINGLE, it was as high as 10%!
Similarly, in ADVANCE, a comparison of dolutegravir and efavirenz in South Africa,
discontinuations were higher with efavirenz and partly responsible for differences
in efficacy (Venter 2019). The broader choice of therapies likely lowers everyone’s
“tolerance level” and causes treatment discontinuations more quickly than before
for understandable reasons.

INSTIs versus PIs

In FLAMINGO, GS103, and ACTG 5257, the integrase inhibitors each also competed
against boosted PIs such as atazanavir/r and darunavir/r, respectively (Clotet 2014,
Clumeck 2014, Lennox 2014). Dolutegravir and raltegravir showed better tolerability,
reflected in the overall response. Thus, raltegravir was superior to PIs darunavir/r and
atazanavir/r in ACTG 5257 primarily due to better tolerability – although slightly
more resistance was observed (Lennox 2014). Two large trials in women in resource-
poor countries tested dolutegravir (ARIA, Orrell 2017) and elvitegravir/c against
170 ART

atazanavir/r (WAVE, Squires 2016). In both, more patients achieved viral loads below
50 copies/mL with INSTIs than with atazanavir (ARIA 11%, WAVE 6%). Toxicity-
related discontinuations were also slightly more common with the PI.
Beyond virologic response and tolerability, what have we learned from these studies?
The sub-analyses of ACTG 5257 in particular, a large three-arm study, are very inform-
ative. For example, after 96 weeks, there were differences between raltegravir and
the two PIs, darunavir and atazanavir, concerning lipid profile (Ofotokun 2015), but
no differences concerning body fat changes (McComsey 2016). Biomarkers regard-
ing atherosclerosis also showed no differences (Kelesidis 2017). Bone density
decreased slightly less with raltegravir than with PIs (Brown 2015). Of note was
another sub-analysis on body weight. A significant body weight/BMI increase was
observed less frequently on either PI than on raltegravir (Bhagwat 2018). This trend
to the disadvantage of INSTIs was also confirmed in many other studies (Hester 2022),
especially in women and blacks and in combination with TAF. The opposite was
expected, as metabolic disturbances from INSTIs had not been expected and PIs had
been associated with lipodystrophy – there is undoubtedly a need for further research
here (see Side Effects).

Resistance among different first-line therapies

What about the most important endpoint of these studies, virologic treatment failure
with the development of new resistance? So far, virtually no new resistance has been
found with three agents in first-line therapy: darunavir/r, bictegravir, and
dolutegravir. Here, the resistance barrier is very high, and the risk is extremely low.
With doravirine, raltegravir, and elvitegravir, the risk is about 1–2%, while with
rilpivirine, depending on the viral load, it is significantly higher.
However, cross-comparisons between studies are problematic, as not only are
different populations studied, but virological failure is defined differently, as is the
cut-off for genotypic resistance testing. For example, in a meta-analysis of 14
randomized trials, 29% of patients with virologic failure did not undergo resistance
testing (Llibre 2018). In other words, some trials look hard for resistance to treat-
ment failure, while others look less hard. The closer you look, the more you’ll find.
Unfortunately, almost no study has reported what happened to those affected by
virologic failure in the long term.
The occurrence of a single resistance mutation may be regarded as a regrettable case
of limited significance. In contrast, two-class resistance is significant since it destroys
some crucial options and significantly impacts the treatment of those affected – for
years and even decades. Even if these cases are rare, they do exist! The following
table shows selected pivotal studies and the frequency of two-class resistance in each
case. The rate was lowest among boosted PIs such as darunavir/r (and atazanavir/r),
but also among the two second-generation INSTIs, dolutegravir, and bictegravir: not
a single case has been described among these first-line therapies.
With raltegravir and elvitegravir, on the other hand, the rate is about 1%, as with
doravirine. The rates are unacceptably high, especially with nevirapine and rilpivirine
in cases of high viremia. These options are no longer considered in first-line therapy.
Individual strategies have pros and cons – the competition for the best first-line
therapy continues. Thus, the pros and cons of the different strategies continue, and
controversy over the best first-line therapy persists. One should be warned against
cross-trial comparisons, often used as marketing strategies to influence health
providers’ effectiveness of a specific treatment (“We achieved over 90% tolerance
rates in our study”). In a systematic evaluation of 10 large-scale randomized trials
with 2,341 therapy-naïve patients receiving AZT+3TC+efavirenz, the success rates
(viral load in the ITT analysis < 50/copies/mL at 48 weeks) ranged between 37% and
5.6. The optimal first-line therapy 171

Table 6.5: Two-class resistance (affecting NRTI backbone and third agent, respectively) emerging in
first-line therapy. Not a single case has been described so far in the comparator arms with atazanavir/r,
darunavir/r, and dolutegravir.
Combination Study (reference) n %
TDF+FTC+nevirapine ARTEN (Soriano 2011) 23/376 6.1%
2 NRTIs + rilpivirine* ECHO/THRIVE (Rimsky 2013) 43/686 6.3%
2 NRTIs + efavirenz ECHO/THRIVE (Rimsky 2013) 8/686 1.2%
2 NRTIs + doravirine DRIVE (Molina 2018, Orkin 2019) 6/751 0.8%
2 NRTIs + raltegravir ARDENT (Lennox 2014) 10/599 1.7%
TDF/FTC/elvitegravir/c Pooled II-III (Margot 2016) 4/867 0.5%
TAF/FTC/elvitegravir/c Pooled II-III (Margot 2016) 5/866 0.6%
* In persons with > 100,000 HIV RNA copies/mL, 10.7%; in others, 2.4%.

77%. This broad range was seen using the same combination in ART-naïve patients!
The rates of adverse events also differed considerably. Heterogeneous patient popu-
lations and study designs (definition of therapy failure), clinician experience, and
patient adherence may lead to variations (Hoffmann 2007).
The following is a more detailed discussion of the study data regarding the most crit-
ical first-line therapies. These include:
1. Two NRTIs plus one NNRTI (Delstrigo® and others).
2. Two NRTIs plus one protease inhibitor (Symtuza® and others)
3. Two NRTIs plus one integrase inhibitor (Biktarvy® and others)
4. NRTI-reducing therapies (Dovato® and others).
5. Unfavorable first-line therapies that should be avoided

1. Two NRTIs plus one NNRTI

The advantages of NNRTI-containing regimens are good long-term tolerability and
lack of (or lesser) weight gain. The disadvantage, at least of rilpivirine, is the rapid
development of resistance. This is why NNRTIs are generally no longer recommended
as first-line therapy in some countries, such as the US. Allergies, typical in the past,
have become less frequent with rilpivirine and doravirine.

Recommended combination
TDF/3TC/doravirine was approved as a fixed combination Delstrigo® in late 2018.
In two partially double-blind randomized Phase III trials of first-line therapy,
doravirine was comparable to or tended to outperform darunavir/r and efavirenz. In
DRIVE-FORWARD, doravirine response was good, and resistance rates were low, even
in high viremia or severe immunodeficiency. Overall tolerability was the same,
including gastrointestinal side effects such as diarrhea or nausea. In contrast, the
lipid profile was more favorable than with darunavir/r (Molina 2018+2020). In
DRIVE-AHEAD, Delstrigo® was non-inferior to Atripla® as a fixed combination and
was better tolerated overall, mainly due to fewer CNS side effects. Again, the lipid
profile was more favorable than the comparator arm with efavirenz (Orkin 2019).
Unlike rilpivirine, there are no food restrictions; however, because of TDF, caution
is advised in patients with renal problems. In patients with no renal issues, we believe
it is the first NNRTI choice in first-line therapy.

Alternatives
TAF/FTC or TDF/FTC plus rilpivirine, the fixed-dose combinations Eviplera® and
Odefsey® (the latter containing TAF instead of TDF) have long been an important
option. In large trials, they were comparably effective and better tolerated than
172 ART

TDF/FTC and efavirenz, especially concerning lipids and CNS side effects (Molina
2011, Cohen 2012+2014). Neither Eviplera® nor Odefsey® have been tested in first-
line therapy against PIs or INSTIs. The main disadvantage is the rapid development
of resistance, often affecting rilpivirine and the NRTI backbone simultaneously. In
the ECHO/THRIVE trials, the rate exceeded 10% in patients with high viremia (see
Table 6.5). Thus, approval is limited to individuals with viral loads below 100,000
copies/mL. In our opinion, rilpivirine can only be considered in first-line therapy if
viremia is very low (well below 10,000 copies/mL) and adherence is perfect. Why
unnecessarily expose individuals to a risk of resistance? Rilpivirine is more suitable
as maintenance therapy. A fat-containing meal of at least 400 calories is also manda-
tory for intake. Otherwise, absorption is poor – this is another problem for some
people. Choosing other ART regimens for patients with chronic gastritis or long-
term PPI co-medication is also preferable.
TDF/FTC/efavirenz or Atripla® was the first single-tablet regimen (STR) and has been
used as the standard arm in countless trials. Generic STR regimens are now avail-
able. However, this combination has taken a back seat in recent years, mainly due
to the CNS side effects typical of efavirenz. In our opinion, it no longer has any place
in first-line therapy. The exception is when starting TB therapy simultaneously – in
this setting, its use can still make sense.
TDF/FTC plus nevirapine was quite frequently used in the past. Generics are avail-
able in Europe, but no STR. The risk of resistance is substantial (Soriano 2011), as is
the risk of allergy: like efavirenz, nevirapine no longer has a place in first-line therapy.
On the other hand, nevirapine has been on the market since 1996. People who can
tolerate it and who are adherent may stay on it. There is little data for TAF and
nevirapine.

Reasons for NNRTI-containing regimens in first-line therapy

• Low viremia below 10,000 copies/mL, preferably lower (rilpivirine).
• No food restrictions (doravirine).
• High risk of interactions with co-medication, such as TBC (good data for efavirenz)
• Cardiovascular disease (favorable lipid profile for doravirine).
Reasons against
• High viremia (rilpivirine should be avoided at all costs).
• Pre-existing resistance or lack of resistance testing (in Europe, approx. 3–5% of
all treatment-naïve patients have transmitted NNRTI resistance, in other countries
even higher rates).
• Adherence problems, expected treatment interruptions.
• Irregular life or irregular food intake (rilpivirine).
• Chronic gastritis requiring PPI use (rilpivirine).

2. Two NRTIs plus one protease inhibitor

This combination is the only triple combination whose efficacy has been demon-
strated by clinical endpoints in randomized trials (Hammer 1997, Cameron 1998,
Stellbrink 2000). Symtuza®, the first PI-containing single-tablet regimen (STR), was
approved in 2017. Given the high resistance barrier of boosted PIs, they remain
attractive for first-line therapy, especially in highly viremic AIDS patients. Resistance
among boosted PIs is virtually non-existent. The most important PI is darunavir.
Atazanavir and lopinavir are still considered alternatives to some extent; all others
no longer play a role. Lopinavir is co-formulated with ritonavir, and darunavir and
atazanavir can also be boosted with cobicistat. Choosing the lower TAF dose of
5.6. The optimal first-line therapy 173

10 mg is important for boosted PI regimens. Disadvantages of PI-containing first-

line therapies include somewhat higher pill counts, at least for atazanavir and
lopinavir, and often gastrointestinal side effects as well as an unfavorable lipid profile.

Recommended combination
TAF/FTC/darunavir/c (Symtuza®). Since February 2009, darunavir has been
approved for first-line therapy and is now the only PI recommended in the guide-
lines. Darunavir has been available as a component of the STR Symtuza® since
September 2017. Symtuza® has been successfully tested against TDF+FTC plus
darunavir/c in treatment-naïve patients in the AMBER trial (Orkin 2019); compar-
isons against other approved STRs are not yet available. Most darunavir trials were
conducted with ritonavir (rather than cobicistat), and TDF rather than TAF was
mainly used in the backbone. Nevertheless, these data can likely apply to Symtuza®
– it has already primarily supplanted all other PI regimens due to its simplicity (one
tablet, with a meal). In AMBER, the TAF-containing STR Symtuza® was less nephro-
toxic than TDF+FTC plus darunavir/c.
TDF/FTC plus darunavir/r was as effective and especially better gastrointestinally
tolerated than TDF/FTC plus lopinavir/r in ARTEMIS (Orkin 2013). The lipid profile
was better compared with lopinavir/r but less favorable compared with doravirine
(Molina 2020). In two larger studies, gastrointestinal symptoms resulted in a slightly
worse virologic outcome than with the INSTIs dolutegravir and raltegravir, respec-
tively (Clotet 2014, Lennox 2014). Exanthem, usually moderate, may occur in about
5–10%; abacavir should be avoided in the backbone. Although dyslipidemias are
mostly moderate, cohort studies suggest a slightly increased cardiovascular risk
(Lundgren 2017).
The resistance barrier of darunavir is very high, and resistance is practically non-
existent in first-line therapy. Therefore, Symtuza® is an option, especially for highly
viremic AIDS patients and in cases of doubtful adherence. It should be noted,
however, that viremia often declines much more slowly than with INSTIs. Sometimes,
it takes up to 6 months to get below 50 copies/mL. Other disadvantages, as with all
boosted combinations, are potential interactions.

Alternatives
TDF/TAF+FTC plus atazanavir/c/r is not available as a fixed combination.
Atazanavir is now only available generically; the original Reyataz® is off the market.
The main drawback is hyperbilirubinemia. In ACTG 5257, atazanavir was inferior to
darunavir because of this side effect (Lennox 2014). In two large trials WAVE and
ARIA in treatment-naive women, this was also true compared to elvitegravir and
dolutegravir (Squires 2016, Orrell 2017). Resistance, however, is a rarity. Atazanavir
is the only PI for which boosting is not mandatory (Malan 2008, Squires 2009) –
perhaps an advantage, although numerous limitations apply (no PPIs or resistance).
The low-dose TAF (10 mg) must be used. In most countries, atazanavir is no longer
part of any reasonable combination.
TDF/TAF+FTC plus lopinavir/r offer generics for these previously widely used
regimens. However, following the results from ARTEMIS and ACTG 5142 (see above),
they have been downgraded in many guidelines. Due to dyslipidemias (cardiovas-
cular risk?), gastrointestinal side effects (diarrhea!), and pill count (four daily, plus
backbone), they no longer play a role.
174 ART

Reasons for Symtuza® in first-line therapy

• High viremia (PIs have a high resistance barrier!).
• Low CD4 T-cells, AIDS disease (“late presenter”).
• Pre-existing resistance mutations (especially NNRTIs), lack of resistance testing.
• Unsteady adherence (“high forgiveness”), breaks in therapy.
Reasons against
• Interacting co-medication, e.g., chemotherapies, DAAs, but also some calcium
antagonists, statins, etc.
• Use of party drugs (possible interactions).
• Cardiovascular history (elevated lipids, possibly slightly increased risk of myocar-
dial infarction for darunavir).
• Gastrointestinal problems before ART initiation.
• If the viral load needs to be reduced very rapidly.

3. Two NRTIs plus one integrase inhibitor

Raltegravir was the first integrase strand transfer inhibitor (INSTI) approved for first-
line therapy in 2009, and there are now four (the fifth, cabotegravir, is not licensed
for first-line, see below). The second-generation INSTIs bictegravir and dolutegravir
are strongly recommended, and raltegravir and elvitegravir are considered alterna-
tives (Table 6.6). The tolerability and efficacy of these regimens are excellent;
however, except for raltegravir, long-term data over more than ten years still need
to be provided. In the PROPHET trial, 407 patients from 24 centers started ART for
the first time in 2014/2015; the INSTI arm was recruited more than twice as fast as
the PI and NNRTI arms combined (Wolf 2015). Besides good tolerability, one advan-
tage of INSTI-based regimens is rapid viral load reduction, which is faster than with
other classes. A disadvantage may be weight gain, which may be greater with dolute-
gravir and bictegravir than with first-generation INSTIs (Hester 2022).
Table 6.6: Factors influencing the selection of a specific INSTI-containing first-line therapy (the long-
acting INSTI cabotegravir is approved only for pre-treated patients).
Dolutegravir Bictegravir Elvitegravir Raltegravir
Pill count plus NRTIs/day 1–2 1 1 3
Once a day? yes yes yes yes
Taking with a meal? no no yes no
Resistance risk 0% 0% 1% 1–2%
Interaction risk low low high very low
Most important side effect Sleep Sleep Diarrhea, ?
disorders disorders headache
Long-term experience, years 5–8 5 8–10 > 10
Preferred backbone (ABC)+3TC TAF+FTC TAF+FTC none
STR Triumeq®, Dovato® Biktarvy® Genvoya®, Stribild® –

Recommended combinations
TAF/FTC/bictegravir has rapidly become a major option in first-line therapy with
the approval of the fixed combination Biktarvy® in June 2018. Biktarvy® was
compared against dolutegravir in two large Phase III trials. In GS-1489, the
5.6. The optimal first-line therapy 175

comparator was ABC/3TC/dolutegravir (Triumeq®), in GS-1490 it was TAF/FTC plus

dolutegravir. In both studies, Biktarvy® was virologically non-inferior to comparator
therapy at 96 weeks. There were few discontinuations and/or virologic failures and
not a single case of resistance. The resistance barrier is expected to be similar to that
of dolutegravir. Tolerability is good and slightly better compared to Triumeq®. In
GS-1489, however, probably TAF versus abacavir made the difference; there seems
to be virtually no difference between bictegravir and dolutegravir (Wohl 2018+2019,
Stellbrink 2019). Nor, incidentally, with regard to the effect on bone, lipids, kidneys,
and weight gain. In both studies, patients gained 4–5 kg in weight after 144 weeks
(Orkin 2020). Neuropsychiatric side effects are also similarly common (Hoffmann
2020). Extensive studies in first-line therapy comparing INSTIs with PIs or NNRTIs
are lacking. A disadvantage is that bictegravir is only available in a fixed combination.
ABC/3TC (or TAF/FTC, TDF/FTC) plus dolutegravir is an essential option in first-
line therapy since the approval of dolutegravir in early 2014. The fixed combination
ABC/3TC/dolutegravir (Triumeq®) was the first STR without tenofovir in mid-2014.
As with all abacavir-containing regimens, prior HLA testing should be considered; if
the decision is made to use tenofovir, the TAF dose of 25 mg should be selected. In
comparison with other agents, dolutegravir-containing combinations always
performed well. In the SINGLE trial, Triumeq® was more effective because it was more
tolerable than Atripla® (Walmsley 2013). In SPRING-2, the non-inferiority of
dolutegravir to raltegravir was demonstrated in a double-blind design (Raffi 2014).
Impressively, data from the FLAMINGO trial showed not only a slightly better
response than under a boosted PI regimen with darunavir but also no single resist-
ance mutation appeared (Clotet 2014) – although neither did with darunavir – this
trial set the bar very high for resistance. In the ARIA trial, dolutegravir showed better
efficacy in women (Orrell 2017). In 1489/1490, it was equal to bictegravir (see above).
The resistance barrier of dolutegravir is probably higher than that of first-generation
INSTIs; however, it is also not unlimited and insufficient for monotherapies.
Tolerability is good, and gastrointestinal side effects are rare. In about 5–6%, mild,
reversible CNS side effects (sleep and other neurologic disturbances such as pares-
thesias, dizziness, and depression) with dolutegravir lead to discontinuation. The
mechanism is unclear; dolutegravir probably penetrates the blood-brain barrier better
than other INSTIs. In our experience, adverse events are more common in women,
the elderly, and when abacavir is initiated concomitantly (Hoffmann 2017). In these,
discontinuation rates are as high as 15%. The combination with TAF/FTC means two
pills; moreover, because of the patent protection of TAF/FTC, over 300 euros in
therapy costs more monthly.
Following the WHO recommendation 2021, TDF/FTC/dolutegravir (“TLD”) has since
become the most widely used HIV regimen in the world. In Europe, TLD is not
available. Before considering TDF/FTC and dolutegravir, it may be wiser to use
dolutegravir/3TC (see below).
Alternatives
TDF/FTC or TAF/FTC plus raltegravir have the most long-term experience; ralte-
gravir was the first INSTI in 2007. In the first years, raltegravir was given twice daily
only. In STARTMRK, raltegravir was at least as effective as efavirenz (Lennox 2010).
Viral load decreased more rapidly, and CD4 T-cells increased more significantly.
Moreover, tolerability was better, with effects lasting 196 weeks (Rockstroh 2011).
Data on raltegravir to date are predominantly data on TDF-based NRTI backbones.
However, a pilot study with ABC/3TC plus raltegravir did not show anything negative
(Young 2010), so one is probably relatively free with the choice of NRTI. In SPRING-2,
raltegravir was slightly weaker than dolutegravir. In the double-blind design in which
176 ART

the NRTI backbone (TDF/FTC or ABC/3TC individually selected) was given open-
label, about 5% fewer achieved a viral load below 50 copies/mL after 48 weeks (Raffi
2014). The resistance barrier is likely lower than for dolutegravir. In the three-arm,
open-label ARDENT trial, raltegravir was superior to the PIs atazanavir/r and
darunavir/r overall, but more resistance occurred (Lennox 2014). Resistance is
expected to occur in 1–2% in first-line therapy, somewhat more frequently than with
darunavir/r or second-generation INSTIs.
Raltegravir-based therapies are excellently tolerated. Discontinuations due to side
effects are virtually non-existent. Another advantage is the very low interaction
potential, which can be used with vulnerable co-medication (chemotherapies, tuber-
culostatics, etc.). The main disadvantage is the lack of an STR. Raltegravir is the only
recommended substance yet to be given as a single agent. Until 2017, even single-
dose administration was not possible (Eron 2011). With a new formulation, two
tablets of 600 mg each have been possible since July 2017, allowing single-dose
administration. The double-blind, randomized ONCEMRK trial demonstrated non-
inferiority in 802 PLWH (Cahn 2017). Nevertheless, the “convenience disadvantage”
remains: raltegravir plus NRTIs is three daily tablets.
TAF/FTC/elvitegravir/c: The fixed combination with TAF (Genvoya®), approved in
January 2016, has largely displaced the old fixed combination with TDF (Stribild®).
However, in most trials, elvitegravir/c was still combined with TDF; in two large
Phase III trials, it was comparably effective to efavirenz or atazanavir over 144 weeks
(Clumeck 2014, Wohl 2014) and even better than atazanavir in women in the WAVE
trial (Squires 2016). Direct comparisons in first-line therapy with other INSTIs are
lacking. Renal problems evident under Stribild® are no longer relevant under
Genvoya® – there were significantly fewer renal and osseous side effects in two
significant Phase III trials (Sax 2015). Genvoya® can also be dosed normally in
moderate renal insufficiency (GFR up to 30 mL/min). Mild increases in creatinine
due to inhibition of tubular secretion usually do not indicate renal dysfunction, but
renal monitoring is more complicated. Other tolerabilities of either are good, with
nausea, moderate headache, and mild diarrhea most likely to occur. Resistance is
rare, although more common than with dolutegravir, occurring in about 1–2% and
often affects two classes. In cases of poor adherence, Genvoya® should be avoided.
Another (and probably the most relevant) disadvantage is the pharmacoenhancer
cobicistat. Therefore, agents metabolized by CYP3A are contraindicated or should
be used cautiously. This is a particular problem in the elderly with extensive
co-medications. Bictegravir, which is also combined with TAF+FTC and does not
require boosting, has already partially replaced elvitegravir. There is probably no
future for Genvoya® in first-line therapy.

Rationale for INSTI regimens in first-line therapy

• High viremia, rapid viral load reduction required.
• Interaction-prone co-medications such as chemotherapies and tuberculostatics
(especially raltegravir is suitable).
• Cardiovascular pre-existing conditions (favorable lipid profile).
Reasons against
• Pre-existing resistance (sporadic).
• High risk of interactions with co-medication (applies only to elvitegravir/c!).
• Renal insufficiency (more difficult monitoring with elvitegravir, dolutegravir, and
bictegravir).
• Sleep disorders (dolutegravir, bictegravir).
• Planned pregnancy (especially for bictegravir, less experience than with other classes).
5.6. The optimal first-line therapy 177

4. NRTI-sparing therapies
The fact that most classic ART regimens in the first line contain two NRTIs each as
the backbone is historical. NRTIs were the first drugs on the market, and by the time
NNRTIs and PIs were in development, treatment with two NRTIs was the standard.
With growing knowledge of the high resistance barrier of modern agents, the
omission of NRTIs is also being investigated in first-line therapy. In this so-called
dual therapy, only one (or even no) NRTI is given – this is usually 3TC, as it is the
least toxic and generically available. Dovato®, a dual therapy (“2DR”), was approved
for the first time in 2019; since 2021, it has been recommended in the EACS guide-
lines for specific conditions and no longer only as an alternative (see below).

Recommended combination (as an alternative)

Dolutegravir/3TC: Dovato®, the fixed combination of dolutegravir and 3TC, became
available in August 2019 as the first 2DR for treatment-naïve patients. It is licensed
from 12 years of age (at least 40 kg), provided there is no resistance to INSTIs or 3TC,
is based on the two GEMINI trials. These compared dolutegravir/3TC in a double-
blind fashion with dolutegravir plus TDF/FTC in 1,433 patients with viral loads less
than 500,000 copies/mL (Cahn 2019). At 96 weeks, 89% versus 86% were below the
limit of detection, and at 144 weeks, 84% versus 82%. Non-inferiority was thus
achieved. Virtually no resistance was seen in the few cases of treatment failure to
date. Serious adverse events were equally frequent, with only a slight difference in
“drug-related AEs” at 96 weeks (20% versus 25%) and in some renal and bone bio-
markers. The fact that response rates were worse with low CD4 T-cells below 200
(79% versus 93% at 48 weeks, small case numbers) led to intensive research. Probably
no trial in recent years was studied more closely than GEMINI. There were no
differences at high viral loads, either in terms of blips or low viremia, even when
measured with ultrasensitive assays (Li 2019). Viral shedding under Dovato® is
virtually identical to a standard regimen in the first few weeks (Gillman 2019), both
in plasma and semen (Charpentier 2019). Interestingly, even with poor adherence,
the response was no worse than with triple therapy (Ait-Khaled 2021).
Overall, a relevant difference between 2DR and conventional regimens is rather
unlikely. However, there are no clear advantages to report so far either. With the
introduction of TAF, the need for 2DR has decreased. The EACS guidelines recom-
mend the combination, limited to patients with less than 500,000 copies/mL, no
HBsAg, and no history of PrEP. We use Dovato® relatively often, though rather
infrequently as first-line. It would be nice if a study could show better tolerability
compared to TAF-containing combinations. A lower weight gain under 2DR would
be a start (up to now, no evidence supports this, however).

2-drug combinations or Dual therapy

In addition to dolutegravir plus 3TC, other 2DR regimens have been tried, mostly
with moderate success. Moreover, the studies were often insufficiently powered.
Darunavir/r plus raltegravir: In NEAT001, 805 PLWH received either darunavir/r
plus raltegravir or standard therapy of darunavir/r plus TDF/FTC (Raffi 2014). At 96
weeks, tolerability and virologic failure were approximately equal (19% versus 15%).
However, a slight virologic disadvantage was seen with low CD4 T-cells and high
viral load. Over 96 weeks, the cumulative risk of resistance for darunavir/r plus
raltegravir was 3,9%. No resistance was observed in the standard arm (Lambert-Niclot
2016). Lipids were also slightly worse. Regarding renal and osseous side effects, Nuke-
Sparing fared better in return (Bernadino 2015). The EACS guidelines briefly included
darunavir/r plus raltegravir as an alternative first-line therapy in 2015, but this
approach has since been removed. There is no argument for this 4-pill ART.
178 ART

Lopinavir/r or darunavir/r plus 3TC: All the individual agents are generically avail-
able. The best data are available for lopinavir/r. For example, in the GARDEL trial,
lopinavir/r+3TC was tested against lopinavir plus 2 NRTIs in 426 patients (Cahn
2014). After 48 weeks, 88% versus 84% were below 50 copies/mL in the dual arm (as
high as 87% versus 79% in the high viral load arm) – more patients in the standard
arm discontinued due to side effects. Lopinavir/r+3TC could save costs in resource-
poor countries. For darunavir/r, there is only preliminary data (Sued 2017). In Europe,
these combos do not make sense.
Darunavir/r plus maraviroc: Yielded disappointing results in the MODERN study
(Stellbrink 2016). After 48 weeks, only 77% were below 50 copies/mL, compared to
87% in the standard arm with TDF/FTC plus darunavir/r. Especially at high viral
loads, nuke sparing was clearly inferior (65% versus 80%). Although the results were
independent of the tropism assay used, it is likely that tropism assay only sometimes
provided valid results. Tolerability was comparable. Although resistance was mostly
absent, this nuke-sparing strategy has no place in first-line therapy. It is weaker, after
all, regardless of the reason.

Dual therapy in first-line therapy

• Sufficient data only for dolutegravir+3TC (Dovato®), which was tested against the
triple combination containing TDF, not TAF.
• Dovato® is approved for first-line since 2019.
• It should not be used with patients with fewer than 200 CD4 T-cells or an HIV RNA
greater than 500,000 copies/mL, with a history of HBsAg, or with previous PrEP use.
• Other dual therapies (with maraviroc or raltegravir) were somewhat weaker than
standard therapies in some cases, especially in high viremia.
• So far, there is no evidence for better tolerability or any other relevant benefit in
the long term.

5. Unfavorable first-line therapies that should be avoided

T-20, maraviroc, etravirine, and tipranavir are not approved for first-line therapy,
nor is Juluca®. Toxic agents like AZT and ddI (withdrawn from the market) should
also be avoided, as should old PIs such as fosamprenavir or saquinavir (QT prolon-
gation!). Unfavorable combinations also include all monotherapies – and apart from
Dovato®, all dual therapies. NRTIs should not compete for the same bases; two
cytidine analogs (FTC+3TC) act antagonistically. TAF plus TDF is also nonsense, of
course. Previously studied strategies such as “swing therapies” (changing regimen at
regular intervals) or cautious “creep-in” (starting every other day or not with a
complete combination) also make no sense in modern times and should be avoided.
Monotherapies: Mainly, PIs were tested. In MONARK, only 64% achieved a viral
load below 50 copies/mL after 48 weeks on lopinavir/r (Ghosn 2010). Darunavir/r
was also weak in a pilot study (Patterson 2009). For dolutegravir, there are isolated
cases (Lanzafame 2017). In most cases, low viremia is measurable. Given the many
well-tolerated combinations, this strategy has no rationale (Gallant 2017).
Induction therapies: Occasionally, even today, the question is raised as to whether
more intensive approaches are necessary when the viral load is high. Given theo-
retical concerns for the rapid development of resistance, an “induction” of four or
five drugs is then started, which is later de-escalated. The effect of this approach,
however, has never been validated; a 2000–2016 meta-analysis showed no benefits
(Feng 2016). More single agents do no good. Two PIs or NNRTIs each instead of one
even had negative consequences. There is also no reason for three NRTIs instead of
5.6. The optimal first-line therapy 179

two. ACTG 5095 showed no differences between Combivir® and Trizivir® in 765
patients on efavirenz (Gulick 2004). But maybe just more than two drug classes? The
larger trials of three drug classes instead of two – mostly with outdated agents such
as nelfinavir and ddI+d4T – found no benefits. The addition of raltegravir to con-
ventional triple ART was of no benefit (Kityo 2019). This was also the case in at least
two studies in which acutely infected individuals had their PI/r-based triple therapy
intensified by maraviroc and raltegravir, respectively (Markovitz 2014, Chéret 2015).
Induction therapies that only produce toxicity and cost should be avoided. Cases
with multiple primary (transmitted) resistances are an exception.
Triple- or quadruple-nuke no longer have a place in first-line therapy. They are too
toxic and less effective (Gulick 2004). Under AZT-free combinations such as
TDF+3TC+ABC, there is also a risk of early virological treatment failure, probably
due to low genetic resistance barrier (Gallant 2005, Khanlou 2005).

Easily avoidable errors in first-line therapy

• All monotherapy or dual therapy (except dolutegravir+3TC), but also a “gradual
introduction” – always start with the full ART!
• T-20, tipranavir, etravirine, maraviroc, long-acting (not approved for first-line
therapy).
• Old drugs: AZT, ddI, saquinavir, fosamprenavir, nevirapine.
• 3TC+FTC (antagonistic), TAF+TDF, Triple- or Quadruple-Nuke.
• Induction with more than 3 drugs, even with high viremia.
• Simultaneous initiation of abacavir, darunavir, and NNRTIs (allergy potential).

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5.7. Management of side effects 183

5.7. Management of side effects

C H R ISTIAN HOFFMAN N

The first generation of antiretroviral therapies has come and gone. AZT, d-drugs,
efavirenz, nevirapine, or most PIs are hardly or not used anymore. Modern thera-
pies are much better tolerated. Adverse drug reactions, which used to require a change
in almost half of the patients, have become considerably less important. On the
other hand, the choice has increased, and there is greater flexibility in responding
to mild side effects or those for which a relationship is questionable. In European
cohorts, the rate of side effect-related treatment modifications is around 20–25%
after one year, with a recent slight downward trend (Helleberg 2012, Pantazis 2015).
On the other hand, some side effects become apparent only after approval – think
of lipodystrophy, neuropsychiatric events, or weight gain. In addition, there is
concern about long-term toxicities.

Switching due to acute adverse events

It is not always necessary to change ART immediately. Gastrointestinal side effects
in the first weeks are not dangerous, can be treated well, and often improve. This is
also true for mild CNS disturbances under INSTIs. For mild allergies, one can also
wait on antihistamines. However, ART must be changed rapidly for some problems
(see box).

Side effects that usually require discontinuation/switch

• Severe diarrhea persisting despite loperamide (lopinavir, darunavir, less
pronounced other PIs, but also elvitegravir, dolutegravir).
• Severe nausea (most likely AZT, rarely TDF).
• Persistent sleep disturbances and other neuropsychiatric events (efavirenz, but
also dolutegravir, bictegravir).
• Polyneuropathies (formerly d-drugs, regression often very slow).
• Severe anemias (AZT).
• Progressive muscle weakness, pancreatitis (formerly d-drugs, now rare).
• Lactic acidosis (formerly d4T+ddI, now very rare).
• Severe allergies with mucosal involvement and/or fever (most likely ABCs,
NNRTIs, less commonly fosamprenavir, darunavir).
• Renal failure (TDF).
• Severe osteoporosis, osteomalacia (TDF, all PIs).
• QT prolongations (saquinavir, also rilpivirine, in principle many others).
• Hepatotoxicity with transaminases > 100 U/l (nevirapine, tipranavir).
• Manifest icterus (nevirapine, atazanavir, tipranavir).
• Rhabdomyolysis (raltegravir).
• Depression, psychosis (efavirenz, possibly also dolutegravir).

Switching due to side effects on virologically successful ART is usually straightfor-

ward. The suspected drug is replaced by another from the same class. It becomes
more complex, however, if other drugs are contraindicated or resistant. Especially in
complex cases with often more than 20 years of previous therapy, decisions can only
be made on an individual basis. In some centers, therefore, “switch consultation
rounds” have been established, in which complex cases are discussed jointly by virol-
ogists (who usually know what might make sense in the specific resistance situation)
and clinicians (who usually know what does not make sense in any particular case).
184 ART

Switch due to potential long-term toxicity

Virologically successful and well-tolerated combinations have been (and still are)
often switched due to concern for potential long-term toxicities such as lipodystro-
phy or renal or bone problems. Unfortunately, in many cases, the evidence for any
benefit of a treatment switch is poor, and switching is just done to do something.
Although the complaints of the patient cannot be attributed to a specific agent
(classic examples: fatigue syndrome, loss of libido or weight gain, etc.), ART is
modified anyway, according to the slogan, “If it gets better, we were right, if not, we
can switch back again”.
The many switch studies conducted in the past decade prove that the market is very
competitive. Every company is trying to bring its products to market with the broad-
est possible license, including both naïve and the larger group of pre-treated patients.
As a result, huge switch studies are designed in which patients are switched to the
company’s own drug immediately or later. The efforts are enormous, but the infor-
mation value remains often limited. In most studies, patients are on successful ART
regimens before switching. Simply showing that a new therapy is not virologically
inferior is not a convincing reason to switch.
In open-label randomized trials, it should be noted that all participants (and their
treating physicians) are influenced by the current setting and access to ART. The
larger the options outside the trial, the more likely even moderate side effects play
a role. Who wants to take an “old” combination today, especially in a clinical trial?
If a patient is then randomized to the efavirenz arm or the arm with “continuation
of the old combination” and not to the new fancy STR, the switch is made quickly
if there are only moderate CNS problems – and already the discontinuation rates of
the old combination are rising, while the new preparation is doing well. One example
is efavirenz, which was used as a comparator arm for many years: the discontinua-
tion rates have sharply risen in recent years. If, on the other hand, new side effects
occur with the new preparation, the manufacturers like to argue that a certain
percentage of patients can always be expected to develop problems after a switch.
Cleverly launched “reviews” financed by the industry suggest that one should “proac-
tively” think about “contemporary” treatment changes – without it being clear why.
Keeping one’s head clear in this setting is not always easy.
Again, simply showing that a new therapy is not virologically inferior in success-
fully treated patients is no longer sufficient today. The more important questions
are actually, “What is the benefit to switching?”, “Are there data on long-term tox-
icity? Is there any argument for switching in the long run?”, “Who should not switch,
when is the risk too high?”, “How relevant are the prior therapies?” Unfortunately,
these questions are either not answered at all or only partially.
Overall, continuing a virologically successful, well-tolerated ART is not malpractice.
Nevirapine still has its fans. Not everyone needs to switch to a new, expensive STR.
The most important recent switch studies are discussed below. A particular focus will
be on what is improved by such strategic switches.

Replacement of the protease inhibitor

PIs undoubtedly have some potential for long-term side effects. The often significant
dyslipidemias could increase cardiovascular risk in the long term. Insulin resistance
cases of diabetes mellitus have been described. Lipodystrophy has also long been
attributed to PIs. However, whether it is due to PIs has been increasingly questioned
recently (McComsey 2016). Interestingly, excessive weight gain is also significantly
more common among INSTIs than PIs (see below).
5.7. Management of side effects 185

Table 7.1: Randomized studies on protease inhibitor replacement (selection).

Study (reference) n Last ART Significant effect of the switch
INSTIs
SWITCHMRK 702 100% LPV/r Switch to raltegravir (NRTIs same):
(Eron 2010) AEs same (rare), lipids better. Study was prematurely
terminated (more VF with RAL).
STRATEGY-PI 443 40% ATV/r Switch to elvitegravir (Stribild®):
(Arribas 2014) 40% DRV/r AEs same (including diarrhea), lipids slightly better
(triglycerides), slight creatinine increase.
NEAT022 415 51% DRV/r Switch to dolutegravir (NRTIs same):
(Gatell 2017) 37% ATV/r DR-AEs more frequent (13% vs 7%, mostly mild),
lipids better, GFR slightly worse, more weight gain.
GS-1878 578 48% DRV/r Switch to TAF/FTC/bictegravir (Biktarvy®):
(Daar 2018) 36% ATV/r DR-AEs more frequent (19% vs. 2%, mostly mild),
lipids little changed, GFR slightly worse.
NNRTIs
SPIRIT 476 37% ATV/r Switched to rilpivirine (Eviplera®): AEs overall same
(Palella 2014) 33% LPV/r (but 7 vs. 0 discontinuations), lipids significantly better.
DRIVE-SHIFT 670 37% DRV/r Switch to doravirine (Delstrigo®): DR-AEs more
(Johnson 2019) 22% ATV/r frequent (22% vs. 2%), mostly mild, lipids better*.
Maraviroc
MARCH 395 35% ATV/r Switch to maraviroc (NRTIs same): Lipids better,
(Pett 2016) 28% LPV/r bone mineral density slightly better.
All studies were randomized open-label against continuation of PI. Where available, 48-week data are
shown. All patients had been on PIs for several months at the switch time point and had a viral load
below the detection limit. VF = Virologic Failure. DR AEs = Drug-related Adverse Events. PI/r can also
mean PI/c. *29 were on non-PI regimens at baseline.

The study situation on replacing a virologically successful PI with other classes

currently provides the following picture: it is largely virologically safe for INSTIs and
NNRTIs if the viral load was previously constantly suppressed and no resistance exists
(Table 7.1). Lipids are almost always favorably affected by the replacement of the PI,
although the backbone also plays specific roles: TDF has a favorable effect, TAF none.
In lipodystrophy, the effects of PI replacement are weaker and less well character-
ized so far. In other respects, too, one should not expect too much benefit. INSTIs
are not always better tolerated; in NEAT22 or GS-1878, more subjective side effects
occurred under dolutegravir or bictegravir, respectively. This also applies to doravirine.
Replacing the PI can also pose virologic risks, especially with long-term pre-treat-
ment. This was the bitter experience MSD made with raltegravir in 2010 in the
SWITCHMRK trials (Eron 2010). A total of 702 PLWH on stable lopinavir/r therapy
were randomized to switch to raltegravir or continue lopinavir/r. Inclusion criteria
were not very strict; the only requirement was a viral load below 50 copies/mL with
at least three months of lopinavir/r therapy. After 24 weeks, only 82% remained
below 50 copies/mL with raltegravir, compared with 88% with continued PI. The
study was terminated early. Breakthroughs were primarily seen in pre-treated patients
with prior treatment failure. Unfortunately, data on resistance, type, and duration
of pre-treatment were unavailable; the study was designed somewhat naively.
Although the experience could not be replicated in a small Spanish study (Martinez
186 ART

2010), something stuck after SWITCHMRK. Companies became more cautious. Since
then, in studies similar to STRATEGY-PI and switch studies with STRs (see below),
patients with previous failure have been consistently excluded, i.e., often precisely
those in whom it would have been interesting to see whether the PI is necessary.

Replacement of NNRTIs
The first-generation NNRTIs nevirapine and especially efavirenz, have some side
effects. In GS-1160, patients switched from TDF/FTC/efavirenz (Atripla®) to
TAF/FTC/rilpivirine (Odefsey®); the switch was safe, but the other effects were
moderate. Interestingly, GFR decreased, but less proteinuria and increased bone
density were measured. Lipids remained very similar (positive effect of switching
efavirenz to rilpivirine, adverse effect of TAF instead of TDF). If switching to rilpivirine
is not desired because of dietary restrictions, doravirine may be an option. However,
in DRIVE-SHIFT, only a subgroup of around 100 patients was on older NNRTIs (mainly
efavirenz), and the switch remained without any changes (Johnson 2019).
A switch to INSTIs may also be considered. In STRATEGY-NNRTI, 439 patients either
remained on their NNRTI therapy (mostly efavirenz) or switched to Stribild®, the
co-formulation of TDF/FTC/elvitegravir/c. The CNS side effects seen with efavirenz
improved, and virologic control persisted (Pozniak 2014). The latter was also true
for patients in STRIVING (Trottier 2017), who had switched from mostly NNRTI-
based regimens to ABC/3TC/dolutegravir (Triumeq®). However, adverse events
occurred more frequently in the switch arms in both studies. For elvitegravir/c, these
were headaches and nausea; for dolutegravir, they were primarily CNS problems.
Again, it became clear that well-tolerated NNRTI regimens do not need to be switched.

Replacement of NRTIs (with each other)

Thymidine analogs such as d4T and AZT thought to play a leading role in mito-
chondrial toxicity, should be replaced by other NRTIs. d4T and ddI no longer have
any place in HIV therapy, and their distribution has been discontinued. Lipoatrophy
improves by switching to TDF or abacavir, as well as lipids, to a large extent (review:
Curran 2011). In particular, subcutaneous adipose tissue in arms and legs increases,
although the improvements are often not visible and only detectable in DEXA scans.
The situation is also evident for AZT: it should be replaced whenever possible, and
lipoatrophy should be improved (Ribera 2013).
What about TDF? It appears to have a direct lipid-lowering effect. In the double-
blind, randomized ACTG A5206 trial, simply adding TDF to ongoing ART improved
lipids versus placebo (Tungsiripat 2010). This was also the case in randomized trials
when switching from ABC+3TC to TDF+FTC, both in patients on PIs (Behrens 2012)
and efavirenz (Moyle 2015). The cause of the lipid-lowering effect remains unclear,
however. A negative effect of switching to TDF is a reduction in bone density
(McComsey 2011, Haskelberg 2012, Rasmussen 2012), which improves after replace-
ment of TDF (Bloch 2014). The potential nephrotoxicity of TDF should also be noted.
With TAF, at least the renal problems are obsolete. In several studies, switching from
TDF to TAF was favorable regarding osseous and renal problems in patients with and
without renal insufficiency (Mills 2016, Pozniak 2016). However, lipid-lowering
effects are no longer present with TAF; in one study, lipids increased significantly
after switching from TDF to TAF (Mills 2016). In GS-1717, a large double-blind,
randomized trial, switching from abacavir to TAF (unlike TDF) did not affect lipids
or renal and bone biomarkers (Winston 2018). Weight gain with TAF is discussed,
and an analysis of multiple studies found a significant effect (DeJesus 2019). However,
it is debated whether TAF merely lacks TDF’s, catabolic effect (which would also need
to be proven).
5.7. Management of side effects 187

Switching to triple-nuke combinations containing tenofovir should be avoided for

virologic reasons alone; the risk of virologic treatment failure is too high (see below).

Switch due to (potential) side effects: What do we know?

• Virological control is almost always maintained.
• Risk of virological failure may be higher with a long treatment history, with resist-
ance in the NRTI backbone, especially with regimens with lower resistance bar-
riers (raltegravir).
• In PI replacement, lipids improve after switching to rilpivirine, INSTIs, or mar-
aviroc, but the clinical relevance of these changes remains unclear.
• It is unclear whether lipodystrophy also gets better (probably not).
• New drugs are not always better; there is a risk of “new” (usually mild) side effects.
• Most agents can be replaced by agents of the same class if mutations are absent.
• Other NRTIs should replace AZT due to its toxicity.
• Lipids are improved after replacing ABC with TDF (but not TAF).
• Replacing TDF with TAF or ABC improves renal function and mitigates the adverse
effects on bone density.

Side effects, classified by organ system

In the following, a practice-oriented overview will be given, which mainly discusses
the consequences with regard to ART. For space reasons, the often remarkably detailed
recommendations on management that go beyond ART modifications are omitted.
The box summarizes the most important things.

Side effects of modern ART, management at a glance

• Dyslipidemia: Replace PIs and efavirenz if possible, preferably use unboosted ART
plus statins, consider TDF instead of TAF, possibly also metformin (caveat: dolute-
gravir), strict LDL target values as in HIV-negative patients (maybe even lower).
• Gastrointestinal: Nausea almost only with AZT, diarrhea mostly with PIs and
elvitegravir. ART change is better than symptomatic treatment (loperamide if nec-
essary).
• Weight gain: all INSTIs (mostly dolutegravir, bictegravir), but maybe also TAF.
Women and blacks are more affected, and the effect of ART switch is still
unclear/unproven.
• Skin: Consider allergies with NNRTIs, darunavir/r, and abacavir (HLA typing
obligatory!) in the first weeks; no prophylaxis is beneficial, and simultaneous start
is not recommended.
• Cardiovascular: myocardial infarctions due to abacavir, possibly PIs. Consider
other regimens if patients are at high risk (the higher, the more urgent).
• Bone: osteoporosis, osteomalacia with TDF, PIs. If there is evidence or risk for
osteoporosis, replace if possible! Use vitamin D; if necessary, also biphosphonates.
• Liver: transaminases mainly elevated with nevirapine, tipranavir, less frequently
all other ARVs (caveat: viral hepatitis, common among MSM!). Bilirubin elevated
with atazanavir, GGT with nevirapine.
• Lipodystrophy: old NRTIs, old PIs. Resolves slowly, incomplete. In case of severe
lipoatrophy, Sculptra®.
• Kidney: TDF!, especially in combination with boosted PIs. Caveat: creatinine
elevation under INSTIs (inhibition of secretion).
• Neuropsychiatric: efavirenz, but also less pronounced, dolutegravir, bictegravir
(mainly sleep disorders, but various clinical manifestations).
188 ART

Lipid metabolism disorders

Hyperlipidemias are common, especially on boosted PIs (especially lopinavir/r),
triglycerides, and triglyceride-rich lipoproteins (VLDL) increase, accompanied by LDL
elevations (Carr 1998, Maggi 2017). This is often compounded by hyperinsulinemia
and insulin resistance. The mechanism is multifactorial and due to both inhibition
of the GLUT4 transporter and increased ApoB release with increased free fatty acid
turnover and lipolysis (Liang 2001). Darunavir or atazanavir have significantly fewer
metabolic side effects than old PIs (Spinner 2016). Dyslipidemias are also typical
under efavirenz; it should be replaced by other NNRTIs or INSTIs. In contrast, (mod-
erate) lipid-lowering effects are observed with TDF but not with TAF (Santose 2019,
Milinkovic 2019). Standard scoring systems (Procam or Framingham) should be used
for cardiovascular risk evaluation. If glucose levels are elevated, HbA1c should be
determined.
If the ten-year cardiovascular risk is above 10%, diet, exercise, and replacement of
the PI (see above) should be discussed. Of course, smoking must also be discussed
(Petoumenos 2016).
The threshold values are stricter than previously defined. The EACS guidelines (2019)
recommend LDL levels of < 80 mg/dl and even < 55 mg/dl in secondary prevention,
high-risk, and/or diabetes mellitus. Admittedly, this is usually not achievable without
statins. Rosuvastatin or atorvastatin are preferable to others; caution is advised
because of interactions, especially if the PI or a booster must remain in the ART
regimen (choose the lowest statin doses). Statins may be of even higher benefit in
PLWH than in HIV-negative people.

Table 7.2: Options for HIV-associated lipodystrophy and metabolic complications.

General measures (adjust diet, physical activity, nicotine cessation).
Switching ART – replacement of PIs, efavirenz, old NRTIs, TDF instead of TAF?
Statins, e.g., atorvastatin or rosuvastatin (generics!), preferably without booster ART (also consider
Genvoya®) because of interactions.
Metformin (generic) – caution with dolutegravir (choose lower metformin doses).
Surgical procedures in cases of severe lipodystrophy.

Metformin (2 x 500–1,000 mg daily) showed a positive effect on insulin resistance

in two studies and a tendency to reduce intra-abdominal (but subcutaneous) adipose
tissue. In addition, it can reverse muscular adiposity when taken together with
endurance training. Interactions with dolutegravir may lead to higher metformin
levels (caveat in renal insufficiency).

Gastrointestinal tract
Gastrointestinal complaints used to be expected, nausea on AZT classic. Instead of
symptomatic treatment with metoclopramide (Paspertin®) or dimenhydrinate
(Vomex®), AZT should just be removed. With TDF or modern antiretrovirals, inter-
vention is very rarely needed. Usually, there is a psychological aversion of the affected
person that leads to nausea or even vomiting. Talk with the patient! Diarrhea is more
likely, observed with all PIs, especially lopinavir, less so under darunavir. Diarrhea is
also seen with elvitegravir and rarely with dolutegravir or bictegravir. If possible, the
PI or elvitegravir should be replaced; symptomatic therapies such as psyllium
(Mucofalk®, 1–2 times daily, one tablespoon, max. 30 g/day) or probiotics (contro-
versial) are rarely helpful. Loperamide or opium tinctures help in the short term, but
there are habituation effects and potential for abuse. Depending on the temporal
occurrence of diarrhea, infectious and other causes such as lactose/fructose intoler-
ance should also be ruled out, primarily if a change in ART does not provide relief.
5.7. Management of side effects 189

Weight gain
Weight gain is probably one of the most important topics of recent years (reviews:
Hester 2022, Kanters 2022). The sheer mass of (mostly) cohort studies is confusing.
The results as well. Several confounding variables need to be considered, and the
causes of weight gain are complex. The potential for bias is large, especially if weight
is not systematically recorded (which is the case in very few cohorts). Who was
weighed, why, and how often? The genesis of obesity is multifactorial.
In addition, most people gain weight over time, which makes it difficult to separate
the additional effects of ART, especially the effect of a single antiretroviral agent.
Moreover, with an average weight gain of one to two kilos, some people have gained
quite substantially, others have a relatively stable weight, and others have even lost
weight. There are increasing calls for standardized evaluations to shed more light on
the problem (Venter 2021).
Especially dolutegravir and bictegravir, but also older INSTIs are probably involved.
Women and black people seem more affected; in the ADVANCE study, South African
women had gained an average of over 9 kg after two years (Venter 2020), predomi-
nantly fat, as evidenced by DEXA scans. In the large Gilead 1489/90 trials, weight
gain was about 4–5 kg after three years with bictegravir and dolutegravir (Orkin
2020). In a pooled analysis of 8 randomized trials of 5,680 treatment-naïve PLWH
2003–2019, over 17% had gained more than 10% of body weight in just two years
(Sax 2019). In the OPERA cohort (US outpatient centers, 5,536 individuals), 18%
gained more than 5% of their weight within 28 weeks, and 9% gained more than
10% within 54 weeks (Hsu 2022). In a nationwide cohort from Greece, the preva-
lence of obesity was 5.7% at ART treatment initiation and 12.2%, 14.2%, and 18.1%
after four years of treatment with NNRTIs, PIs, and INSTIs, respectively (Pantazis
2022).
In treatment-naïve patients, however, a “return-to-health” effect has to be consid-
ered. This effect is possibly greater among INSTIs due to their more rapid viral load
reduction. Those who start their ART with an INSTI and who are in an advanced
clinical stage will quickly lower their viral load – and first gain weight, viewed pos-
itively. However, the “return to health” effect does not explain everything. Even with
good viral suppression, more significant weight gain is common with INSTIs. After
switching to dolutegravir, there was a moderate but significant increase in weight in
the Swiss cohort (n=2,186); overall, 22% had gained at least 5% body weight, with
risk factors again being women and blacks (Mugglin 2019). In NEAT22, patients
switched from darunavir/r to dolutegravir; within one year, this resulted in one kilo
of weight gain (Waters 2018). Several studies have now looked at mechanisms. It is
speculated that INSTIs affect adipocytes, adiponectin, mitochondria, insulin resist-
ance, and melanocortin receptors (Domingo 2020, Ayissi 2022, Jung 2022). Partly,
there is good evidence from animal models; partly, it is conjecture. There is proba-
bly also a genetic predisposition (Cindi 2021), and the gut microbiome may also be
involved.
However, it’s probably not only an INSTI problem. The NRTI backbone also plays a
role, especially TAF. In ADVANCE, weight gain was particularly pronounced on
dolutegravir plus TAF (Venter 2019), and a pooled analysis of 7 studies showed a
weight gain of at least one kilo per year, compared with TDF (DeJesus 2019). The
effects do not appear to be related to HIV. Participants also gained weight in the
largest (and double-blind randomized) PrEP trial, DISCOVER: by 1.7 kg after 96 weeks
on TAF+FTC, compared with only 0.5 kg on TDF+FTC (Ogbuagu 2021).
In switch studies, low baseline weight was identified as a risk factor for severe weight
gain. In addition, more significant weight gain occurred when switching from
190 ART

efavirenz or TDF (Erlandson 2022). It is possible, then, that “catabolic” effects play
a role in addition to INSTI effects. There are good arguments for this as well. Weight
loss with TDF-containing PrEP (review: Shah 2022), a lack of any visible effect from
stopping TAF in the randomized TANGO trial (Osiyemi 2022), and more gain with
dolutegravir+3TC than with TDF-containing dolutegravir regimens in the GEMINI
studies (Cahn 2022).
In summary, the data situation is growing rapidly, to the disadvantage of INSTIs and
partly also TAF. However, the mechanisms remain unclear (effect or side effect?);
they are possibly heterogeneous. Little is known about the consequences of weight
gain (diabetes? hypertension? CVD?). There is an urgent need for standardized and
detailed weight measurements in all future pivotal trials with longer follow-ups. We
also need well-controlled switch studies and more basic research (predisposition,
CNS effects – e.g., melanocortin-4 receptors). Much work remains to be done.
Standardized parameters must be defined. Opinions about acceptable weight gain
may differ, both among patients and among their clinicians. The only consensus
today is that the effects probably have nothing to do with lipodystrophy (see below)
but are somewhat due to increased food intake (appetite!).

What we know (and don’t know) about weight gain

• Mostly, INSTIs such as bictegravir and dolutegravir are involved.
• Many mechanisms are suspected (including “return to health”), and a predispo-
sition is likely.
• The effects are either enhanced by TAF or reduced by TDF; there are now good
arguments for both theories.
• Weight gains can be substantial in some cases (10–20%), but the clinical conse-
quences have not yet been worked out.
• It is unclear whether switching to other therapies can slow, stop, or reverse weight
gain or metabolic changes

Skin and allergic reactions

Allergies have become rarer than before. They still occur mainly with NNRTIs,
darunavir, and abacavir in the absence of HLA testing. NNRTI allergy is a reversible,
immunologically mediated, systemic reaction. It typically manifests as macu-
lopapular, pruritic, and confluent exanthema – particularly on the trunk and arms.
It is most commonly seen with nevirapine but also with other NNRTIs. Fever may
precede; other symptoms include myalgias, fatigue, and mucosal ulceration. Allergy
usually begins in the second or third week of therapy. Women are more frequently
and severely affected, especially with nevirapine (Bersoff-Matcha 2001). Symptoms
more than eight weeks after initiation of therapy almost always have other causes.
Severe courses such as Stevens-Johnson syndrome, acute toxic epidermolysis (Lyell
syndrome), or anicteric hepatitis are rare. Alarm signals of a severe skin reaction
include mucosal involvement, blistering, exfoliation, transaminase elevation
(> 5-fold above average), or fever > 39 °C. The NNRTI must then be discontinued
immediately and forever. Approximately 50% of NNRTI allergies remit despite con-
tinuation of therapy. Antihistamines can be helpful, but prophylactic administra-
tion of corticosteroids or antihistamines is ineffective.
The exanthema with the sulfonamide-containing PI darunavir is clinically indistin-
guishable from NNRTI rash. It is reversible and responds well to antihistamines or
steroids. In most cases, darunavir can be continued (Nishijima 2014). The incidence
is about 10%, so darunavir should not be started concurrently with NNRTIs or
abacavir.
5.7. Management of side effects 191

Abacavir hypersensitivity reaction (HSR) is a systemic event that manifests during

the first weeks of treatment, often in the first few days, and can be fatal (see above).
HSR is closely associated with the HLA-B*5701 allele, which shows a prevalence of
5%, with country-specific estimates ranging from 1.5 to 7.8% (Orkin 2010). HLA-
B*5701 prevalence is highest in the self-reported white population (6.5%) and lowest
in the black population (0.4%). Abacavir interacts with the allele and induces a poly-
clonal T-cell response (Illing 2013). In the prospective Predict study in 1956 indi-
viduals from 19 countries, HLA-B*5701 testing prevented HSR when abacavir was
omitted if the test was positive (Mallal 2008). HSR without the allele is extremely
rare. The diagnosis is made clinically. Skin is involved in 70%, and fever is in 80%.
Gastrointestinal symptoms with nausea and diarrhea are often associated. Stevens-
Johnson syndrome has also been described (Bossi 2002). After cessation of abacavir
therapy, symptoms should remit rapidly. Specific therapeutic options for HSR do not
exist. After documented or suspected HSR, re-exposure is contraindicated.

Cardiovascular system
As noted in the drug review of this book (Section 5.2), various cohort studies (Young
2015, Marcus 2016, Dorjee 2018, Jaschinski 2022) found increased myocardial risk
with abacavir. It was moderate and was increased about 1.5–2.5-fold, especially if
there had been an exposure within the previous six months. Whereas potential con-
founders should be considered in the analysis of cohort studies, the prothombogenic
pathomechanisms are now well explained, making the observations plausible. The
mechanisms include increased platelet aggregation and activation (Mallon 2018,
O’Halloran 2018, Taylor 2018).
We have moved to replace abacavir with other options, especially for high cardio-
vascular risk. The higher the risk, the faster and more active. In this era of dual ther-
apies, the drug seems largely dispensable. Triumeq®, the combination of dolutegravir
plus ABC/3TC, has largely disappeared from everyday use and has been replaced by
Dovato® (dolutegravir plus 3TC) and other agents.
Increased cardiovascular risk has also been consistently described in cohorts for PIs
such as darunavir (Lundgren 2017), possibly due to dyslipidemia – but the effect is
likely weaker than for abacavir and tends not to influence treatment decisions.

Bones
A loss of bone density of 2–6% is observed in the first two years after ART initiation
on all regimens (Brown 2015, Hoy 2017). The magnitude of this demineralization is
similar to that seen in women in the first two years after menopause (Finkelstein
2008). After the first years, bone density remains relatively stable (Bolland 2011).
Causes include increased osteoclastogenesis and bone turnover (Seminari 2005), and
the risk of osteoporosis is increased 2–3-fold (Brown 2015). The SMART study also
showed significantly higher bone density loss and fracture rates with continuous
therapy compared to breaks in therapy (Grund 2009). In contrast, other studies found
no increased fracture rate (Mundy 2002). In the START trial, bone density loss was
one of the few disadvantages of early ART initiation (Hoy 2017).
Although bone loss is always multifactorial, there is evidence for some antiretroviral
drugs. PIs, as potent cytochrome P450 inhibitors, also interact with vitamin D-1α
hydroxylase, among others. A meta-analysis found a slightly increased risk of osteo-
porosis among PIs (Brown 2015), but this disappeared after adjustment for risk factors.
Cohort studies also yielded conflicting data. Some found an increased risk of frac-
ture (Womack 2013), while others did not (Costaglia 2019).
TDF is also involved (review: Shiau 2020); bone density decreases more than under
other agents. In some cases, increased fracture rates were found (Horizon 2011, Borges
192 ART

2016), but not in others (Cooper 2010, Hill 2018). After switching to TAF, bone
density and osseous activation markers improve, sometimes significantly, but overall
fracture risk remains the same. Biphosphonates appear more effective than TDF
replacement in osteopenia (Hoy 2019).
In addition to osteoporosis, TDF is also involved in osteomalacia, an insufficient
mineralization of bone. This usually results from impaired uptake, activation, or
receptor action of vitamin D or a deficiency of calcium and phosphate mineraliza-
tion substrates. Vitamin D deficiency is much more common in HIV-infected
individuals than in the general population. TDF leads to renal phosphate loss via
mitochondrial tubulopathy, which is usually reversible after discontinuation
(Wanner 2009).
What remains as a consequence of ART? According to the current EACS guidelines
(EACS 2021), consideration should be given to replacing TDF in the following
situations: manifest osteoporosis, progressive bone loss, and previous fragility
fracture. We would further advise reconsidering the need for TDF if classic risk factors
exist. These include older age, female sex, hypogonadism, family history of hip
fracture, low BMI, smoking, physical inactivity, history of fracture with minor
trauma, increased alcohol consumption, and prolonged steroid use.

Liver
For all PIs, NNRTIs, NRTIs, but also maraviroc, and all INSTIs, there are reports of
liver enzyme elevations up to severe hepatotoxic reactions (Núñez 2010). However,
they are rare and tend to affect high-risk patients with viral hepatitis, alcohol
problems, or potentially hepatotoxic comedication. Liver injury has different
mechanisms, and important clues are provided by the onset time (Cai 2019).
Hypersensitivity reactions with liver involvement are typical for abacavir (HLA
status?), NNRTIs, especially nevirapine, and darunavir. They are dose-independent
and occur in the first 4 to 12 weeks. Particularly with nevirapine, caution is always
advised (see above)! Rapid normalization can be expected upon discontinuation. In
contrast, direct drug toxicity develops slowly within months (Price 2010). Also,
hepatic steatosis caused by mitochondrial toxicity under NRTIs often manifests only
after years. This is also true for the hepatotoxicity of some PIs, especially in chronic
hepatitis (Sulkowski 2004). Tipranavir causes the most marked liver elevations of all
PIs, and fatal courses have been described (Chan-Tack 2008). Inhibition of UDP-glu-
curonyltransferase is typical for atazanavir, which often leads to hyperbilirubinemia
and icterus – it should no longer be used. Liver value changes (usually moderate)
have also been described for all INSTIs. Increased GGT is typical for nevirapine (less
commonly efavirenz) and can be tolerated if moderate. However, it sometimes
exposes patients to the suspicion of excessive alcohol consumption.
Elevated liver values are not always an expression of specific toxicity. Thus, an immune
reconstitution syndrome may be the cause; it usually occurs in severe immunodefi-
ciency in the first months under ART, regardless of the regimen (Price 2010).
Differentially, viral hepatitis should always be considered: Is there acute hepatitis A,
C, or E? Is there a rebound of hepatitis B with discontinuation of HBV-active drugs
such as TDF or TAF? Or an initial flair under hepatitis C therapy, especially with hep-
atitis B coinfection (Bersoff-Matcha 2017)? Ultimately, other causes are possible, and
it is not uncommon for athletic activity to have caused a moderate GPT elevation.
Liver enzymes should be monitored before and during ART, preferably after
Four weeks and then every three months. Without clinical symptoms, ART can be
continued with moderate GPT elevation under closer monitoring. Liver biopsy can
differentiate NRTI-induced steatosis from other liver damage. However, it is now only
considered in exceptional situations.
5.7. Management of side effects 193

Lipodystrophy
Although the syndrome includes morphologic and laboratory chemical changes
(Carr 1998), this section will focus on fat distribution abnormalities. Classical lipody-
strophy is now rare, predominantly caused by D-drugs, AZT, and probably older PIs
such as indinavir or saquinavir (Srinivasa 2014). However, regression often remains
incomplete, placing a heavy burden on many patients treated for many years. Often,
clinical diagnosis is complicated by physiological aging processes that can be
misinterpreted as lipodystrophy. A good definition or classification is still lacking.
Diagnostically, a DEXA scan, CT, or MRI can objectify changes. Simpler – but less
accurate – are anthropometric measurement methods such as waist circumference
or waist-to-hip ratio. However, these tests are rarely helpful in individual cases.
Typical is the simultaneous loss of subcutaneous adipose tissue (lipoatrophy) in the
face (periorbital, buccal, temporal), buttocks, and extremities (“stork legs”), often
combined with an accumulation of visceral adipose tissue (“buffalo hump”,
“crix-belly”) (Grunfeld 2010). In addition, there are metabolic changes, such as
insulin resistance, diabetes mellitus, and dyslipidemia. Lipodystrophy is explained
by the mitochondrial toxicity of NRTIs in adipose tissue (Brinkman 1999).
Therapy of lipodystrophy remains difficult. NRTIs and old PIs should be removed
from ART if possible. Peripheral fat loss often takes years to improve (see above).
Recombinant human growth hormone (HGH, e.g., Serostim®, 4–6 mg/d s.c.) has been
tested in studies over 8–12 weeks to reduce marked visceral fat accumulation.
Unfortunately, the effects were not durable after discontinuation. Surgical inter-
vention (e.g., liposuction) is only indicated in isolated cases (Guaraldi 2011). In cases
of pronounced facial lipoatrophy, repeated injection with poly-L-lactic acid
(Sculptra®) may be useful (Lafaurie 2005). However, it belongs in experienced hands.

Neuropsychiatric adverse events (NPAEs)

With efavirenz, central nervous symptoms such as dizziness, sleep disturbances, and
nightmares occur in up to 40% (Ford 2015). It should be replaced whenever possible.
A switch can be considered even in the absence of symptoms under efavirenz. Often,
affected individuals have become “accustomed” to the side effects and only notice
them after discontinuation.
There is also increasing evidence of NPAEs for INSTIs, particularly dolutegravir and
bictegravir (Hoffmann 2020). They are less pronounced than seen with efavirenz but
may lead to discontinuation in 5–10% of cases, depending on the vigilance and
alertness of the treatment provider. Raltegravir and elvitegravir are less commonly
implicated. NPAEs with INSTIs may be unspecific, comprising vague feelings such as
“helmet on my head”, “foggy-brained”, “tetchy” or “prone to tears”. Those events
are often not written in electronic records or even considered drug-related by the
patients. Thus, they are commonly not captured with retrospective studies checking
the electronic medical records or prospective RCTs without specific questionnaires.
With heightened awareness of health care providers and patients, reports of NPAEs
will probably increase in the future.
Sometimes, affected persons describe these problems only when asked. Much is
challenging to distinguish from psychiatric diagnoses; however, in our experience,
people without any previous psychiatric illness are also affected. NPAEs among INSTIs
are difficult to objectify and not defined, so the true prevalence is difficult to determine.
The symptoms can occur even after years; they are by no means limited to the first
weeks of exposure. Cross-intolerance does not appear to be high: those who cannot
tolerate bictegravir may tolerate dolutegravir, and vice versa (Hoffmann 2020).
The causes continue to be controversial. It is discussed whether there is a genetic
predisposition or a connection with plasma levels. There are no valid diagnostic tests.
194 ART

If neuropsychiatric side effects occur or are suspected, ART can be switched empiri-
cally for a few weeks in most cases. Affected individuals should be taken seriously,
and the possibility of NPAEs should be addressed openly. Of course, not every
psychiatric problem is a side effect. However, an empirical switch of ART is often the
easiest solution. NPAEs are reversible: improvement can be expected after a few days
if the problems are indeed due to ART. A randomized trial showed clear improvement
in several sleep and depression scores when switching from dolutegravir to darunavir
(Cabello-Úbeda 2022).

Kidneys
Tenofovir-DF (TDF) usually causes mild and reversible renal dysfunction (see chapter
HIV and nephrology). For all TDF-containing preparations, there are detailed instruc-
tions for renal monitoring. Before initiation, calculate creatinine clearance and
monitor renal function at 2–4 weeks, three months, and every 3 to 6 months after
that – or more frequently if abnormalities and/or renal risk are present. Severe renal
impairment is rare (Cooper 2010). In a meta-analysis, discontinuation rates due to
renal events were 0.6% (17/2,689) on TDF (Hill 2018). An increased risk was found
only with boosted regimens. In the Swiss cohort, 46 of 2,592 patients (1.6%) had to
discontinue TDF due to renal toxicity after a mean of 442 days (Fux 2008). Renal
failure is also observed in the setting of Fanconi syndrome, a defect of proximal
tubule transport. TDF should be avoided in the presence of renal damage. Elderly
and lightweight PLWH are also at risk, as are those with boosted PIs (Young 2012)
and potentially nephrotoxic comedication. Concurrent administration of ampho-
tericin B, foscarnet, vancomycin, or cidofovir should be avoided. NSAIDs such as
ibuprofen, diclofenac, or even ASA can lead to renal failure requiring dialysis in high
doses together with TDF. Tenofovir-AF (TAF), approved in 2016, causes complica-
tions much less frequently (Gupta 2019) and can be used in renal failure up to a GFR
of 30 mL/min. Switching from TAF to TDF significantly improved eGFR in patients
with and without renal impairment (Mills 2016, Pozniak 2016). TAF is always prefer-
able to TDF for renal problems.
Older PIs such as atazanavir can lead to nephrolithiasis; they should no longer be
used. The INSTIs dolutegravir, bictegravir, and elvitegravir (as well as the booster
cobicistat) often cause a moderate increase in serum creatinine because they inhibit
proximal tubular creatinine secretion. Cystatin-C or protein/creatinine ratio are then
better markers of renal function.

Varia (rare)
Hematologic changes: AZT is myelosuppressive and may lead to anemia. Even
without anemia, mean corpuscular red cell volume (MCV) is regularly increased.
When AZT is combined with other myelosuppressive drugs such as cotrimoxazole,
ribavirin, or interferon, the effect may be potentiated. AZT should be avoided today.
Coagulopathies: Very rare. In hemophiliacs, spontaneous bleeding into joints and
soft tissues has been observed in increased numbers during PI-containing therapies.
Rarely, intracranial and gastrointestinal bleeding occurs. The hemorrhages occurred
several weeks after the initiation of PI therapy (Wilde 2000), and the cause remained
unclear. Far more common are (overlooked) interactions between some NOAKs and
boosted ART regimens, some of which can cause life-threatening bleeding. Caveat:
Rivaroxaban plus ritonavir or cobicistat!
Lactic acidosis: This potentially life-threatening complication used to be observed
with d4T and ddI and less frequently with AZT. Since the d-drugs have disappeared,
ART-associated lactic acidosis is a rarity.
5.7. Management of side effects 195

Myositis: Rare, formerly with AZT. Isolated cases with raltegravir. Cave rhabdomy-
olysis in combination with simvastatin and boosted ART. Differential diagnosis
comparatively harmless macro-CK under TDF (Schmidt 2013).
Polyneuropathy: Also due to the d-drugs, unfortunately, occasionally persisting,
even after many years. Treatment is often complex (see Neuro).

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5.8. Simplification, de-escalation 199

5.8. Simplification, de-escalation

C H R ISTIAN HOFFMAN N

Simplification: Switching to a single-tablet regime (STR)

Not only therapy-naïve but also pre-treated patients are asking about STRs today.
Can they switch? The power of the large studies conducted to date (Table 8.1) remains
limited for two reasons. First, the patients were mostly heterogeneously pre-treated,
sometimes with different drug classes and different backbones – possible positive
and negative effects of switching are not always clear. Secondly, care was taken in
most studies to ensure that neither resistance nor previous virological failure was
present. A maximum of two prior therapies was almost always allowed; in GS-109,
participants came from three previous Gilead studies (and were highly selected). Not
surprisingly, virological control was maintained by almost all participants in all
studies.

Table 8.1: Randomized studies on the switch to so-called single-tablet regimens (STRs) in virologically
successfully treated patients (mostly > six months).
STR, study (reference) n Last ART Significant effects of switching to an STR,
week 48
Triumeq® 551 42% PIs DRAEs more frequent (21% vs. 1%),
STRIIVING 26% INIs more Nausea (10% vs. 1%), Fatigue
(Trottier 2017) 31% NNRTIs (7% vs. 1%), Psychiatric (13% vs. 3%)
Biktarvy® 578 56% DRV/r/c DRAEs more frequent (19% vs. 2%),
GS-1878 44% ATV/r/c mainly headache (12% vs. 4%),
(Daar 2018) lipid changes dependent on prior therapy
Biktarvy® (women only) 472 53% Genvoya® DRAEs slightly more frequent (9% vs. 6%),
GS-1961 (Kityo 2019) 42% Stribild® lipids and renal values idem
Biktarvy® 567 96% Triumeq® DRAEs less frequent (8% vs. 16%),
GS-1844 mainly gastrointestinal (0% vs. 5%),
(Molina 2019) lipids and renal values minimally better
Genvoya® 1,443 42% ATV/r/c DRAEs more frequent (21% vs. 16%,
GS-109 32% Stribild® primarily mild), GFR +3.3 mL/min,
(Mills 2016) 26% EFV bone density better, lipids worse
Symtuza® 1,141 58% DRV/r DRAEs more frequent (18% vs. 7%,
EMERALD 21% ATV/r primarily mild), GFR idem, bone density
(Orkin 2017) 13% DRV/c better, lipids slightly worse
Delstrigo® 670 37% DRV/r DRAEs more frequent (20% vs. 2%,
DRIVE-SHIFT 22% ATV/r primarily mild), headache (7% vs. 2%),
(Johnson 2019) 17% EFV lipids slightly better vs PIs
Eviplera® 476 37% ATV/r AEs overall same (but 7 vs. 0
SPIRIT 33% LPV/r discontinuations), lipids overall
(Palella 2014) 20% DRV/r significantly better
Odefsey® 1,505 58% Atripla® AEs same, renal values, bone density better,
GS-1160/1216 42% Eviplera® lipids hardly changed
(Hagins 2018)
The exclusion criteria were always virological failure and/or resistance – except for EMERALD.
DR AEs = Drug-Related Adverse Events. GFR = Glomerular Filtration Rate.
200 ART

In EMERALD, the only study in which prior treatment failure was allowed, 70% of
the participants were pre-treated with darunavir/r or darunavir/c and then switched
to a darunavir/c-containing STR (good to know, but little could go wrong).
The effects on kidneys, bones, and lipids were partly due to the backbone. When
switching to TAF, lipids increase; when switching to TDF, they decrease – and vice
versa. Notably, “drug-related AEs” (DRAEs) were more common in many studies due
to the switch – no surprise since most studies switched from stable therapies. In
GS-1844, the only study in which fewer DRAEs were observed as a result of the inter-
vention (switching from Triumeq® to Biktary®), the switch was precisely not only
from dolutegravir to bictegravir but also from the possibly gastrointestinally less
tolerated NRTI abacavir to TAF (Molina 2019).
STR is possible if no resistance or previous therapies have failed. In the case of a
therapy that has worked well up to now, however, a change is likely to result in new
(usually mild) side effects. Thus, the argument used by the manufacturers in these
cases that the patients had previously been on stable, well-tolerated ART can be read
differently: not every satisfied patient needs to switch to an STR. It is not malprac-
tice to remain on a functioning therapy, even if it consists of more than one pill.
De-escalation to less than three drugs
Can HIV infection be treated with a sequence of intensive induction therapy fol-
lowed by reduced (potentially less toxic, cheaper) maintenance therapy? The ques-
tion was asked as far back as the 1990s, and the answer was always no. Randomized
trials such as Trilège, ADAM, or ACTG 343 consistently disappointed. However, they
used outdated drugs such as saquinavir, indinavir, or nelfinavir. Only in recent years
has the question of maintenance therapy been raised again. Agents with a high resist-
ance barrier are now available and are being investigated as part of dual or monother-
apies.
It is time to dedicate a new chapter to de-escalation strategies. De-escalate is
admittedly a strong word. It is also misleading: it implies that escalation has taken
place beforehand. Ultimately, however, standard therapies – most of which are well
tolerated – are reduced by one or two agents. These strategies are described below.

Officially approved STR options for dual therapy

In 2018, Juluca®, the combination of dolutegravir and rilpivirine, was approved as
the first dual maintenance therapy. In 2019, Dovato® was added, the combination
of dolutegravir and 3TC, for which the indication has since been expanded to include
treatment-naïve individuals (see above). Since the end of 2020, the long-acting
combination of Vocabria® and Rekambys®, the combination of cabotegravir and
rilpivirine given every 4–8 weeks, is the first long-acting option for pre-treated
patients, also consisting of only two agents.
Dolutegravir plus rilpivirine (Juluca®) was the first official combination to forgo
NRTIs entirely. Two large Phase III trials (SWORD I+II, n=1,028) tested Juluca® against
continuation of successful first-line or second-line ART (Llibre 2018, Aboud 2019).
Virologic failure was sporadic, and INSTI resistance did not occur at all. However,
after 148 weeks in a long-term follow-up, six people (0.6%) had developed NNRTI
resistance (van Wyk 2020) despite stringent inclusion criteria: a maximum of two
prior therapies, no virological failure, no resistance, and no hepatitis B. In other
words, patients would certainly not expect treatment failure. Another downer:
CNS side effects from dolutegravir were more likely to lead to discontinuation
(9 versus 1 case), and mild side effects were also more common, at 17% versus 2%.
In one sub-study, bone density did improve, especially when TDF was discontinued
(McComsey 2017).
5.8. Simplification, de-escalation 201

To ensure adequate absorption of rilpivirine, Juluca® must be taken with food. It

remains unclear so far who would benefit from such a choice. The argument that
switching to TAF-based regimens may have the same benefits on bone density is also
valid. Thus, at the moment, Juluca® seems particularly useful if one wants to be nuke-
free and, for example, prevent the progression of lipoatrophy – but these are often
people with extended previous therapy and resistance – so they are not eligible.
WISARD, a large Phase III study with Juluca® in pre-treated PLWH, in which specific
resistance is allowed, is still ongoing (and suffers from slow enrollment), and results
are pending.
Apart from Juluca®, other combinations of INSTIs and NNRTIs have been tested in
mostly uncontrolled trials, including raltegravir plus nevirapine (Calcagno 2016) or
etravirine (Casado 2015). These strategies have little role now. Due to unfavorable
PK data, Dolutegravir and etravirine should not be combined (Song 2011).
Dolutegravir plus 3TC (Dovato®): In treatment-naïve patients in the GEMINI trials,
this 2DR therapy was so effective that it was approved, with certain restrictions, in
first-line therapy (see above). Of course, it can also be considered for pre-treated
patients. In two large, open, randomized trials, non-inferiority was shown for switch-
ing to Dovato®.
In TANGO, 743 PLWH were randomized to open-label switching to Dovato® or to
remain on their successful triple regimen (TAF-based regimen only, 66% Genvoya®).
Inclusion criteria were strict: first-line therapy, including viral load below the limit
of detection for at least six months, no AIDS-related illness, no hepatitis B, no resist-
ance or prior treatment failure. After 144 weeks, viral suppression was maintained
in all subjects, and no resistance occurred. Blips were also not observed to increase
with dual therapy (Osiyemi 2022). Of note, adverse events occurred more frequently
with Dovato® (15%; 4% led to discontinuation) than with TAF-based therapies (5%;
1%). No relevant changes in renal function and inflammatory and bone biomark-
ers were observed.
The SALSA trial had a similar design, but non-TAF therapies were allowed (often
efavirenz-based). None of the 493 participants met the criteria for virologic failure
(Llibre 2022). Again, adverse events occurred more frequently with Dovato® (20%)
than with continued ART (6%). Renal function and bone turnover biomarkers
improved on Dovato® (unlike TANGO, 44% had TDF on existing ART here). Changes
in lipids and inflammatory biomarkers remained minimal. Similar results to SALSA
and TANGO were also obtained in the somewhat smaller Spanish DOLAM study
(Rojas 2021).
In the absence of resistance and hepatitis B, the switch is quite possible. However, a
real advantage has not been seen either. Inflammatory or atherogenic parameters
remained almost unchanged (Llibre 2022). Thus, Dovato® currently continues to
serve the intuition of patients and their clinicians: less is more, especially with life-
long therapy. What is not necessary (tenofovir) can be saved.

De-escalation to dual therapy with Dovato® and Juluca®

• Strict selection: No hepatitis B, first-line or at most second-line therapy, no prior
treatment failure, no resistance, no adherence problems.
• De-escalation carries some risk of new side effects from dolutegravir (especially
neuropsychiatric events).
• Significant advantages have not been seen so far; however, 2DR is a long-term
therapy with as little toxicity as possible.
• Nutritional restrictions for Juluca® should be observed.
• Close monitoring of viral load can be considered to minimize the risk of resistance.
202 ART

Long-acting
The administration of depot injections, also known as “long-acting”, is undoubtedly
an innovative, forward-looking concept in HIV medicine. It is especially interesting
for those patients who (unfortunately still) are worried that their HIV infection will
become known to family, friends, or roommates. These people willingly visit the HIV
center every 4–8 weeks for injections. However, according to surveys, many other
patients would also accept the injections – so they do not have to worry about taking
their daily pill for the remaining month. Coming to the doctor’s office once a month
to pick up a shot (or two) seems surprisingly attractive: in a French survey, 64% said
they preferred monthly injections to pills, and the figure was as high as 76% for
bi-monthly doses (Khuong-Josses 2019).
But is this also true after careful explanation? This new depot therapy harbors a
whole series of potential problems in everyday life. The logistical effort is significant;
different dosages of cabotegravir may be a potential source of error. The drugs must
be stored in a cool place in the pharmacy and brought to room temperature (not
above 25 °C) before use. Two deep intramuscular injections of 2–3 mL per month
are pretty planning- and labor-intensive, not free of risks and painless. Following
administration, patients should be monitored for a few minutes. The management
at the beginning and the end of such a therapy, in case of delayed administration
or in case of potential interactions, is complex. Moreover, it remains unclear which
patients are at risk for virological failure, which occurs in 0.5–1% per year and is
often accompanied by INSTI and NNRTI resistance (see below).
However, especially for people with adherence problems, parenteral administration
will usually not be a good solution. People who find it challenging to comply with
today’s standard antiretroviral therapy of only one tablet a day will find it more dif-
ficult to keep regular and fixed appointments for injections. In the case of depot
doses, this bears a high risk for resistance. If doses are missed, a prolonged decline
in plasma levels is to be expected – unlike with tablets. The agents are often still
detectable in subtherapeutic ranges for many months, which provides the virus with
ideal conditions for selecting resistance mutations. With such resistance mutations
to cabotegravir and rilpivirine, two of the most important antiretroviral substance
classes would be permanently compromised.
It is also unclear whether there is any other advantage for the depot administration
apart from convenience. The price is probably not – it is no lower than conventional
STRs. The assumption of a lower “burden” that is often widespread among patients,
which is still partly fueled by lay media (“monthly injection instead of pill cock-
tail”), is also not tenable. However, this may be true for frequent travelers. Both
agents come from conventional antiretroviral drug classes; the exposure is the same,
and a similar therapy has been available for years as STR.
Cabotegravir plus rilpivirine LA: Dual therapy of monthly injections with cabotegravir
(Vocabria®) and rilpivirine (Rekambys®), colloquially CARLA (in the US: Cabenuva®),
demonstrated non-inferiority to conventional therapies in two significant Phase III
trials. In ATLAS, 705 people were successfully pre-treated with different ART regimens
for a mean of four years; in FLAIR, 629 treatment-naïve people had initially received
several months of induction therapy with ABC/3TC/dolutegravir (Triumeq®), and
566 were randomized (Review: Bares 2022). In November 2017, ATLAS was expanded
to include ATLAS-2M. This study compared four- versus eight-week injections and
demonstrated non-inferiority of the 8-week arm at 96 weeks (Jäger 2021). Virologic
failure was rarely seen but was mainly accompanied by resistance in 9/522 cases.
Nevertheless, approval for CARLA spans both 4- and 8-weekly injections. Tolerability
has been good so far, and problems at the injection site (pain, swelling, redness) only
led very rarely (less than 1%) to discontinuation.
5.8. Simplification, de-escalation 203

As mentioned above, whether and which people are at increased risk of treatment
failure is not yet fully understood. Data from participants randomized to long-acting
CARLA Q4W or Q8W dosing within the Phase 3 FLAIR, ATLAS, and ATLAS-2M studies
through Week 48 were pooled in a post-hoc analysis. There were three risk factors
for virological failure, namely a pre-existing rilpivirine resistance (from proviral DNA
analysis at baseline), the presence of HIV subtype A6 or A1, and a BMI of at least 30
kg/m2 (Cutrell 2021). The risk of virological failure (often with resistance against
both INSTI and NNRTI) was 1% during the first year and increased significantly in
the presence of at least two factors. Of all participants with at least two factors, the
rate was 26% (n = 9/35). Of note, plasma levels in cases of treatment failure were
relatively low but not too low to explain the failure. Plausible explanations thus
remain lacking.
Although there are now also some centers that use long-acting on a large scale, many
continue to shy away from the effort. The industry is taking note of this. It is no
coincidence that alternative routes of administration are being investigated, both
subcutaneous injections and those into the thigh, and initial results have already
been published (Benn 2022, Han 2022). Subcutaneous administration, in particular,
should significantly increase acceptance, as should longer intervals.

De-escalation of long-acting agents, practical aspects

• Note strict selection as with all dual therapies: only first-line or, at most, second-
line therapy with virological suppression, no prior treatment failure, no resist-
ance, no hepatitis B.
• “Lead-in” with oral cabotegravir and rilpivirine for one month, then two injec-
tions at one-month intervals, then every two months thereafter.
• Use the same side for each injection (“Rekambys right side”), trained personnel!
• Indicate possible pain at the injection site; use longer hypodermic needles in
obese patients.
• Accurate scheduling (plus/minus seven days allowed), including “oral bridging”
if necessary.
• If discontinued within 4–8 weeks, start new ART.
• Rarely, failure and development of resistance occur, sometimes unexplained – it
is better to check viral load every 1–2 months in the beginning.
• Possibly more co-payments, indeed more doctor’s visits for those affected.

More options
Given the approval of two STR options, other 2DR concepts are increasingly moving
into the background. Nevertheless, they will be briefly discussed here.
Darunavir (and other PIs) plus 3TC worked well in therapy-naïve patients in the
GARDEL study (see above) and pre-treated patients. Four larger studies examined
de-escalation to atazanavir/r, lopinavir/r, and darunavir/r plus 3TC (see Table 8.2).
The combination proved similarly effective, and blips were not observed more
frequently. Limitations remain, however: all studies examined only the discontinu-
ation of TDF and abacavir, not TAF. Patients with resistance to 3TC or the PI, previous
virologic failure, and hepatitis B were excluded. Switching had, at best, only mod-
erate effects on the kidney and bone when TDF was discontinued and mainly resulted
in risk-neutral increases in HDL + LDL. The clinical relevance of these changes
remained questionable. Apart from cost considerations (no longer relevant after the
price decline of TDF), there is little argument for this approach other than intuition
(“less is better”). Moreover, 2DR is not entirely correct: the PI is boosted with ritonavir,
so there are still three agents, strictly speaking.
204 ART

Table 8.2: Randomized trials of dual therapy in virologically successfully suppressed patients (TDF was
omitted in 61–82%, abacavir in 15–26%).
Study, reference Dual therapy (n) Main results
DUAL GESIDA DRV/r+3TC AEs equal, lipids idem (increase in HDL/LDL),
Pulido 2017 (n=249) GFR idem
ATLAS-M ATV/r+3TC AEs same, lipids idem (increase in HDL/LDL),
Di Giambenedetto 2017 (n=266) GFR slightly better
SALT ATV/r+3TC AEs same, lipids slightly worse, GFR/BMD
Perez-Molina 2015 (n=286) unchanged
OLE LPV/r+3TC AEs same, lipids slightly worse, GFR/BMD
Arribas 2015, Crespo 2016 (n=250) slightly better (if switching from TDF)
Exclusion criteria in all studies: hepatitis B, resistance to 3TC and the PIs in question. * In SALT, patients
switched from different therapies, including NNRTIs. GFR = glomerular filtration rate, AE = adverse
events.

Experimental 2DR combinations

A variety of dual combinations, as well as monotherapies, have been tested in recent
years. Benefits are currently not apparent, and some participants lost virological
control in some studies. Such experiments are not recommended outside of trials,
and participation in such studies must also be justified. The following is a brief
overview.
Darunavir/r plus raltegravir: The NEAT study showed promising efficacy in treat-
ment-naive patients (see above). In pre-treated patients, the data are much more
limited. In a pilot study, darunavir/r+raltegravir did not improve renal function
(Nishijima 2014).
Darunavir/r plus dolutegravir: Was investigated in the DUALIS study, which was
underpowered (Spinner 2020). Neither showed advantages over classical ART with
regard to weight, renal function, or lipids (Monin 2020). Other PIs, such as atazanavir
or lopinavir, should not be used, and neither treatment failure (van Lunzen 2016)
nor lipid deterioration was observed (Martin 2013).
Darunavir/r plus etravirine or rilpivirine: These combinations have also not shown
any benefit. According to small studies, they seem possible in selected cases
(Bernadino 2014, Maggiolo 2016). Combinations with lopinavir and older NNRTIs,
on the other hand, were too weak and/or toxic (Fischl 2007).
PIs plus maraviroc: Probably not the best idea. In the three-arm MARCH trial,
patients either switched from a PI-based regimen to a PI plus maraviroc, replaced
the PI with maraviroc, or maintained their previous PI-based regimen; the failure
rate was worryingly high (Pett 2016). This was also true in the smaller GUSTA trial
(Rossetti 2017). Although very little resistance occurred, there is currently little to
be said for this strategy. Incidentally, both studies are also arguments against the
concept that a drug with a high resistance barrier (in this case, the PI) is sufficient
as maintenance therapy.
INSTIs plus maraviroc: These nuke-saving combinations are experimental; their
benefit is questionable. That they can also go wrong was shown by ROCnRAL, a pilot
study in 44 people with lipodystrophy (Katlama 2014). These had received a median
of 15 years of ART and a median of 5 years of viral load below the detection limit.
After switching to “Nuke+PI sparing” with raltegravir+maraviroc, 7 individuals
developed treatment failure, including 3 with RAL resistance, so the study had to be
discontinued. Unfortunately, ROCnRAL shows too well that not everything works,
5.8. Simplification, de-escalation 205

and one must remain cautious even with longstanding viral suppression. In 33 highly
selected individuals who switched to raltegravir+maraviroc after initial quadruple
therapy, one developed INSTI resistance (Pradat 2016).
TDF plus efavirenz: Bad idea! In the COOL study, several breakthroughs occurred
(Girard 2006).

Experimental monotherapies
Monotherapies have been investigated and, in some cases, propagated in numerous,
primarily underpowered studies. Those times are over. Monotherapies should be
avoided whenever possible; there is rarely anything to be said against at least main-
taining 3TC in the backbone. Lopinavir/r was too toxic; low viremia was common
(Pulido 2008, Meynard 2010).
Darunavir/r: With MONET, MONOI, and PROTEA, there are several larger ran-
domized trials. In MONET, at least for the primary endpoint, non-inferiority was not
fully demonstrated at 96 weeks (Clumeck 2011). At 96 weeks, 82% in the standard
arm were below the detection limit of 50 copies/mL, compared with 78% in the
darunavir arm. At 144 weeks, the difference had increased from 4% to 6% (Arribas
2012). The PROTEA study also showed a slight difference (Girard 2017). The differ-
ence was no longer present unless virologically successful treatment switches were
counted as failures. In MONOI, transient viremia was slightly more common with
monotherapy after 96 weeks, and durable control with continuous VL below
50 copies/mL without any blip was found at 59% vs. 70% (Valantin 2012). Treatment
failure was associated with shorter prior therapy and reduced compliance (Lambert-
Niclot 2011). In MONOI, lipoatrophy improved in some patients (Valantin 2012).
In an analysis of more than 2,000 subjects from 13 randomized trials, PI monother-
apy was slightly worse regarding virologic control, with an average of 8.3% more
virologic failure. However, with subsequent re-intensification, these differences were
no longer present. New resistance was rare, occurring in 14/1091 compared with
7/1109 in standard therapies (Arribas 2016). No options were lost in a pragmatic trial
(PIVOT) in which 587 individuals were randomized to continue their PI-containing
triple combination or to continue with the PI only (Paton 2015).
Dolutegravir: The relatively high resistance barrier of this INSTI initially made
monotherapy seem possible. It is probably not sufficient. In four studies of 416 people
(Fournier 2022), dolutegravir monotherapy significantly increased the risk of viro-
logic failure (7% versus 0%). Dolutegravir monotherapies are no longer recom-
mended. Those who still propagate them and expose patients – for no reason – to
the risk of resistance must accept harsh criticism (Gallant 2017).

Monotherapies
• A monotherapy with PI/r is slightly less effective than triple therapies – the dif-
ference is consistently observed in all studies (about 8%). Whether PI monother-
apies actually save long-term toxicity is not evident either.
• Low viremia without resistance usually occurs and disappears with re-intensifi-
cation; the risk of resistance is low (< 1%) with PIs.
• The risk of resistance is higher with dolutegravir mono! Generally not recom-
mended!
• Poor adherence, prior virologic failure, and low CD4 nadir are considered risk
factors for failure.
206 ART

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safe and effective in suppressed patients with HIV – a subanalysis of the DUALIS study. Abstract MOPEB269, IAS
2019, Mexico.
Trottier B, Lake JE, Logue K, et al. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed
patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label, Phase IIIb study. Antivir Ther 2017,
22:295-305.
Valantin M, Kolta S, Flandre P, et al. Body fat distribution in HIV-infected patients treated for 96 weeks with
darunavir/ritonavir monotherapy versus darunavir/ritonavir plus nucleoside reverse transcriptase inhibitors: the
MONOI-ANRS136 Substudy. HIV Med. 2012, 13:[Link] 14.
van Lunzen J, Pozniak A, Gatell JM, et al. Brief Report: Switch to Ritonavir-Boosted Atazanavir Plus Raltegravir in
Virologically Suppressed Patients With HIV-1 Infection: A Randomized Pilot Study. J Acquir Immune Defic Syndr
2016, 71:538-43.
Van Wyk J, Ajana F, Bisshop F, et al. Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose Two-
Drug Regimen Versus Continuing a Tenofovir Alafenamide-Based Three- or Four-Drug Regimen for Maintenance
of Virologic Suppression in Adults With HIV-1: Phase 3, Randomized, Non-inferiority TANGO Study. Clin Infect
Dis. 2020 Jan 6.
van Wyk J, Orkin C, Rubio R, et al. Brief Report: Durable Suppression and Low Rate of Virologic Failure 3 Years
After Switch to Dolutegravir + Rilpivirine 2-Drug Regimen: 148-Week Results From the SWORD-1 and SWORD-2
Randomized Clinical Trials. J AIDS 2020, 85:325-330.
5.9. Virological failure 209

5.9. Virological failure

C H R ISTIAN HOFFMAN N

Virologic treatment failure has fortunately become rare. However, many mistakes
can be made when it does occur: experience, finesse, and decisiveness help. On the
one hand, there is a risk of further resistance; on the other hand, rapid change is
not always the right solution, as rapid changes in therapy can be unsettling and con-
fusing. If a given ART regimen – for whatever reason – is not taken correctly, the new
one often will not be either. A switch can provoke new misunderstandings and further
resistance. It is essential to explain to patients who are often skeptical about when
and why treatment changes must be made.
As a rule, ART should be changed quickly if viral suppression is insufficient. The
virus continues to mutate, resistance mutations accumulate, and further options may
be permanently lost. Virologic failure should be assumed if the viral load is repeat-
edly not below the detection limit of 50 HIV RNA copies/mL. The limit above which
action should be taken is 200 copies/mL. Very high values above 1,000 copies/mL
usually indicate a break in therapy. Values below 200 copies/mL must be clarified to
determine whether they are transient viremia (blips) or persistently low viremia.
These usually do not require a change (see Therapy Principles). Individual resistance
mutations must be considered: for example, with the K65R mutation, which is
frequently selected by tenofovir, both abacavir and 3TC/FTC lose significant efficacy.
Viral replication at insufficient plasma levels is an ideal ground for resistance.
However, the reality is often different: in an analysis from Great Britain, 34% of 694
persons remained on a virologically failing combination for more than six months.
Factors associated with rapid switching were low CD4 T-cells, high viral load, and
older age (UK Chic 2008).
However, the situation looks different once the first resistance mutations are present.
There are, of course, only a few good studies on whether to switch immediately or
delay the switch in the setting of virological failure. Randomized trial results suggest
that waiting a little is possible (Nasta 2006, Tenorio 2009). However, these studies
suffered from small case numbers – motivating patients for such strategy studies is
difficult.

Arguments for a rapid switch Arguments for a later switch

in the case of virologic failure in the case of virologic failure
The virus becomes incapable of New therapies bear the risk of new
generating further resistance intolerances/toxicities
Options are maintained With low viremia, patients often remain
immunologically stable for a long time (also
clinically, anyway)
The switch is more successful Replication fitness is sometimes reduced
with less resistance with resistance
The lower the viral load at the time With a low viral load, resistance testing
of the switch, the better the response is often not yet possible (although resistance is
to the new therapy already present)
Often, the subsequent regime does not Switching from a well-tolerated, simple regimen
have to be more complex than the current can be challenging to communicate to patients
one – some things can be simplified!
210 ART

At least with failing PI therapies, there is probably a bit more time. In the prospec-
tive Johns Hopkins cohort, there was no association between delay in ART modifi-
cation and mortality during virologic failure, at least for PI treatment (Petersen 2008).
In the TITAN study, the number of acquired PI mutations did not play a role in the
success of darunavir (De Meyer 2008).
In case of clinical or immunological failure (AIDS, CD4 drop/lack of increase), the
success of switching is questionable if the viral load is below 50 copies/mL. However,
some agents, such as TDF+DDI or AZT, tend to be unfavorable for immunologic
reconstitution; switching should be used in such a combination. However, ART
switches alone are unlikely to improve immunologically (see Treatment Principles).

What to clarify before the switch

In the case of virological failure, it is crucial to analyze the situation in detail.
Specifically, one should ask some questions:
What is the reason for the measurable viral load? A viral load above 50 copies/mL
does not necessarily mean that resistance has occurred. A common (if not the most
common) cause is blips or transient viral load increases. These blips are usually
insignificant (see detailed discussion in chapter 5.4.) and almost always below 200
(maximum 400) copies/mL. Thus, a treatment switch should be considered only if
the viral load remains detectable after a short-term check after four weeks. Of course,
the viremia may also be due to insufficient plasma levels (measure plasma levels!),
which in turn may have different causes: malabsorption (is the patient taking PPIs?)
or even too low dosage (for example, in very tall, heavy people). Interactions are also
important.
How is the patient’s adherence? Adherence is critical. It should be addressed openly,
and possible problems with taking the therapy should be discussed. Is the therapy
taken every day, as discussed? If not, why not? Is it the number of pills and the pill
size? Is it possible to take food at the same time? Would once daily be better? Are
there other causes (depression)? Misunderstanding about the dosages? Many patients
do not know their medication, even after years. The risk of resistance due to poor
adherence should be addressed repeatedly.
How vulnerable is the present combination? NNRTIs are very sensitive, and cross-
resistance can develop rapidly for the whole class. A prompt change in therapy is
more vital than the other drug classes. Delaying the switch a few days and weeks
can already be too long! The rapid development of resistance can also be expected
quickly with 3TC and FTC, but probably also with raltegravir and elvitegravir. With
PI- or dolutegravir-containing regimens, one probably has more time for the switch.
Again, however, the higher the viral load at the time of switching, the lower the
chances of success – one should not wait too long.
What options does the patient have, and what are the consequences of the treat-
ment change? The more available options and accessible they are to implement,
the sooner they should be utilized. Therapy can sometimes be intensified quite
quickly. Using agents with a high resistance barrier, such as darunavir/r, bictegravir,
or dolutegravir, is essential. Especially if and as long as the patient’s adherence is
uncertain, it makes little sense to waste new drug classes. Therefore, it should always
be clarified before the change whether the patient is capable of switching.
5.9. Virological failure 211

Virological failure: What to consider pre-switch

• How vulnerable to resistance is the current therapy? NNRTIs, 3TC/FTC, raltegravir,
elvitegravir: rapid development of resistance – rapid switch recommended!
• The lower the viral load, the greater the success of treatment change.
• Always use agents with a high resistance barrier: darunavir/r, dolutegravir,
bictegravir! If NNRTIs are to be included, use etravirine, doravirine.
• Are you sure it is a virological failure, not a temporary blip? Check viral load
within 2–4 weeks!
• Are there other reasons for a detectable viral load? Resorption problems? What
concurrent therapies are taken? Whether “stomach pill from the family doctor”
(PPIs?) or “herbal agents from the alternative practitioner”: it all should be on
the table.
• Is the present ART taken correctly, or are there possibly misunderstandings?
• Was the therapy interrupted? What do the plasma levels say? What does the
patient say?
• What options are available, and what does a change mean? Can the patient take
a new therapy?
• Is a reasonably up-to-date resistance test available? (if not, do one!)
• If relevant mutations to the current agents have already developed, calmly wait
and prepare the person for a new regimen, possibly with more adherence coun-
seling.

Choice of the follow-up regime

In principle, the same conditions apply to first-line therapy. Adherence, intake
modalities, concomitant diseases, and co-medications/interactions should be con-
sidered. In addition, prior therapy and possibly existing resistance now play a deci-
sive role. Resistance testing is desirable in cases of virologic failure before any switch
but is not always practical. Knowing the essential resistance mutations is helpful,
especially for the nucleoside analogs (Table 9.1).

Table 9.1: Resistance mutations are to be expected with different NRTI backbones.
Failing Nuke Backbone Mutations
AZT or d4T plus 3TC M184V and sequential thymidine analog mutations
AZT/3TC/ABC (the longer the failure)
TDF or TAF plus 3TC or FTC K65R and/or M184V
ABC/3TC M184V and/or L74V > K65R
AZT or d4T plus ddI TAMs, Q151M, T69ins
TDF plus ABC or ddI K65R

The following applies to any switch in case of virological failure: the faster, the better.
The virus should not be given too much time to generate further resistance muta-
tions. The longer one waits, the more complex the resistance pattern becomes (Wallis
2010). And, the more agents that are switched, the greater the likelihood that the
new therapy will take hold. It is also crucial that agents with a high resistance barrier
are used whenever therapy fails. These include, above all, darunavir/r, dolutegravir
and bictegravir. Especially in uncertainty about the existing resistance situation, these
three agents are preferable to first-generation INSTIs or NNRTIs (see Table 9.2).
212 ART

Table 9.2: Possible switch of first-line therapy without knowledge of the resistance situation*.
Failing First-line therapy Promising switch
2 NRTI + 1 NNRTI Replace NNRTI with preferably darunavir/r (or also bictegravir,
dolutegravir) or darunavir/r plus dolutegravir.
2 NRTI + 1 PI/r 1–2 new nukes plus INSTI (preferably dolutegravir or bictegravir)
or possibly doravirine+dolutegravir (data more scarce).
2 NRTI + 1 INSTI 1–2 new nukes plus darunavir/r (if acted upon quickly).
* In individual cases, other modifications or even a wait-and-see approach may be appropriate. Chose
drugs with a high resistance barrier if possible: darunavir/r, dolutegravir, bictegravir. For more complex
resistance situations, see also Salvage.

Virologic treatment failure with NNRTIs. With nevirapine or efavirenz, cross-resis-

tance is usually present, and the development of resistance also occurs very rapidly.
This is also true for rilpivirine, which is very vulerable to high viral loads.
Continuation of an NNRTI in the presence of resistance is useless, as it does not
affect the replicative fitness of the viruses. More so, since cumulative resistance could
also affect the efficacy of second-generation NNRTIs, the NNRTI should be stopped
immediately in case of virological failure, especially in the case of resistance:
etravirine and doravirine can be considered later; other options should be used first.
There is now a large amount of data on NNRTI failure, mainly from Africa. Preference
should be given to a boosted PI regimen and/or a second-generation INSTI. Darunavir/r
is better than lopinavir/r (Aboud 2019). The PI can be combined with two NRTIs but
also with raltegravir alone. In at least two large randomized trials (SECOND-LINE
2013, La Rosa 2016), the combination of lopinavir/r plus raltegravir was shown to
be equivalent to standard PI/r therapy. In EARNEST (Paton 2014), 1,277 individuals
were randomized in a three-arm design to receive either a PI/r regimen (lopinavir/r
plus 2–3 NRTIs = standard), a PI/r plus raltegravir (mostly lopinavir/r or darunavir/r
= nuke sparing), or a PI/r alone after 12 weeks of raltegravir induction (= mono). The
rate with viral load below 400 copies/mL at 96 weeks was 86% in the standard arm,
86% with nuke-sparing, and 61% in the mono arm. The data may not be generaliz-
able to Europe. Though the data may not be generalizable to Europe, they show that
nuke sparing can be an alternative. However, they also show that monotherapies are
not a good idea in cases of (possibly adherence-related) virological treatment failure.
Newer data have described the potential of second-generation INSTIs:
In NADIA, 465 people were assigned to dolutegravir or darunavir/r and 3TC plus
either tenofovir or AZT in a randomized 2x2 design (Patel 2022). Dolutegravir was
non-inferior to darunavir/r at 96 weeks (90% versus 87% below 400 copies/mL);
however, nine (4%) subjects developed resistance versus none on darunavir/r. The
resistance barrier of darunavir/r may be somewhat higher after all. Interestingly, in
the second comparison, tenofovir was slightly better than AZT (92% versus 85%),
which was also true for patients with tenofovir resistance. These data show that it
is not always necessary to switch nukes in second-line therapy in the event of NNRTI
failure. AZT can and should be omitted.
The 2SD trial enrolled 795 participants with viral suppression on a boosted PI regimen
(in whom a previous first-line regimen of two NRTIs and an NNRTI had failed and
for whom there were no data regarding the presence of drug-resistance mutations).
A switch to dolutegravir treatment was non-inferior compared to a continued boosted
PI regimen (Ombajo 2023).
The double-blind, randomized GS-4030 trial was set to evaluate the potential of
Biktarvy® in 565 pre-treated PLWH. The trial explicitly allowed resistance to NRTIs,
NNRTIs, and PIs (Acosta 2020). Patients on dolutegravir-containing regimens were
5.9. Virological failure 213

enrolled and randomized to Biktarvy® or dolutegravir plus TAF+FTC. Efficacy

remained good despite significant baseline resistance, particularly in the NRTI drug
class. Over 100 participants had NNRTI resistance but remained almost all virologi-
cally suppressed – bictegravir and dolutegravir appear to have similar potential in
salvage therapy. It should be noted, however, that all patients from GS-4030 had
suppressed viral loads, and the resistance was determined from proviral DNA only –
so strictly speaking, it was not virologic failure.
Darunavir/r plus dolutegravir may also be considered. Two agents with a high resist-
ance barrier may still be better than one, but adequately powered studies are lacking
(Capetti 2017, Hawkins 2019, Armenia 2021). Darunavir should be preferably given
as the STR Symtuza® (TAF/FTC/darunavir/c) to save pills (in some countries,
darunavir/c is also available as Rezolsta®) but also to preserve a possible M184V muta-
tion with FTC. In the case of an NNRTI failure, the combination of Symtuza® with
Tivicay® remains pretty effective, but perhaps it is too much – at least in cases with
limited mutations.
Virologic treatment failure with PIs. There are relevant cross-resistance mutations.
First-generation PIs should be replaced by darunavir/r. Should darunavir/r fail, ART
does not always need to be switched immediately. Low-level viremia on PIs is not
uncommon and does not always indicate treatment failure. Even with the NRTI
mutation M184V, ART can be continued. The effect of a fully active boosted PI is
sufficient for virologic success; continuing cytidine analogs 3TC or FTC will preserve
M184V and compromise viral fitness (Hull 2009). However, if sufficient other agents
are active, it may also be appropriate to omit NRTIs (Tashima 2013). If the PI regimen
fails (repeatedly viremia above 200 copies/mL, detection of resistance), switching to
an INSTI-based regimen is recommended. In contrast, a new NNRTI with continua-
tion of NRTIs alone is often insufficient (Abgrall 2007).
Dolutegravir or bictegravir should be used as INSTIs. The first-generation INSTIs ral-
tegravir and elvitegravir/c were relatively weak in 145, a double-blind, randomized
trial (Elion 2013). In the double-blinded SAILING trial in predominantly PI-pretreated
individuals (n=715), dolutegravir was better than raltegravir (Cahn 2013). Rates with
viral load below 50 copies/mL were 71% versus 64% at 48 weeks; moreover, there
were significantly fewer resistance mutations associated with dolutegravir. The
GS-4030 study showed comparable efficacy for bictegravir and dolutegravir in resist-
ance (evaluated from proviral DNA) to NRTIs, NNRTIs, and/or PIs (Acosta 2020).
Dolutegravir plus rilpivirine, available since 2018 as the combination tablet Juluca®,
could theoretically also be considered, provided there is no NNRTI resistance. However,
the pivotal studies only examined individuals on first- or second-line therapy who
had not yet experienced treatment failure (Llibre 2018). The combination of dolute-
gravir and doravirine (DoDo) may be more promising, but robust data are lacking
(Denyer 2022).
Virological treatment failure with INSTIs. Fortunately, it is rare so far, expected to
happen in first-line therapy with elvitegravir or raltegravir at a maximum of 1–2%.
In order to not waste the whole class, action should be taken very quickly! For limited
INSTI resistance against first-generation INSTIs, dolutegravir can be tried at a higher
dose (see Salvage). However, it is better to switch to a darunavir-containing regimen,
especially in cases of concurrent NRTI resistance or complex resistance settings,
preferably Symtuza®. For more pronounced resistance, consideration may be given
to adding another agent. NNRTIs alone may be too vulnerable in concurrent NRTI
resistance but can be added. There is good etravirine data from the DUET trials (see
Salvage), and doravirine is also an option. Maraviroc, which is often forgotten, should
also be considered. Ultimately, the decision must be made individually according to
the resistance.
214 ART

Literature on switching in case of therapy failure

Aboud M, Kaplan R, Lombaard J, et al. Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside
reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed
(DAWNING): an open-label, non-inferiority, phase 3b trial. Lancet Inf Dis 2019, 19:253-64.
Acosta RK, Willkom M, Andreatta K, et al. Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF)
From Dolutegravir (DTG)+F/TAF or DTG+F/Tenofovir Disoproxil Fumarate (TDF) in the Presence of Pre-existing
NRTI Resistance. J AIDS 2020, 85:363-371.
Armenia D, Bouba Y, Gagliardini R, et al. Virological response and resistance profile in highly treatment-experi-
enced HIV-1-infected patients switching to dolutegravir plus boosted darunavir in clinical practice. HIV Med 2021,
22:519-525.
Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-
inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING
study. Lancet 2013, 382:700-8.
Capetti AF, Cossu MV, Orofino G, et al. A dual regimen of ritonavir/darunavir plus dolutegravir for rescue or sim-
plification of rescue therapy: 48 weeks’ observational data. BMC Infect Dis 2017, 17:658.
De Meyer S, Hill A, Picchio G, et al. Influence of baseline protease inhibitor resistance on the efficacy of
darunavir/ritonavir or lopinavir/ritonavir in the TITAN trial. J AIDS 2008, 49:563-4.
Denyer R, Zemskova J, Benator DA. HIV treatment with dolutegravir and doravirine: rationale for selection and
clinical outcomes in a highly treatment experienced population. Int J STD AIDS. 2022 Sep 16:9564624221116533.
Elion R, Molina JM, et al. A randomized phase 3 study comparing once-daily elvitegravir with twice-daily ralte-
gravir in treatment-experienced subjects with HIV-1 infection: 96-week results. J AIDS 2013, 63:494-7.
Hawkins KL, Montague BT, Rowan SE, et al. Boosted darunavir and dolutegravir dual therapy among a cohort of
highly treatment-experienced individuals. Antivir Ther 2019, 24:513-519.
Hull M, Moore D, Harris M, et al. A lamivudine (3TC)-based backbone in conjunction with a boosted protease
inhibitor (PI) is sufficient to achieve virologic suppression in the presence of M184V mutations. Abstract H-916,
49th ICAAC 2009, San Francisco.
La Rosa AM, Harrison LJ, Taiwo B, et al. Raltegravir in second-line antiretroviral therapy in resource-limited set-
tings (SELECT): a randomised, phase 3, non-inferiority study. Lancet HIV 2016, 3:e247-58.
Llibre JM, Hung CC, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the mainte-
nance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and
SWORD-2 studies. Lancet 2018 Jan 5.
Nasta P, Matti A, Cocca G, et al. Early vs deferred HAART switch in heavily pre-treated HIV patients with low viral
load level and stable CD4 cell count. Abstract 523, 13th CROI 2006, Denver.
Ombajo LA, Penner J, Nkuranga J, et al. Second-Line Switch to Dolutegravir for Treatment of HIV Infection. N
Engl J Med 2023, 388:2349-2359.
Paton NI, Kityo C, Hoppe A, et al. EARNEST Trial Team. Assessment of second-line antiretroviral regimens for HIV
therapy in Africa. N Engl J Med 2014, 371:234-47.
Paton NI, Musaazi J, Kityo C, et al. Efficacy and safety of dolutegravir or darunavir in combination with lamivu-
dine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from
a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial. Lancet HIV 2022, 9:e381-e393.
Petersen ML, van der Laan MJ, Napravnik S, et al. Long-term consequences of the delay between virologic failure
of highly active antiretroviral therapy and regimen modification. AIDS 2008, 22:2097-106.
SECOND-LINE Study Group, et al. Ritonavir-boosted lopinavir plus nucleoside or nucleotide reverse transcriptase
inhibitors versus ritonavir-boosted lopinavir plus raltegravir for treatment of HIV-1 infection in adults with viro-
logical failure of a standard first-line ART regimen: a randomised, open-label, non-inferiority study. Lancet 2013,
381:2091-9.
Tashima K, Smeaton L, Andrade A, et al. Omitting NRTI from ARV Regimens Is Not Inferior to Adding NRTI in
Treatment-experienced HIV+ Subjects Failing a Protease Inhibitor Regimen: The ACTG OPTIONS Study, Abstract
153LB, 20th CROI 2013, Atlanta.
Tenorio AR, Jiang H, Zheng Y, et al. Delaying a treatment switch in antiretroviral-treated HIV type 1-infected
patients with detectable drug-resistant viremia does not have a profound effect on immune parameters: ACTG
A5115. AIDS Res Hum Retroviruses 2009, 25:135-9.
Torti C, d’Arminio-Monforte A, Pozniak AL, et al. Long-term CD4+ T-cell count evolution after switching from
regimens including HIV nucleoside reverse transcriptase inhibitors (NRTI) plus protease inhibitors to regimens
containing NRTI plus non-NRTI or only NRTI. BMC Infect Dis 2011, 11:23.
United Kingdom Collaborative HIV Cohort Study, Lee KJ, Dunn D, et al. Treatment switches after viral rebound
in HIV-infected adults starting antiretroviral therapy: multicentre cohort study. AIDS 2008, 22: 1943-50.
Wallis C, Papathanasopoulos M, Conradie F. Early switch based on virological failure reduces complexity of HIV-
1 drug resistance. Abstract 594, 17th CROI 2010, San Francisco.
5.10. Salvage therapy 215

5.10. Salvage therapy

C H R ISTIAN HOFFMAN N

The term salvage therapy is not defined. Like in oncology, it is used in various ways
in HIV. While some only speak of salvage when all drug classes have failed, for others,
this applies as of second line of therapy. As well, the term HTE (“heavily” or “highly
treatment-experienced”) has become widespread. It is not defined, is vague, excludes
those people with transmitted resistance, and should be avoided. Today, salvage is
usually referred to when there is at least triple class resistance (TCR) or at least triple
class failure (TCF). Classes in this context are usually NRTIs, NNRTIs, PIs, and INSTIs.
Viruses with even more extensive resistance are also called MDR viruses (“multi-drug
resistant”), as in MDR tuberculosis.
The number of “salvage patients” is decreasing. Mainly people with mono- or dual
therapy from the 90s are affected. In the Swiss cohort, the prevalence of viruses with
TCR decreased from 9.0% to 4.4% between 1996 and 2013. Among individuals who
started their ART after 2006, the rate was below 0.4% (Scherrer 2016). Only 14 cases
of four-class resistance (QCR) were seen in the cohort. In EuroResist, an analysis of
nearly 40,000 patients from 7 European countries, QCR prevalence was recently well
below 1% (Dewandre 2021). Transmission of multidrug-resistant viral strains also
remains a rare event to date. However, local outbreaks have been described in recent
years (Viciana 2016, Esashika 2019), as well as cases of superinfection (Castro 2014).
A range of still surprisingly effective agents are now available, even with multiple
resistance mutations. This is encouraging – and has changed the goals of therapy:
even in intensively pre-treated patients with multi-drug resistant viruses, the aim
should always be to reduce the viral load to below the limit of detection. In our
experience, this is successful in up to 90% with TCR and even 55–70% of those with
QCR (Däumer 2018, Parisi 2019). If the viral load is not suppressed sufficiently, the
risk of AIDS may increase (Parisi 2019).
However, the small number of viremic individuals with multiple viral resistances
makes conducting meaningful studies difficult or impossible. For the BRIGHTE study
evaluating fostemsavir, 168 centers worldwide were required for 371 patients!
Homogeneous populations hardly exist; the individual therapy history and resistance
situation are often very heterogeneous. The design of salvage studies is also prob-
lematic. Since the sole use of a new agent is ethically questionable, the remaining
ART must always be optimized (= OBT, optimized background therapy). If OBT is
too good, the effect of the new agent may be lost since too many achieve good viral
suppression even with OBT alone. On the other hand, if OBT is poor, the effect of
the new compound is often transient or weak – the window in which the effect of
a new compound can be shown is small. It has become difficult to bring new agents
to market. The fact that three new drugs – ibalizumab, fostemsavir, and lenacapavir
– have recently been successfully launched is a great success. Fosamprenavir and
lenacapavir may revolutionize salvage therapy.

General
First, it should not be forgotten to encourage patients with resistance problems, who
often look back on a long therapy and now find themselves supposedly on the edge
of a precipice. There is no “beyond treatment”; this misnomer is even more misplaced
in HIV medicine than in other specialties. Moreover, it usually takes years for viro-
logical therapy failure to be followed by immunological and, finally, clinical therapy
failure. Fortunately, those affected – part of the furniture of every outpatient clinic,
who have usually been treated for 25 years or more and have suffered through much
216 ART

Table 10.1: Case study of what has become possible in salvage therapy today.
Date (HA)ART CD4 T-cells Viral load
Jun 95 AZT (later ddC, ddI) 0 n.a.
Jun 96 "HAART": AZT+ddC+RTV 25 62,000
Oct 96 d4T+3TC+IDV 10 167,000
Jul 97 d4T+ddI+3TC+NVP+IDV 173 69,000
Jan 99 d4T+ddI+ABC+3TC+SQV/r 212 106,000
Sep 99 d4T+ABC+3TC+DLV+LPV/r 231 74,000
Dec 01 TDF+ddI+DLV+HU 174 84,000
Oct 03 TDF+3TC+DDI+TPV/r 77 733,000
May 04 AZT+3TC+TDF+LPV/r+T-20+DLV 43 123,000
Dec 04 AZT+3TC+TDF 32 204,000
Dec 07 AZT+3TC+TDF+DRV/r+RAL+T-20 7 > 1,000,000
Jan 08 54 < 50
Apr 09 AZT+3TC+TDF+DRV/r+RAL+ETV 83 < 50
Feb 20 TAF+FTC+DRV/c+DOL 192 < 50
Dec 21 236 < 50
Comment: Not all therapy switches are listed. The 2007 switch was done when darunavir and ralte-
gravir were both available so that they could be used simultaneously. T-20 was initially "recycled"
because it remained unclear after the resistance situation whether darunavir was still active. Notably,
viral load was permanently suppressed after many years at high ranges. The current ART consists of
2 tablets daily and is well-tolerated.

Figure 10.1: Long-term trends of CD4 T-cells/μl (dark, primary axis on the left) and HIV RNA copies/mL
(gray, secondary axis on the right) in four patients with three-class resistance. Top and bottom left,
three patients in whom INSTI-based regimens (mostly raltegravir) achieved sustained viral suppres-
sion between 2005 and 2008. Bottom right, a patient with multidrug-resistant virus in whom no single
effective substance was available in 2016 – continuous drop in CD4 T-cells, now severe immunodefi-
ciency.
5.10. Salvage therapy 217

– are often less nervous than their younger HIV doctors! They have learned that there
is always a way. Many resistance mutations from the old days are also becoming less
important: no one uses AZT, efavirenz, and lopinavir today. People with multidrug-
resistant viruses also have a right to well-tolerated therapies! The case in the table
Table 10.1 above illustrates the history of someone on antiretroviral therapy.
Although the latest knowledge was consistently applied, virus suppression was unsuc-
cessful for years. This could only be achieved by new agents (raltegravir, T-20) at the
end of 2007, after more than 12 years of virological failure.
Individuals with multiple resistance may have a somewhat less favorable prognosis,
especially if viral load cannot be reduced. For example, in the Italian PRESTIGIO
cohort of 148 QCR individuals, the risk of AIDS was doubled with viremia at 48
months (Parisi 2019). However, multidrug-resistant viruses have lower replication
fitness and are presumably less aggressive. Individuals with MDR viruses should still
be closely monitored and have regular physical examinations, something often
neglected today. Weight loss, B-symptoms, oral thrush, an OHL, or cognitive dete-
rioration are early signs of disease progression that should not be overlooked. Affected
individuals should also be co-managed in larger centers where new options are more
readily available and experience with complex salvage regimens exists. A single new
drug should not always be used up immediately – several active agents should be
used if possible!

Strategies with conventional drug classes

Many agents have proven effective for PLWH with limited options over the past 20
years: the PIs darunavir and tipranavir, the NNRTI etravirine, the CCR5 antagonist
maraviroc, and the INSTIs.
Some were tested in large placebo-controlled trials enrolling patients with confirmed
virologic failure and multi-class resistance. Such study designs are now hardly prac-
tical given the rarity of viremia, but also for ethical reasons. As shown in Table 10.2,
inclusion criteria varied significantly: in some cases, they were linked to resistance
mutations; in others, three-class failure was sufficient. The definition of treatment
failure differed significantly in some cases, as did the background therapy.
Not surprisingly, given the different inclusion criteria and the changing options for
optimized background therapy, success rates varied considerably even in the placebo
arms. For example, the proportion with a viral load below 50 copies/mL after 48
weeks ranged from 10% to 40% (and 11% to 62% when T-20 was added). The success
rates of patients with a maximum of one active substance according to resistance
status and who received a placebo ranged from 1% to 24%, indicating different
potent background regimens.
INSTIs were also randomly tested against each other in patients with treatment
failure. In BENCHMRK, raltegravir with 0–1 additional active agent still managed a
rate of 48% below 50 copies/mL (see table). The effect of elvitegravir was compara-
ble to that of raltegravir in the 145 study (Elion 2014). In SAILING, dolutegravir
showed a clear advantage over raltegravir, with 71% versus 64% achieving an unde-
tectable viral load (Cahn 2014). Here, resistance to at least two classes was a prereq-
uisite, in addition to a viral load of at least 400 copies/mL. Participants had to have
at least one fully active additional agent as an option. In the VIKING trials, dolute-
gravir was effective even in the presence of INSTI resistance. Of 183 PLWH, as many
as 69% achieved viral loads below 50 copies/mL at 24 weeks in VIKING III (Castagna
2014). Moreover, higher doses of dolutegravir can help overcome resistance in the
case of raltegravir and elvitegravir (Castagna 2014, Akil 2015). Bictegravir has never
really been tested in the salvage setting but appears to have a very similar resistance
profile to dolutegravir.
218 ART

Table 10.2: Large randomized trials in salvage therapy.

Reference Study (agent) Main inclusion criteria
Lalezari 2003, TORO 1+2 TCF or TCR or both, VL > 5,000
Lazzarin 2003 (T-20)
Hicks 2006 RESIST 1+2 TCF and 1-2 primary PI resistance, VL > 1,000
(Tipranavir)
Clotet 2007 POWER 1+2 TCF and ≥ 1 primary PI resistance, VL > 1,000
(Darunavir)
Lazzarin 2007, DUET 1+2 ≥ 1 NNRTI resistance and ≥ 3 primary PI
Katlama 2009 (Etravirine) resistances, VL > 5,000
Gulick 2008, MOTIVATE 1+2 TCR or TCF or both, VL > 5,000 (interruption
Fätkenheuer 2008 (Maraviroc) at baseline allowed), R5 tropism only
Cooper 2008, BENCHMRK 1+2 TCR, VL >1000
Steigbigl 2008 (Raltegravir)
TCR/TCF = Triple Class Resistance/Failure, VL = Viral Load (HIV RNA copies/mL).

Table 10.3: Large randomized trials, essential data.

POWER RESIST MOTIVATE BENCHMRK DUET
Study drug DRV TPV MVC RAL ETV
n total 245 1,509 1,049 701 612
Baseline characteristics
Median VL, log RNA/mL 4.5–4.6 4.7 4.9 4.5–4.7 4.8
Median CD4/μl 153–163 195–196 187–195 102–140 99–109
0–1 active* substance, % 49–55 43–45 38–44 48–51 54
Background therapy
with de novo T-20, % 29–33 18–23 40–44 20 25
with darunavir, % 100 0 0 25–50 100
with tipranavir, % 0 100 14–16 19–23 0
Response n. 48 Wo**
total, % 45 vs. 10 23 vs. 10 44 vs. 17 64 vs. 34 61 vs. 40
with de novo T-20, % 58 vs. 11 28 vs. 14 61 vs. 27 84 vs. 62 71 vs. 59
0–1 active ingredient, % 37 vs. 1 n.a. 37 vs. 6*** 48 vs. 12 57 vs. 24
* The definition of an active agent was inconsistent (different resistance scores)
** Viral load < 50 copies/mL *** Data at week 24. n.a. = not stated.

The “three new ones”: ibalizumab, fostemsavir, lenacapavir

The progress continues. Very recently, three new compounds have entered the scene.
Ibalizumab in 2020, fostemsavir in 2021, and lenacapavir in the summer of 2022.
Especially with the introduction of fostemsavir and lenacapavir, many other strate-
gies and concepts are no longer necessary. It should be noted that the indication is
still very narrow for all three. It is limited to “multidrug-resistant HIV for whom no
other suppressive regimen can be composed.”
Fostemsavir (Rukobia®) inhibits attachment to the CD4 receptor by binding directly
to the gp120 glycoprotein. Fostemsavir was given to 371 intensively pre-treated
patients with three-class failure and treatment failure (> 400 copies/mL) in combi-
nation with optimized background ART in a Phase III trial (BRIGHTE). Less than half
5.10. Salvage therapy 219

of the participants still had more than one active agent. After 96 weeks (Lataillade
2020), 60% achieved a viral load below 40 copies/mL (37% in those without active
drugs. The response rates were not only dependent on the number of active agents
in the optimized adjuvant ART but also on viral load and CD4 T-cells. The higher
the viremia, the lower the CD4 T-cells the lower the response rates (Ackerman 2021).
Overall tolerability was good; side effects above grade 1 were rare and predominantly
gastrointestinal.
Lenacapavir (Sunlenca®) is a first-in-class capsid inhibitor. Sufficient levels can be
achieved for six months with a single subcutaneous administration. In CAPELLA, 72
patients on failing ART were also treated with lenacapavir subcutaneously or placebo
every six months (Segal Maurer 2022). Two weeks after the first injection, viral load
had fallen by at least 0.5 log levels in 88% compared with 17% on placebo. Despite
limited options in background therapy, up to 81% achieved viral loads below
50 copies/mL, including 4/6 individuals in whom lenacapavir was the only active
agent. The effects were seen over 52 weeks (Ogbuagu 2023). Reactions at the injec-
tion sites were the most common problems but have rarely led to discontinuation.
Resistance does not appear to be entirely uncommon and has been observed even
in treatment-naive individuals (Gupta 2022) – possibly indicating that the resistance
barrier is not very high. In August 2022, the EMA approved lenacapavir based on
the CAPELLA data. The tablets are intended as a “lead-in” before depot injection.
Ibalizumab (Trogarzo®) is a monoclonal antibody that binds directly to the CD4
receptor, preventing HIV entry. It must be infused at two-week intervals for 30–60
minutes each. In a Phase IIb study, ibalizumab was given every 2 or 4 weeks in 113
intensively pre-treated patients. At week 24, 59% and 31%, respectively, had achieved
viral loads below 50 copies/mL (Khanlou 2011). In another study, 43% of 40 inten-
sively pretreated individuals achieved a viral load below 50 copies/mL at 24 weeks
– with biweekly infusions. The effect mainly persisted until 48 weeks (Emu 2018).
Tolerability was good. In early 2022, Theratechnologies announced that it would
market ibalizumab only in North America. In cases where ibalizumab is necessary
in Europe, there is the possibility of importation in some countries. It is crucial to
clarify the coverage of costs by the health insurance.

A practical procedure for multi-class resistance

Guidelines cannot be relied upon in the most complex cases. Opinions differ even
on how many effective agents should be used: As a rule, however, at least two, prefer-
ably including one with a high resistance barrier. In some guidelines, such as those
of EACS, three active agents are “preferably” recommended, although there is actu-
ally no data for this.
In any case, a current resistance test should be available, preferably not done during
a therapy break. All old resistance tests should also be considered; the resistance
situation should always be assessed cumulatively. It can be assumed that previously
detected resistance mutations are still present, even if they are undetectable. These
resistances are also likely to persist over time (Nishizawa 2015). It is also essential to
consider previous intolerances so that people are spared unnecessary side effects or
dangerous re-exposures. Good documentation of therapy history saves time and
efforts.
In complex resistance settings, it is advisable to first go through all drug classes and
examine possible options in each case before putting together a regimen. Previously
widely used agents such as AZT, tipranavir, or T-20 (enfuvirtide) are generally no
longer necessary. Raltegravir, still a life-saving salvage drug in 2007, is no longer
useful because there are now INSTIs with a higher resistance barrier. This is prima-
220 ART

rily also true for maraviroc, with which there is a risk of dual-topic viruses (and thus
loss of efficacy), especially with low CD4 T-cell nadir. Ibalizumab, now only avail-
able outside the US as an import, is unnecessary in most cases.
If possible, complex cases and decisions should be discussed as a team with experi-
enced HIV care providers and virologists. The resistance situation must be examined
and discussed, as well as the individual situation. What can be expected of those
affected? As in other cases, many factors also play a role in the treatment decision
in the case of multidrug resistance:
• Co-morbidities (hepatitis B/C, renal insufficiency, cardiovascular problems)
• Concurrent medication (interactions!)
• Intolerances (weight gain with INSTIs or TAF?)
• Preferences (dietary restrictions, number of pills, desire for children)
• Current situation (virologic failure or suppression? Immune status?)
NRTIs: Because the M184V mutation reduces replication fitness (Campbell 2005,
Castagna 2006), it has long been recommended to continue with 3TC or FTC despite
its presence. HIV is forced to conserve M184V at the expense of fitness. However,
randomized trials such as ACTG 5241 (OPTIONS) or NUKE OUT showed that
ineffective NRTIs can be discontinued if other effective agents are still available –
treatment success is not compromised (Tashima 2015, Llibre 2016, Gandhi 2020).
Even in the VERITAS study, there was no virological rebound due to discontinuation
of ineffective NRTIs (Trottier 2015). Nevertheless, many virologists continue to
adhere to this strategy. The strategy often followed in the past of “recycling” AZT
and combining it with TDF due to divergent resistance pathways (Stephan 2010) is
no longer useful. AZT is too toxic.

Table 10.4: Strategies in salvage settings, for different drugs classes salvage settings.
Medication Strategies, remarks
NRTIs Attempts can be made to conserve replication fitness-reducing resistance, such
as M184V with 3TC or FTC. TAF or TDF can also be considered
NNRTIs If < 3 NNRTI resistances, use etravirine (only approved with boosted PI/r),
possibly also doravirine; otherwise, discontinue NNRTIs
PIs If there are not many PI resistance mutations, consider darunavir/c as STR along
with TAF+FTC, otherwise twice daily (or consider PI omission)
INSTIs Prefer dolutegravir and bictegravir, both also effective for some INSTI resistances
Fostemsavir No cross-resistance to other agents but very limited approval; twice-daily
administration required
Lenacapavir No cross-resistance to other agents but very limited approval; resistance barrier
may not be very high, no oral administration (six-monthly injections).

NNRTIs: For fewer than 3 NNRTI resistance mutations, etravirine is best considered,
but it is only approved in combination with boosted PIs (darunavir preferred).
Doravirine may still work for single NNRTI resistance mutations. Otherwise, NNRTIs
should be discontinued. Resistance, once generated or detected, is likely to persist.
However, among pregnant women who had received nevirapine once for transmis-
sion prophylaxis at birth, no increased rate of virologic treatment failure was observed
on subsequent nevirapine-containing ART when ART was started later than six
months after birth seems possible that NNRTI resistance may disappear or not inter-
fere with subsequent therapy if there is a longer wait (Lockman 2007). However,
there is no data on the possible recycling of NNRTIs.
5.10. Salvage therapy 221

PIs: Only darunavir/r should be considered; tipranavir/r is too toxic and offers no
benefits. In cases of multiple resistance, twice-daily administration of darunavir/r is
preferred. A double-PI strategy is no longer appropriate. All other PIs usually do not
make sense.
INIs: Dolutegravir and bictegravir are preferred due to their higher resistance barrier.
The VIKING studies showed that in the case of raltegravir resistance, higher doses
of dolutegravir (50 mg BID instead of OD) could help overcome this (Castagna
2014+2017). Dolutegravir at the twice-daily dose has thus become an essential
component of salvage therapy – it should always be considered in complex cases,
possibly in combination with darunavir (Capetti 2017). The resistance profiles of
dolutegravir and bictegravir largely overlap.
Maraviroc: An up-to-date, valid tropism test should always be available.
Unfortunately, tropism correlates closely with the CD4 T-cell nadir. The lower the
nadir, the more frequently non-R5 tropism is present, and maraviroc will not be
effective. Especially in those who have been pre-treated for decades, a very low nadir
is often present. In most cases, therefore, it is to be expected that maraviroc will not
be effective. On the other hand, it may well be a highly effective substance that is
also excellently tolerated. It should be considered.
Fostemsavir and lenacapavir: If at least one agent is still effective among NRTIs,
NNRTIs, and PIs, an INSTI is often sufficient to reduce the viral load below the
detection limit. Even in this situation, the new options would still be preserved.
When INSTIs are questionable, fostemsavir or lenacapavir can be considered at the
latest. Combination is also an option. Although there is virtually no data to date,
these two fully effective agents are possible because of the lack of cross-resistance.

Is simplification possible?
Simplification can also be considered in the salvage setting. Although multidrug-
resistant viruses can be expected to persist for life, de-escalation can be considered,
especially in “historically grown” regimens that have been intensified over the years.
Smaller studies show this is possible in selected patients (Valantin 2019, Vizcarra
2019). However, given the limited options, special care must be taken to maintain
viral suppression. At least two fully effective agents, including one with a high resist-
ance barrier, should remain. Often, creative use of existing STRs can noticeably reduce
the number of tablets.
Especially when INSTIs are fully effective, some things are possible: for the combi-
nation elvitegravir/c+TAF+FTC (Genvoya®) plus darunavir (Prezista®), there are good
data in carefully selected individuals (Chicken 2022). Darunavir is boosted here by
cobicistat and does not require ritonavir.
For the very similar combination of darunavir/c+TAF+FTC (Symtuza®) plus dolute-
gravir (Tivicay®), there are only data from uncontrolled trials (Capetti 2017, Hawkins
2019, Armenia 2021). However, the resistance barrier is likely to be even higher with
dolutegravir replacing elvitegravir; emerging resistance with both darunavir plus
dolutegravir is very rare (Armenia 2021). We would, therefore, favor this combina-
tion.
Other STRs like Juluca®, but also Delstrigo® or Biktarvy® can be considered and often
cleverly incorporated into creative regimens. What is combined and how depends,
of course, on the individual resistance situation and your perhaps off-label creativ-
ity. Of course, ensure that the backbone dose is not accidentally doubled (i.e., do
not combine Biktarvy® and Symtuza®!).
222 ART

Salvage therapy, practical tips

• Clarify in advance. Which previous therapies were given for how long, and how
successful were they? Test current resistance situation (not during therapy breaks)!
• Choose two to three new (active) agents if possible; try not to use only one active
agent when possible.
• Do not wait too long and thus allow the virus to generate further resistance muta-
tions; the higher the viral load at the switch, the poorer the chances of success.
• Refer patients to larger centers, if possible, as they have more experience with
salvage therapies.
• Encourage the person! There is no longer such a thing as “beyond treatment”!
• Don’t give the wild type a chance – in the absence of options, it may make sense
to continue a “failing” therapy.
• Consider clinical trials (islatravir? bNAbs?).

Other salvage strategies

Here, some salvage strategies will be discussed. Some were tried a lot in the past and
are partly obsolete today; others can still be promising in individual cases, possibly
in combination.
Treatment interruptions have been evaluated in the hope that possible resistance
might disappear due to “overgrowth” by the wild type. After initial positive data
from GIGHAART (Katlama 2004), studies with negative results predominate. In
CPRC064, four months were paused before salvage therapy in each case. There were
no differences in virological response with or without the pause (Lawrence 2003).
Pauses resulted in lower CD4 T-cells and more frequently severe clinical events. Many
other randomized studies found no virological benefit (Benson 2006, Walmsley 2007,
Holodny 2011), so strategic treatment interruptions are not recommended.
Exploit NNRTI “hypersusceptibility”: This occurs when the 50% inhibitory
concentration in phenotypic resistance assays for NNRTIs is lower than that of wild-
type. This phenomenon, first described more than 20 years ago, is rare with NRTIs
but common with NNRTIs – interestingly, especially for viruses with NRTI resistance
mutations (Haubrich 2002). In more than 17,000 blood samples, the prevalence in
NRTI-naive individuals was 9% and 11% for efavirenz and nevirapine and 26% and
21% for NRTI-pretreated individuals (Whitcomb 2002). In particular, NRTI mutations
at codons 215, 208, and 118 render viruses hypersensitive. Some evidence suggests
that NNRTI hypersusceptibility improves response (Haubrich 2002, Clark 2006).
Although the significance and molecular correlation of NNRTI hypersusceptibility
remain obscure: NNRTIs should be considered in the presence of NRTI mutations
and the absence of NNRTI resistance.
Partial interruption means that ineffective ART is partially continued based on the
consideration that multidrug-resistant viruses are somewhat less aggressive than wild
types, at least for some time. Thus, 3TC still positively affects viral load in M184V
resistance (Campbell 2005). In a randomized trial (Castagna 2006, Gianotti 2008) of
50 individuals with an M184V mutation and a viral load greater than 1,000 copies/mL
on a 3TC-containing regimen, ART was either paused completely or 3TC alone was
continued. The rationale again was that the M184V decreases the replicative fitness
of HIV. Indeed, with 3TC, the viral load increased by only 0.6 logs instead of
1.2 logs, and CD4 T-cells did not fall as rapidly. In all subjects on 3TC, the M184V
mutation persisted, and no accumulation of new mutations occurred. In contrast,
without 3TC, a shift to wild-type virus was always observed. The beneficial effect
5.10. Salvage therapy 223

was observed over 144 weeks (Castagna 2007) when 3TC was continued. Also, daily
FTC (not weekly) seems effective (Soria 2010). However, this concept is obsolete in
the era of lenacapavir and fostemsavir.
Other: Other agents beyond ART may also have a moderate antiviral effect. Acyclovir
is one of them, but also foscavir or interferon. A meta-analysis showed an average
decrease in HIV viral load of 0.33 logs by acyclovir or valaciclovir (Ludema 2011).
The effect can be further increased by higher doses of valaciclovir (Perti 2013).
For interferon, the antiviral effect is 0.5 to 1 log (Hatzakis 2001, Rivero-Juárez 2016).
For foscavir, there are single case reports (Delory 2016). In individual cases, one can
consider integrating these drugs into a salvage regimen. However, this is hardly
necessary (provided that there is access to fostemsavir and/or lenacapavir).

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226 ART

5.11. Treatment interruptions

C H R ISTIAN HOFFMAN N

Therapy breaks are not uncommon. Although there is actually hardly any rational
argument for them anymore, they are part of antiretroviral therapy. Adherence
problems and treatment fatigue often exist, usually in combination. In the ART
Collaboration Cohort (21,801 individuals from 18 cohorts from Europe/North
America 2002–2009), the probability of treatment discontinuation was about 12%
after three years of ART (Abgrall 2013). The likelihood is about threefold higher
among drug users. Younger people (under 30 years) were also more likely to drop
out of treatment.
In addition to the wishes of the patients, there are also situations in which ART must
be interrupted. These can be illnesses that preclude oral intake, such as severe
gastroenteritis or pancreatitis, or an accident or surgical intervention. Sometimes,
only access to ART is interrupted (left on the plane and now in Bolivia, etc.).
Interruptions of a few days are usually without consequences. Nevertheless, attempts
should be made to keep therapeutic breaks as short as possible.
A particular case is “analytic” treatment interruptions (ATIs), where a possible
rebound is investigated, usually after an experimental intervention (see Cure). If ATIs
are planned, there are important ethical issues to consider. There are now recom-
mendations on how to proceed and inform participants in such studies (Julg 2019).
This chapter provides an up-to-date overview of therapy pauses in chronically infected
PLWH. For therapy pauses in acutely infected PLWH, see Acute HIV Infection.

Viral load and CD4 T-cells during treatment interruptions

Almost all patients who stop their therapy experience a rebound of the viral load
within a few weeks – even if it had been below the detection limit for years. In most
cases, the viral load is detectable again after only 10–20 days; the doubling time in
the blood is about 1.6–2.0 days (Chun 1999, Davey 1999). Since viral load parallels
in compartments such as the CNS but also semen and vaginal fluid (Garcia 1999)
and can also be detected very rapidly in semen within a few weeks (Ananworanich
2011), patients should be made aware of the increased risk of infection during treat-
ment interruptions (Burman 2008). Swiss data suggest that approximately 14% of
new infections are caused by individuals who have taken a break from therapy (Marzel
2016). There may also be an increased risk of maternofetal transmission, even if ART
was interrupted only during the first trimester (Galli 2009). An exuberant rebound
is often observed during a break (De Jong 1997), and only after weeks does the viral
load settle at the pre-therapeutic level (Hatano 2000). The virus apparently does not
come from latent reservoirs – other cell populations must exist from which new virus
is produced so rapidly (Chun 2000, Ho 2000). The duration to rebound varies widely,
and recent attempts have been made to predict rebound with biomarkers (Hurst
2015, Giron 2022).
Immunologically, pauses in therapy can have considerable consequences. Often, CD4
T-cells drop back to their pre-therapy level within a short period. The ground gained
on ART can be quickly lost. The decline is biphasic and most severe in the first months
(Fagard 2005). CD4 losses of 200 or 300 cells/µl within a few weeks are possible, but
the range is wide. The higher the CD4 T-cells and the faster they rose on ART, the
faster they fall (Tebas 2002). Other factors such as CD4 nadir, thymus size, and age
also play a role. The lower the nadir, the smaller the thymus; the older the individ-
ual, the faster CD4 T-cells fall (Maggiolo 2004, Skiest 2006). An association probably
also exists with the level of proviral DNA before therapy interruption (Piketty 2010).
5.11. Treatment interruptions 227

Figure 11.1: Trajectories of CD4 T-cells and viral load in two asymptomatic individuals illustrate treat-
ment interruptions’ long-term consequences. On the left, the patient started ART during acute HIV
infection; on the right, ART was started during chronic infection. The dark line shows absolute CD4
T-cells/μl (primary axis on the left), and the dashed line shows viral load in RNA copies (secondary axis
on the right, logarithmic). Despite years of viral suppression (almost 20 years on the right!), the former
CD4 T-cell levels seen before the treatment interruptions were never again reached. In both cases, there
seems to be a plateau below the initial values.

The CD4 T-cell drop due to a pause is not recovered as quickly. In a prospective study,
we saw a significant disadvantage for treatment interruptions. After 18 months, CD4
T-cells were more than 120/µl lower compared to matched individuals who had
continued therapy without a break (Wolf 2005). This was also seen in the SMART
study (see below). Figure 11.1 illustrates that this can remain so for years.

The risks: Resistance, clinical problems, AIDS

Viral resistance always has to be anticipated whenever replication occurs in the
presence of suboptimal drug levels, and thereby, resistant mutants gain a selection
advantage over wild-type viruses. As a result, there are concerns that resistance may
occur both during the drug washout phase (still low levels in the blood but already
increasing replication) and when therapy is resumed (still replicating despite optimal
levels). In the case of a single treatment interruption, the probability of this does
not seem exceptionally high (Neumann 1999). However, no one can say whether
resistant isolates may ultimately emerge during treatment interruption, requiring
only a certain amount of time to become established against the wild-type virus.
Mathematical models say that the risk is at least theoretically not low, especially if
the viral load rises to high levels (Dorman 2000, Bonhoeffer 2000).
The risk of resistance is higher with repeated treatment interruptions. In several
studies, it was mainly resistance to NNRTIs or 3TC that occurred (Martinez-Picado
2002, Schweighardt 2002, Ruiz 2007). There is a high risk if ART is discontinued and
started at fixed intervals (see below). It seems advisable to use only agents with a
high resistance barrier if a treatment interruption is necessary.
The sharp increase in viral load during treatment interruption may present as an
acute retroviral syndrome. The symptoms are similar to acute HIV infection, with
swelling of the lymph nodes, fever, asthenia, and malaise. Thrombocytopenia also
occurs in up to 25%, especially in patients with a history of low platelets
(Ananworanich 2003, Bouldouyre 2009). The blood count should, therefore, be mon-
itored. Finally, attention should be paid to patients with hepatitis B coinfection. If
HBV-active therapy with 3TC, FTC, or tenofovir is discontinued, life-threatening HBV
rebounds with fulminant hepatitis may occur (Sellier 2004, Dore 2010). Monitoring
these patients carefully and checking the liver enzymes at least every two weeks is
advisable.
The risk of AIDS is likely low, provided the immunodeficiency is only moderate. In
the Swiss Cohort, the risk of progression was not increased (Taffe 2002). In 133
228 ART

patients who interrupted treatment, we observed no increased risk of AIDS after 24

months compared to 262 matched controls (Wolf 2005). However, almost all patients
in this study were immunologically stable throughout. The risk is probably higher
in patients with severe immunodeficiency (Deeks 2001, Lawrence 2003). The
CPRC064 Study in which 270 patients with MDR virus and severe immunodeficiency
(median 144 CD4 T-cells/µl) were randomized before a salvage regimen either to a
four-month treatment interruption or not was stopped because of high risk of
progression. Compared with the control group, a significantly higher progression to
AIDS (17 versus 5) occurred in the group interrupting therapy. In a multivariate
analysis, two factors predicted death or progression: treatment interruption and the
CD4 T-cell count at the time of interruption. The risk increased by 1.4 with every
drop of 50 CD4 T-cells. This study demonstrates that severely immunocompromised
patients are particularly at risk of developing AIDS during treatment interruptions
of several months. Treatment interruptions should be avoided in such patients. Data
from the SMART Study show that even with higher CD4 T-cells, treatment inter-
ruptions can lead to the development of AIDS (see below).

Interruptions for immunological reasons: obsolete!

Individual cases such as the “Berlin patient”, who, acutely infected, received tem-
porary ART in a Berlin practice more than 20 years ago and later remained below
the limit of detection for years without therapy (Lisziewicz 1999) raised hopes. While
there are currently still attempts, at least in acutely infected individuals, to use inter-
ruptions to improve the HIV-specific immune response in the sense of “endogenous
vaccination,” these attempts are obsolete in chronic infection. In the Spanish-Swiss
SSITT study, 133 individuals undertook four ten-week cycles of therapy, each with
eight weeks of ART and two weeks off (Oxenius 2002). Subsequently, ART was dis-
continued. None of the 32 subjects with a pre-ART viral load above 60,000 copies/mL
was subsequently able to reduce the viral load to below 5,000 copies/mL. Thus,
despite repeated interruptions, the viral setpoint is reduced in very few people (with
mostly previously low viral loads). If at all. Improvement in HIV-specific immune
response is unlikely. Treatment breaks based on immunological considerations are,
therefore, not justified. Strategies to prolong the duration with immunomodulatory
agents such as hydroxyurea, mycophenolate, steroids, or interleukin-2 also failed
and are obsolete.

Interruptions as a strategy for MDR viruses: obsolete

In most individuals with multi-drug-resistant viruses, treatment interruptions lead
to a gradual shift back to the wild-type. Resistance testing during treatment inter-
ruptions is often useless since the mutations may disappear from the blood after
only two weeks (Devereux 1999). In advanced and long-treated HIV, it often takes
longer (Miller 2000). PI mutations disappear first; NNRTI mutations take longer
because they have little effect on viral fitness (Deeks 2001). It can be assumed that
the wild type only overgrows the resistant mutants. With special PCRs, small amounts
of resistant viruses could still be detected during therapy breaks, and when ART is
resumed, the viral resistances quickly dominate again (Delaugerre 2001). There are
only isolated cases in which resistance was “washed out”. For example, a patient
from Erlangen (Walter 2002) was described who did not achieve sufficient viral
suppression despite intensive ART and subsequently interrupted his therapy. During
the seven-month therapy break, reversion to wild type occurred. Virus suppression
was achieved for several years after the resumption of ART (which should not have
been effective at all, according to the previous resistance tests).
5.11. Treatment interruptions 229

Can patients with MDR viruses improve the effectiveness of salvage therapy if they
take a break from therapy beforehand? While two early studies suggested an
advantage (Miller 2000, Katlama 2004), this hypothesis is now contradicted by many
studies that found no virological advantage and, in some cases, even an increased
risk of AIDS (Lawrence 2003+2006, Holodny 2011). Given the AIDS risk and the
questionable benefits, interruptions are not justified as a salvage strategy.

Interruptions to reduce toxicity: questionable

Can treatment side effects be reduced? Although elevated transaminases or lipids
may decrease relatively quickly after discontinuation (Hatano 2000, Wolf 2005), it
is questionable whether the risk of cardiovascular disease decreases. In SMART (see
below), the risk of cardiovascular and metabolic complications was increased during
STIs; in contrast to other studies, lipids barely improved (Lampe 2010). In SMART,
increased biomarkers for cardiovascular events were observed during treatment inter-
ruptions (Olmo 2012). It is highly questionable that treatment interruptions have a
favorable effect on the cardiovascular risk profile – adverse effects are more likely.
What about lipodystrophy and mitochondrial toxicity? Some studies have shown
that mitochondrial DNA can regenerate during treatment interruptions (Cote 2002,
Kim 2007), but only after several months. In contrast, another study found no effect
(Negredo 2006). Whether clinically manifest lipodystrophy improves has also not
been proven. Short breaks in therapy had no effect (Hatano 2000). In another study,
however, functional parameters of the adipose tissue improved after a six-month
therapy break, but again, no macroscopic benefit was visible (Kim 2007). However,
a sub-study of SMART showed a moderate benefit on peripheral fat and lipids by
CD4-guided treatment interruptions (Martinez 2010).
Though the data are not convincing overall, the following pages will outline some
relevant data on treatment interruptions. It is essential to distinguish between
structured intermittent treatment with fixed intervals and individualized interruptions
based on CD4 T-cell count, in which case the interruption period depends on the
patient’s immunological situation.
Structured intermittent therapy with short breaks (4-on-3-off): ART on weekdays
only? In pilot studies such as FOTO (Cohen 2007) or ANRS 162-4D (de Truchis 2017),
short treatment interruptions of 2–3 days hardly led to resistance. In the largest study
to date, the French QUATUOR trial (ANRS 170), 647 successfully pre-treated patients
were randomized to continue taking their ART daily or only on 4 of 7 days. ART
consisted primarily of INSTIs (48%) and NNRTIs (46%), with TDF+FTC (56%) pri-
marily used in the backbone. After 48 weeks, 96% remained below the detection
limit in the experimental arm. Within 96 weeks, resistance occurred in only 7/621
participants (Landman 2022). All 7 cases had received regimens with NNRTIs or first-
generation INSTIs. Renal function improved minimally with this strategy; otherwise,
there were no differences in side effects. According to the authors, the study demon-
strated non-inferiority. Although one can disagree about the ethical aspects of this
study – it shows that repeated treatment interruptions mostly remained without con-
sequences, even over longer periods. Nevertheless, we would still strongly advise
against this strategy. Seven cases of resistance are seven too many, and nothing got
better. Moreover, some patients are only confused by such concepts.
Longer treatment interruptions of 7 days (week-on-week-off, “WOWO”) increased
blips and induced virologic failure (Cardiello 2005). Longer, fixed breaks are even
less favorable. In a randomized NIH trial, treatment failure and resistance to NNRTIs
and 3TC occurred significantly more often in the interruption arm (one month pause,
two months ART), which is why the trial was stopped (Dybul 2003). There was also
230 ART

some resistance in SSITT (two-week break, two months of ART) (Yerly 2003). In an
African study (three-month breaks), there was even an increased risk of AIDS (DART
2008).
CD4-driven treatment interruption: A CD4-driven, individualized strategy must
be distinguished from rigid intervals. ART is interrupted in patients with good
immune status until the CD4 T-cell count drops to a pre-defined immunological cut-
off, and only then is it resumed. Many non-randomized studies with different designs
and populations concluded that this approach is safe and that a substantial amount
of medication can be saved (Maggiolo 2004, Skiest 2004, Fernandez 2005). Some
randomized trials now compare CD4-guided treatment interruption with continu-
ously continued ART (Table 11.1). The results differed considerably. While TIBET,
Staccato, or ACTG 5170 concluded that CD4-guided treatment interruptions are at
least clinically safe, two studies, Trivacan and SMART, drew different conclusions.
Table 11.1: Randomized trials. Continuous therapy versus CD4-guided treatment interruptions.
Study, source n BL-CD4 CD4 T-cells Significant outcomes in the interruption
at restart arm vs. continuous therapy
TIBET 201 >500 <350 More complaints due to ARS, more NNRTI
Ruiz 2007 >6 mo resistance, but otherwise clinically safe
(not a single AIDS case)
SMART 5,472 >350 <250 Morbidity and mortality risk are low but
El Sadr 2006 significantly increased! See Table 11.2
Trivacan 326 >350 <250 Morbidity significantly increased (doubled)
Danel 2006 due to invasive bacterial infections
Staccato 430 >350 <350 Clinically safe (slightly more AE in the ART
Ananworanich 2006 arm, more candidiasis in the pause arm),
no evidence of resistance
ACTG 5170 167 >350 <250 Overall safe, risk increased only with low
Skiest 2007 CD4 nadir
LOTTI 329 >700 <350 Clinically safe: more pneumonias,
Maggiolo 2009 but fewer cardiovascular events,
no increased risk of resistance
ARS = acute retroviral syndrome. FU = Follow-up. BL = baseline. AE = adverse events.

In particular, the results of SMART caused a sensation. In this trial (one of the largest
randomized trials in HIV medicine ever), the CD4 cut-offs for interruption were 350
and 250 CD4 T-cells/µl for resumption. The trial, independent of the pharmaceutical
industry, was highly successful worldwide – in terms of participation. In total, 318
centers from 33 countries recruited 5,472 of the planned 6,000 subjects. As expected,
the baseline data of both groups did not differ, given the enormous number of cases.
The Data Safety Monitoring Board concluded in January 2006 that treatment inter-
ruptions led to an excessively increased risk of mortality and morbidity – within only
17 months, about twice as many AIDS cases were observed in the intervention arm
compared to continuous treatment. This was true for both severe OI and malignan-
cies. Although the overall risk was low, the risk was so clearly increased that the deci-
sion was made to stop the trial prematurely. In addition, cardiovascular events were
not (as hoped) less frequent in the intervention arm but more frequent (see Table
11.2). Quality of life also did not improve under treatment interruptions – it worsened
(Burman 2008). Recent studies showed that clinical and immunological disadvantages
persist even when ART is resumed (El Sadr 2008).
5.11. Treatment interruptions 231

However, even after SMART, some questions remain unanswered. For example, the
high incidence of clinical events was striking compared to Staccato, a study that was
not small either, with 430 patients. Presuming the same AIDS/death rates observed
in SMART, there should have been at least 17 cases in Staccato – instead, there was
not a single case. Also, the suggestion that the risk of AIDS-defining malignancy was
significantly increased during treatment interruptions (Silverberg 2007) is put into
perspective because most patients who developed Kaposi’s sarcoma or lymphoma in
SMART had previously suffered from these AIDS-related conditions. Why had these
individuals been enrolled in the SMART study in the first place?

Table 11.2: Events in SMART, per 100 patient-years (El Sadr 2006).
Treatment interruptions Continuous ART Hazard Ratio**
Disease progression or death 3.7 (120) 1.3 (47) 2.6 (1.9–3.7)*
Death 1.5 (55) 0.8 (30) 1.8 (1.2–2.9)*
Cardiovascular, renal, 1.8 (65) 1.1 (39) 1.7 (1.1–2.5)*
and hepatic events
Grade IV toxicity 5.0 (173) 4.2 (148) 1.2 (1.0–1.5)
*Significant difference **95% confidence interval in parentheses

We can also only speculate about the increased cardiovascular events during the
breaks. However, some studies have shown that inflammatory or coagulatory
parameters increase (Calmy 2009, Olmo 2012). Cystatin C, a measure of renal
dysfunction, also increases (Mocroft 2009).
Nevertheless, the conclusion remains: According to SMART, there is no argument
for treatment interruptions. Even the quality of life decreases. Patients should be
encouraged to continue ART. In 2023, side effects appear less or are better managed.
However, if a break in therapy is still absolutely desired, this should be respected.
The break will usually be taken anyway. A supervised interruption is better than one
done behind the physician’s back. Under strict surveillance, the risk of clinical
complications is relatively low.

Practical tips for treatment interruptions

• It is better to avoid treatment interruptions! But the wish for a break should be
respected. A supervised treatment interruption is better than an unsupervised one.
• Treatment interruptions as a strategy (regression of resistance or for immuno-
logical considerations) are not useful.
• A positive effect on cardiovascular events or lipodystrophy has not been proven;
according to the SMART study, it is at least questionable.
• Patients should be informed about clinical (retroviral syndrome, AIDS), immuno-
logic (CD4 drop), and virologic (resistance) consequences.
• Patients need to know that infectivity increases – even after prolonged suppres-
sion, the viral load returns to the old level after 4–6 weeks.
• Caution in case of HBV co-infection (risk of hepatitis flare-up)!
• CD4 T-cells (also percentage), viral load, and blood count (platelets!) should be
checked monthly during breaks.
• The risk of resistance is higher with NNRTIs (it is better to choose more robust
regimens and discontinue NNRTIs a few days before, given their long half-life).
• Resistance testing is not helpful during treatment interruptions; it usually detects
wild-type viruses.
• Do not restart ART too late!
232 ART

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234 ART

5.12. Monitoring ART

C H R ISTIAN HOFFMAN N, C H R ISTIAN NOAH

Which parameters should be included in routine laboratory monitoring of PLWH?

What results can be expected? This section deals with viral load, CD4 T-cells, routine
checks, and plasma levels. Resistance and tropism tests are the subject of a separate
chapter (see HIV Resistance Testing). For the tests to be performed on the initial
presentation, see The New Patient.

Viral load
Viral load is the amount of HIV RNA in the blood. Alongside the CD4 T-cell count,
viral load is the most important surrogate marker of HIV infection (Hughes 1997,
Mellors 1997, Lyles 2000, Ghani 2001, Phillips 2004). It provides information on
how high the risk is for disease progression. Above all, however, it is the critical value
in determining the success of therapy. Viral load assays measure the amount of HIV
RNA (viral genetic material), which correlates directly with the number of virions.
It is expressed in HIV RNA copies/mL (or genome equivalents) and is reported as
either a natural, integer, or logarithmic number. A change of one or more logs occurs
when the viral load increases or decreases by one or more decimal powers. Thus, a
decrease from 100,000 (5.0 logs) to 100 (2.0 log) copies/mL corresponds to a decrease
of three logs. Changes of less than 0.5 logs are not considered significant. This means
that a decrease from, for example, 4.3 to 3.9 log/mL (equivalent to approximately
20,000 to 8,000 viral copies/mL) does not indicate a relevant decrease in viral load.
Many laboratories report both values, i.e., the whole number and the logarithm.
Unlike HCV or HBV, the standardized specification of the viral load in International
units/mL has not yet been established.

Assessment
The higher the viral load, the higher the risk of CD4 T-cell decrease, with subsequent
progression or occurrence of AIDS-related illnesses (Mellors 1997, Lyles 2000, Phillips
2004). A viral load above 100,000 copies/mL (sometimes above 50,000 copies/mL)
or 5.0 log is considered high. In contrast, a viral load below 10,000 copies/mL (occa-
sionally below 5,000 copies/mL) is considered low. However, the thresholds are not
absolute and only provide points of reference.
The effects of plasma viremia on immune status can vary greatly between individu-
als. There are some patients whose CD4 T-cells remain stable for relatively long
periods despite having a high viral load, while others experience a rapid drop.
However, the viral load is relatively low. Even in the so-called elite controllers where
the viral load is undetectable without ART, a slow but constant drop in the CD4 T-cells
can be observed (Stellbrink 2008). Viral load is probably lower in women than in
men. In a meta-analysis, the difference was 41% or 0.23 logs (95% CI 0.16–0.31 logs)
(Napravnik 2002). The reason for this phenomenon remains unclear, and whether
it should impact the indication for treatment is still the subject of debate.

Methods
Usually, nucleic acid amplification tests (NAT) such as the polymerase chain reac-
tion (PCR) and related techniques are used for viral load measuring. Briefly, after
extraction of the blood sample, the viral RNA is first transcribed into DNA in several
enzymatic steps and then amplified. Detection and quantification are performed
using fluorescently labeled DNA fragments. An overview of the most commonly used
commercial test systems is listed in Table 11.1. The testing systems differ in their
detection limits and the linear range within which measurement is reliable or
5.12. Monitoring ART 235

reproducible. The formerly widely used branched DNA (b-DNA) method is no longer
available. The test system market has been very dynamic in recent years. New test
systems and instrument platforms have become available, and existing ones have
been further developed and improved. In addition to the established companies,
new manufacturers such as Qiagen, Hologic, or Cepheid have also entered the market.
A real advance that significantly increases the reliability of diagnostics is the so-called
“dual-target detection”. In this process, not one section of the viral RNA is ampli-
fied – as was previously the case – but two sections simultaneously. If amplification
fails in one section due to the high variability of the HIV genome (the result would
be falsely negative), amplification in the other section takes effect.
Current developments also focus on reducing the detection limit, which is currently
20 copies/mL for the most sensitive test. However, the clinical relevance of a viral
load below 50 copies/mL is questionable due to a lack of validated data. Higher
sensitivity may lead to uncertainty or more frequent (and unnecessary) controls. In
principle, the intra-assay variance of the test systems is good, but the measurement-
related fluctuations should be considered, especially in low viremic ranges (see
above). The same applies to an increase. Changes of almost threefold are usually not
relevant! This fact should be pointed out to the patients, who are often unnecessar-
ily frightened or euphoric with such numbers.
The results of the different techniques can diverge considerably. The laboratory
should also have experience or make a sufficiently large number of measurements.
The following rule applies: use one method, one laboratory. In addition, specific
subtypes are detected differently (Alvarez 2015, Ndiaye 2015). Particularly in PLWH
from Africa and Asia with non-B subtypes, clinicians should be vigilant if a viral load
appears disproportionately low at initial determination. In such cases, it may then
be prudent to change the methods on an exceptional basis. However, newer versions
can usually sensitively measure even unusual HIV subtypes due to improved primers.
It should also be noted that all techniques have a linear range outside of which it is
impossible to give an exact figure.

Table 12.1: Comparison of the most important test systems for viral load determination.
Manufacturer Test Tech- Detection limit Linear range
nology (copies/mL) (copies/mL)
Roche Diagnostics cobas HIV-1 RT-PCR 14 20–10,000,000
Abbott Molecular RealTime HIV-1 RT-PCR 40 40–10,000,000
Hologic Aptima HIV-1 Quant Dx TMA 12 30–1,000,000
Cepheid Xpert HIV-1 Viral Load RT-PCR 18 40–10,000,000

Plasma for viral load determination should be separated from whole blood within
24 hours after collection. The samples should reach the laboratory quickly.
Alternatively, the whole blood can be centrifuged on-site, frozen, and refrigerated.
Otherwise, excessively high values may be measured (Portman 2012). Viral load deter-
mination is also vulnerable to contamination.

Influencing factors
Apart from methodological variability, a host of other factors may influence the viral
load level. These include vaccinations and intercurrent infections. During active
opportunistic infections, the viral load is often remarkably high. One study showed
an increase of 5 to 160-fold elevated viral load during active tuberculosis (Goletti
1996). The viral load can also increase significantly during syphilis, at least in
236 ART

untreated individuals, and declines again after successful syphilis therapy (Buchacz
2004, Palacios 2007). In an extensive retrospective analysis, intercurrent infections
were the cause of transient viremia in 26% of the cases (Easterbrook 2002). In these
situations, determining the viral load is of limited use.
Following vaccination against influenza (O’Brien 1995) or pneumococcus (Farber
1996), but also with other vaccines, the viral load may also be transiently elevated
(Kolber 2002). Since the peak is one to three weeks after vaccination, routine viral
load measurements should be avoided until four weeks after vaccination.
It should be noted that not every increase must indicate virological therapy failure.
Temporary, slight increases in viral load (“blips”) are usually of no significance (see
Therapy Goals). Last, one should always consider the possibility of sample mix-ups.
Implausible values should first be discussed with the laboratory and then checked if
no cause is apparent there – people make mistakes. Should there be any doubt about
an individual result, the laboratory should be asked to repeat the test or to send part
of the sample to a cooperating laboratory that uses a different test system.

Virus kinetics on ART

The introduction of viral load measurement in 1996–1997 fundamentally changed
HIV therapy. The breakthrough studies by David Ho and his group showed that HIV
infection has significant in vivo dynamics (Ho 1995, Perelson 1996). The changes in
viral load on antiretroviral therapy clearly reflect the dynamics of the viral produc-
tion and elimination process. The concentration of HIV-1 in plasma is usually reduced
by 99% as early as two weeks after ART initiation (Perelson 1997). In one large cohort,
the viral load in 84% of patients was already below 1,000 copies/mL after four weeks.
The decrease in viral load follows biphasic kinetics. In the first phase, i.e., within the
first three to six weeks, an extremely rapid drop occurs, followed by a more extended
phase during which the viral load gradually decreases further (Wu 1999). The higher
the viral load at the initiation of therapy, the longer it takes to drop below the detec-
tion level. In one study, the range was between 15 days with a baseline viral load of
1000 and 113 days with a baseline of 1 million viral copies/mL (Rizzardi 2000).
Typical viral load decay curves in individuals with and without resistance can be
found in the ART Therapy Targets.
Many studies have addressed whether durable treatment success becomes apparent
early on (Thiebaut 2000, Demeter 2001, Kitchen 2001, Lepri 2001). In one study of
124 individuals, a drop of less than 0.72 log levels after one week predicted virologic
treatment failure in more than 99% of cases (Polis 2001). Similarly, in another
prospective study, virologic response at 48 weeks could be predicted at seven days
(Haubrich 2011). However, these observations are of little practical relevance. From
our point of view, it makes no sense to measure the viral load after only one or two
weeks.
According to the German-Austrian guidelines, the viral load should be measured at
four-week intervals during the first months after the start of therapy until it has
fallen below the detection limit of 20–50 copies/mL. Thereafter, measurement every
three to four months is sufficient. Eventually, longer intervals are possible
(Chaiwarith 2010). In case of rebound or after a switch in therapy, closer monitor-
ing becomes necessary. Within the first four weeks of treatment initiation, the viral
load should be reduced by a factor of 100; after 3–4 months (after six months in the
case of a high initial viral load), it should be below the detection limit.
Viral load can also be measured in bodily fluids other than blood or plasma (for
example, cerebrospinal, vaginal, or seminal). However, such tests are usually per-
formed for scientific purposes and are not officially licensed for other reasons.
5.12. Monitoring ART 237

Practical tips for dealing with viral load (see also chapter 5.4.)
• Use only one assay whenever possible.
• Use only one experienced laboratory, if possible, no home-brewed assays.
• Watch for assay variability (up to half a log) and explain this to the patient.
• Monitor viral load every four weeks with new ART until the viral load is below
the detection level (50 copies/mL).
• Measure viral load sparingly – on successful ART, every three months is sufficient.
• Not on ART; measurement every three months is usually sufficient.
• Do not measure shortly after vaccinations or with concurrent infections.
• Implausible results should be rechecked after 2–4 weeks.
• Consider differences between subtypes (in some cases, it may be helpful to use
another method).

CD4 T-cells
CD4 T-cells are T lymphocytes that express the CD4 receptor on their surface. This
lymphocyte subpopulation is also referred to as T helper cells. Alongside viral load,
measurement of the CD4 T-cell level is the most critical parameter or surrogate marker
in HIV medicine. It allows for a reliable estimate of the individual risk of develop-
ing AIDS. Two reference values are generally accepted: above 400–500 CD4 T-cells/µl,
severe AIDS-related diseases are very rare; below 200 CD4 T-cells/µl, the risk of AIDS-
related morbidity increases significantly with increased duration of immunosup-
pression. Most AIDS-related illnesses occur below 100 CD4 T-cells/µl.
Several points should be considered when measuring CD4 T-cells (usually by flow
cytometry). Blood samples should be processed within 18 hours. Depending on the
laboratory, the lower average values are between 400 and 500 cells/µl. Samples should
always be sent to the same (experienced) laboratory. The same applies to viral load
for CD4 T-cells: the higher the level, the greater the variability. Differences of
50–100 cells/µl are not unusual. In one study, the 95% confidence intervals with an
absolute value of 500 cells/µl were between 297 and 841 cells/µl. At 200 CD4
T cells/µl, the 95% confidence interval was between 118 and 337 cells/µl (Hoover
1993).
The measurement of CD4 T-cells should be repeated in case of highly implausible
values. As long as the viral load remains below the detection limit, there is no need
to be concerned, even with larger decreases in the CD4 T-cells. In such cases, the
relative values (CD4 percentages) and the CD4/CD8 ratio (CD4 to CD8 T-cells) should
be referred to; these are usually more robust and less prone to fluctuation. As a general
point of reference, with values above 500 CD4 T-cells/µl, more than 29% fluctua-
tions are expected, with less than 200 CD4 T-cells/µl fluctuations of up to 14%.
Individual laboratories may define the normal ranges for the relative values and the
ratio differently. If there are considerable discrepancies between absolute and rela-
tive CD4 T-cells, any treatment decisions should be carefully considered – if in doubt,
it is better to recheck the values. The remaining differential blood count should also
be scrutinized carefully – is leucopenia or leukocytosis present?
Today, clinicians sometimes forget that the result of the CD4 T-cell count is still of
existential importance for many patients. To go to the doctor and discuss the test
results can involve a great deal of stress for many patients. Insensitively informing
the patient of a supposedly lousy result can lead to further negative results. A drop
from 1,200 to 900 cells/µl is usually insignificant! From the start, patients must be
238 ART

Figure 12.1: Untreated patients: drop in absolute CD4 T-cells/μl (dashed: viral load copies/mL, secon-
dary axis on the right). On the left, an untreated patient with a course over almost ten years – note
the considerable variability. On the right, a patient who experienced a massive drop from 1,000 CD4
T-cells to below 50 within only four years (during which no controls were performed). The patient deve-
loped AIDS (PCP, Kaposi’s sarcoma), which could have been prevented with regular controls and timely
ART initiation. Since the beginning of 2012, viral suppression and immune reconstitution.

informed about laboratory tests’ possible physiological and method-related

variability. In the long run, this saves time and discussions, and the patient is spared
unnecessary ups and downs. We do not consider it advisable for non-physician
personnel (without extensive HIV experience) to inform patients of results.
Once CD4 T-cells within the normal range are reached, in addition to adequate viral
suppression, measurement every six months should suffice, in our opinion. The like-
lihood of CD4 T-cells dropping again to ranges below 350/µl is low in such cases
(Phillips 2003). Individuals with HIV RNA below 200 copies/mL and CD4 counts
above 300 cells//µl had a 97.1% probability of maintaining CD4 T-cells above 200/µl
for four years. When non-HIV causes of CD4 lymphopenia were excluded, the prob-
ability rose to 99.2% (Gale 2013).
Therefore, In the US, measurement is considered optional in patients with stable
viral suppression (Whitlock 2013). Patients who sometimes insist on more frequent
monitoring of immune status can be assured that there are usually no detrimental
changes in the CD4 T-cell count as long as HIV remains suppressed.

Influencing factors
Several other factors can influence CD4 T-cell counts apart from laboratory-related
variables. These include concurrent infections, leucopenia of varying etiology, and
steroids or other immunosuppressive therapies. During opportunistic infections, but
also syphilis, CD4 T-cells are decreased (Kofoed 2006, Palacios 2007). Extreme exertion
(marathon running), surgical procedures, or pregnancy also lead to temporarily lower
levels. Even diurnal variation occurs. CD4 T-cells are low at noon and highest in the
evening around 8 p.m. (Malone 1990). On the other hand, psychological stress plays
a minor role at best, even though patients often assume otherwise.

Kinetics of CD4 T-cells

Most patients see a continuous CD4 T-cell decline if untreated. However, there are
discontinuous cases where the decline may be rapid after a long, stable period. In
an observational cohort collaboration study on 34,384 ART-naive individuals, the
mean CD4 T-cell decline was -78 (95% CI, -80 to -76) cells/µl per year. The decline
was strongly associated with a higher current viral load: for every 1 log10 copies/mL
higher, CD4 T-cells declined by an additional 37.6 cells/µl per year (COHERE 2014).
Of note, neither sex, race, nor transmission by injecting drug use was associated with
a change in the viral load or the CD4 T-cell count.
5.12. Monitoring ART 239

In contrast, the increase in CD4 T-cells under ART is often biphasic (Renaud 1999,
Le Moing 2002): after a rapid increase in the first three to four months, the CD4 T-cell
gain is subsequently lower. In a study of almost 1,000 patients, CD4 T-cells increased
by 21/µl per month during the first three months. In the following 21 months, it
was only 5.5/µl per month (Le Moing 2002). The initial rapid increase in CD4 T-cells
is possibly caused by redistribution. It is followed by new production of naïve T cells
(Pakker 1998). Initially, reduced apoptosis may also play a role (Roger 2002).
It is debated whether the immune system steadily continues its recovery even after
a long period of viral suppression or whether a plateau is reached after three to four
years, beyond which there is less improvement (Smith 2004, Viard 2004). Several
factors can influence the extent of immune reconstitution during ART. The degree
of viral suppression is crucial – the lower the viral load, the more pronounced the
effect (Le Moing 2002). Also, the absolute increase is higher if CD4 T-cell counts were
high at the start of ART (Kaufmann 2000). Naïve T cells still present at the initiation
of therapy also help determine long-term immune reconstitution (Notermans 1999).
Age is also essential (Grabar 2004). The larger the thymus and the more active the
process of thymopoiesis, the more pronounced the rise (Kolte 2002). Due to age-
related thymic degeneration, CD4 T-cells do not increase as much in older people
as in younger ones (Viard 2001). However, we have seen 20-year-old patients with
very poor recovery and 60-year-old patients with excellent, above-average increases.
The regenerative capacity of the human immune system seems to vary considerably,
and no method to date has been capable of reliably predicting this capacity.
In the past, there were antiretroviral therapies, such as ddI+tenofovir, for which

Figure 12.2: Increase in absolute (solid) and relative (dashed) CD4 T-cells in four patients on ART (arrows
mark the ART initiation). Substantial variability with 200 CD4 T-cells or more in some cases. Patients
should be advised that a single count is of little value. Bottom right: a patient who developed Kaposi’s
sarcoma with consistently high values (viral load in gray here).
240 ART

Figure 12.3: The course of viral load (dashed, right axis, logarithmic) and absolute (solid) CD4 T-cells
under long-term ART. The patient on the left had considerable adherence problems until 1999. After
the onset of two AIDS-related diseases (TBC, NHL), consistent use of ART with rapid and good immune
reconstitution plateau in the last ten years. One can ask here how much CD4 T-cells still need to be
measured. On the right, an older patient (> 60 years) with two breaks in therapy and only moderate
immune reconstitution.

immune reconstitution was less good than for others. Whether current antiretrovi-
ral agents differ has not been demonstrated. Concomitant immunosuppressive med-
ications must also be considered; they may impair immune reconstitution.
Further typical courses of CD4 T-cells can be found in chapter 5.4. Beyond CD4
T-cells, some assays test the qualitative capacity of the immune system to specific
antigens (Telenti 2002). However, these methods are unnecessary in routine
diagnostics, and their usefulness is questionable. They may one day help identify
those (few) people at risk of opportunistic infections when their CD4 T-cells are
supposedly good. In the following, two more examples of long-term treatments from
practice, here with immune status and viral load.

Practical tips for dealing with CD4 T-cells

• As with viral load, use only one (experienced) laboratory.
• The higher the values, the greater the variability (consider numerous factors) –
compare the relative (percentage) values and CD4/CD8 ratio with previous results.
• Do not worry the patient if there are decreases – if viral suppression is sufficient,
the drop is usually not HIV-related. Highly implausible measurements can be
repeated!
• If the viral load is below the detection level, three-monthly measurements are
sufficient.
• In good viral suppression and normal immune status, CD4 T-cells (not viral load)
may also be checked less frequently. The value as a surrogate marker is limited in
these patients.
• In untreated patients, they remain an essential surrogate!
• The patient should have time to discuss the CD4 count and viral load with the
physician.

Routine checks – what else should be monitored?

Besides the CD4 T-cell count and viral load, several other parameters should be mon-
itored in the HIV-positive patient. The following recommendations apply to clini-
cally asymptomatic patients with normal results on routine laboratory evaluation
5.12. Monitoring ART 241

who have been on stable treatment for several months or are not taking antiretro-
viral therapy. Of course, if treatment is started or changed or if the patient develops
complaints, more frequent monitoring is required. Depending on the problem,
additional tests may be necessary. On the other hand, the rate of new lab abnor-
malities decreases as more time elapses post-ART initiation (Taiwo 2012). This
suggests that monitoring frequency may be reduced in subgroups without early
abnormalities as time on initial ART increases.
A complete physical examination should be performed regularly, and this often leads
to the discovery of important findings such as Kaposi’s lesions or mycoses (thrush).
The lower the CD4 T-cells, the more frequently patients should be examined.
In patients with less than 200/µl, we usually perform fundoscopies every three to
six months to exclude CMV retinitis. Close cooperation with an HIV-experienced
ophthalmologist is essential. The better the CD4 T-cells, the less often fundoscopies
are necessary – in our opinion, when CD4 counts have normalized, these can be
stopped completely. In contrast, regular gynecological examinations with PAP smears
are recommended regardless of CD4 count. Many experts now also recommend rectal
examination (including proctoscopy) to detect precancerous lesions and anal cancer
early.

Table 12.2: Minimal evaluations per year in stable asymptomatic patients.

Patient on ART Not on ART,
per year per year
Blood count, LDH, GPT, Crea, Bili, lipase, γGT, Glucose 4x 2–4 x
Viral load 4x 2–4 x
CD4 T-cells 2–4 x 4x
Lipids 1–2 x 1x
Physical examination, urine status 2x 1–2 x
Gynecological examination 1x 1x
Fundoscopy for CD4 T-cells < 200/μl 1–2 x 4x

However, such guidelines or recommendations can be interpreted very differently.

In our opinion, in cases of good immune status, unless there is a specific suspicion,
routine X-rays or ultrasound examinations (exception: patients with chronic hepa-
titis – hepatocellular carcinoma is not rare in such cases), multiple serologies or lactate
measurements are not necessary. An annual ECG is only indicated in our view in
patients with a specific risk profile (see HIV and Cardiac Disease). The tuberculin test
(the Mendel-Mantoux skin test with 5 IE once a year) should only be repeated if it
is negative initially.
Finally, it is essential not to forget cancer screening. In many countries, for example,
colonoscopy is recommended for early detection of colorectal cancer for every indi-
vidual older than 50–55 years (colonoscopy should be performed every ten years).
For further information, see the WHO website, [Link]
tion/en/.

Therapeutic Drug Monitoring (TDM)

Plasma levels of many antiretroviral drugs may vary considerably for diverse reasons
(e.g., adherence, metabolism, absorption). Measurement of drug concentrations in
serum or plasma is also referred to as therapeutic drug monitoring (TDM).
242 ART

Adequate plasma levels are essential for the success of virologic treatment (Acosta
2000). In the VIRADAPT study, adequate PI levels were even more important than
knowledge of resistance mutations (Durant 2000). However, these data are from the
early years of ART.
Whether TDM with subsequent dose adjustments can improve virologic response
today has not been proven (Kredo 2009). Only a few large randomized studies have
provided data regarding this question. In one randomized trial, TDM showed no
virologic benefit in 183 patients with treatment failure who switched to a new PI
and subsequently, if levels were too low, adjusted the dose of the PI. A positive trend
in viral load was merely restricted to the subgroup with only a partial PI effect
(Albrecht 2011). Another randomized trial found no positive effect on viral sup-
pression (Best 2007). The favorable effects of TDM continue to remain questionable,
and the method is still regarded as experimental (review: Liu 2010).
On the other hand, very high levels also correlate with a higher rate of side effects.
Hepatotoxicity under nevirapine (Gonzalez 2002) or CNS problems under efavirenz
(Marzolini 2001) were associated with very high plasma levels. TDM will remain a
tool for therapy observation. Not every interaction between antiretroviral agents or
with concomitant drugs has been investigated. Measurement of plasma levels of
NNRTIs or PIs may currently be reasonable in the following situations:
• Complex drug combinations, including boosted PIs
• Patients with very high or low body weight
• Side effects
• Treatment failure (resistance?)
• Suspected absorption or adherence problems
• Severe liver or renal diseases
• ART in children, pregnancy
• Use of new drugs (unknown interactions)
Nevertheless, several problems with TDM limit its broader use. For example, TDM
makes little sense with NRTIs since these are only converted into their active metabo-
lites intracellularly. Intracellular measurement is not available in routine clinical
practice. Valid data are also still lacking for integrase inhibitors.
Measuring NNRTIs or PIs may determine levels of only one component of a failing
combination. Further problems include viral strains with different levels of resist-
ance, different inhibitory concentrations, variable protein binding, time-dependent
variability of plasma levels, methodological problems with the assays, and lack of
clearly defined limits. Many uncertainties remain in the assessment of therapeutic
drug plasma levels. Until data from randomized studies is available, proving the clin-
ical value of TDM, the measurement, and interpretation of results should be left to
specialized centers.
Before performing TDM, it is essential to consider what the question is to answer.
If the efficacy of ART is under evaluation, trough levels are essential – trough levels
should be measured just before administering the next dose. If toxicity is the issue,
peak levels 1–3 hours after intake are of interest.
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5.13. Global Access to HIV Treatment 245

5.13. Global Access to HIV Treatment

ROB CAMP

The data has changed significantly and positively since the last report:
• Some 3,550 people become infected with HIV every day, 46% of whom are women
and girls, 30% under 25.
• There are some 39 million people infected, 1.3 million newly infected in 2022,
a drop of 38% since 2010. 630,000 people died of AIDS-related causes in 2022,
a drop of 51% since 2010.
• Approximately 29.8 million people are currently receiving ART, and while that is
more than laudable, too many are not on optimal regimens – UNAIDS now rec-
ommends DLG first line. The rest (approx. 10 million) are waiting or do not know
they have HIV.
Access to drugs depends not only on financial and human resources. It depends also
on people being aware of their HIV status, knowledgeable about treatment, and
empowered to seek it. Public information and education are important elements
in widening access and therapeutic maintenance, alongside efforts to build or
strengthen health services.
Stigma has been and remains a major stumbling block in wanting, seeking, and
taking the treatment regimen correctly. The campaign for universal access to life-
saving drugs for HIV and AIDS, started originally by grassroots AIDS activists, is today
a major focus of attention of UN agencies and most all influential organizations.
The Declaration of Commitment on HIV/AIDS, unanimously endorsed by the UN
General Assembly in 2001, embraced equitable access to care and treatment as a
fundamental component of a comprehensive and effective global HIV response.
Access to treatment has helped mobilize communities in response to HIV, preserved
the health and viability of people and households vulnerable to HIV, and strength-
ened HIV prevention efforts in many parts of the world. The UN underscored this
goal in 2011, upholding their belief in TRIPS flexibility regarding public health drugs
and global trade agreements.
In the goal to reach universal access to HIV prevention, treatment, care, and support,
leadership at a national level is required to establish policies that support treatment
scale-up, and is now a very central part of being able to achieve the new funding
levels needed to eradicate HIV:
• increasing the number of people who choose to know their HIV status;
• reducing HIV stigma;
• building human capacity to sustain treatment through education and training and
better use of human resources;
• improving supply management and integrating HIV care with other health services.

Major Players
PEPFAR Update
The President’s Emergency Plan for AIDS Relief (PEPFAR) was launched in 2003 to
combat global HIV/AIDS. PEPFAR is the largest commitment by any nation to address
these three diseases in the world; to date, its funding has totaled more than $110
billion, including contributions to the Global Fund to Fight AIDS, Tuberculosis and
Malaria (Global Fund), to which the US government is the largest donor. PEPFAR is
the cornerstone of the US Global Health Initiative, which has helped countries
improve and expand access to health services. PEPFAR focuses on sustainability (see
below) and serves as a platform for expanded responses to a broad range of global
health needs. PEPFAR partnerships in more than 70 countries have directly supported
care for millions of people affected by HIV/AIDS.
246 ART

U.S. Funding for the President’s Emergency Plan for AIDS Relief (PEPFAR),
FY 2004 – FY 2024 Request (in Billions)

Figure 1: PEPFAR has also provided ARV treatment support for 20.1 million people as of 2022 (see
TOTALS in references).

The program goals are:

1. Reach global 95-95-95 targets for all ages, gender, and population groups.
2. Reduce new HIV infections dramatically through effective prevention and treat-
ment, in support of UNAIDS targets.
3. Close equity gaps for priority populations, including adolescent girls and young
women, key populations, and children.
4. Transform the PEPFAR program towards sustaining HIV impact and long-term
sustainability by strengthening the capabilities of government to lead and manage
the program, in collaboration with communities, the private sector, and local
partners.
5. Make measurable and sustainable gains in partner country public health systems
and health security strengthen public health prevention, data, and response
capabilities for HIV and other health threats.
The latest PEPFAR reports supported the prevention of mother-to-child transmission
programs, preventing millions of babies from being born with HIV. It has also pro-
vided care for over 7 million orphans and vulnerable children (OVC). PEPFAR has
also directly supported HIV counseling and testing for millions of people, including
community-based services and rapid tests.
In late 2022, PEPFAR released its new five-year strategy Fulfilling America’s Promise to
End the HIV/AIDS Pandemic by 2030, which outlines its approach to contributing to
and supporting global efforts to reach the UN Sustainable Development Goal 3 (SDG
3) target of ending the global AIDS pandemic as a public health threat by 2030, while
also strengthening public health systems. Complemented by three “enablers”
(community partnerships, innovation, and leading with data), the strategy focuses
on five strategic pillars:
• ensuring health equity for priority populations,
• achieving long-term sustainability in the HIV/AIDS response,
• leveraging public health systems to respond to health threats,
• strengthening partnerships, and
• ensuring programs are guided by science.
The strategy is intended to align with the UNAIDS Global AIDS Strategy 2021–2026,
and one of PEPFAR’s goals is to reach the 95-95-95 targets and the Global Fund
Strategy for 2023–2028 (PEPFAR 2022). PEPFAR activities include the provision of
5.13. Global Access to HIV Treatment 247

antiretroviral treatment, pre-exposure prophylaxis, voluntary male circumcision,

condoms, and other commodities related to HIV services (see Figure 1) (PEPFAR 2023,
KFF 2023). In addition, PEPFAR has launched specific initiatives in key strategic areas.
For example, PEPFAR offers DREAMS, a public-private partnership that aims to reduce
HIV infections in adolescent girls and young women by offering them education
and employment.
Recently, in 2023, PEPFAR has run into [Link] has had wide political support
all along since its inception, but some members of the US Congress may now halt
its moving forward in 2023 for indirectly supporting abortion programs. PEPFAR‘s
reauthorization discussions are underway, which, despite a push from advocates and
administration leaders for a “clean reauthorization” (one in which there are no policy
changes to the existing legislation), may encounter challenges as more divisive issues,
including abortion and other issues, arise. As PEPFAR enters its next phase, there are
several key challenges facing the program that will likely have implications for its
future, including:
• addressing the short- and long-term impacts of COVID-19 on the HIV response;
• accelerating progress toward epidemic control in the context of flat funding;
• achieving the optimal mix of services provided, populations served, and geogra-
phies targeted;
• supporting and strengthening community-led responses and sustainability;
• defining PEPFAR’s role in pandemic preparedness and broader health systems
strengthening efforts while ensuring synergies with other US global health and
development programs; and
• continuing to coordinate with other donors and entities in the HIV ecosystem,
especially the Global Fund.
As a recent Perspective article in The New England Journal states, “…(a full) reau-
thorization is critical not only to the global AIDS response but also to responses to
future pandemics and threats to global security.“

The Global Fund

The Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM) is an interna-
tional financing institution that invests the world’s money to save lives. It supports
large-scale prevention, treatment, and care programs against the three diseases.
It dedicates resources to drug procurement, human resources, program management,
training, infrastructure, monitoring, and evaluation. For 2023–2025, The Global
Fund will allocate $ 13.1 billion to 126 countries. The Gates Foundation and the EC
are the only two in the top 10 contributors, not sovereign countries. In August 2023,
through its competitive tenders, the Global Fund, together with its partners and
generic pharmaceutical manufacturers, will be able to offer tenofovir disoproxil
fumarate, lamivudine, and dolutegravir (TLD), a first-line HIV treatment for under
US$45 per person, per year for the first time. This pricing – a 25% reduction – will
allow governments in resource-limited settings to expand access to HIV services.
The Global Fund uses its Pooled Procurement Mechanism to aggregate order volumes
on behalf of participating grant implementers to negotiate prices and delivery con-
ditions with manufacturers. In 2021, the Pooled Procurement Mechanism managed
approximately US$1.5 billion in orders, serving grant implementers in 90 countries.
Health products available include antiretroviral, antimalarial, and essential medi-
cines, antimalarial medicines, essential medicines, insecticide-treated mosquito nets
for preventing malaria, and tests for monitoring disease progression.
In the near future (2024–2026), GFATM projects resource needs of $ 29.3 billion, of
which they have raised 78%.
248 ART

UNAIDS
The Joint United Nations Programme on HIV/AIDS (UNAIDS) leads and inspires the
world to achieve its shared vision of zero new HIV infections, zero discrimination,
and zero AIDS-related deaths. UNAIDS works closely with global and national
partners towards ending the AIDS epidemic by 2030.
UNAIDS provides technical support to countries, assisting them with expertise and
planning for national AIDS programs to help ‘make the money work’ for the people
on the ground. UNAIDS tracks, evaluates, and projects the financial resource require-
ments at global, regional, and country levels to generate reliable and timely
information on the epidemic and the response. Based on these evaluations, UNAIDS
produces guidelines and progress reports. .
They are making a good effort on tackling major social issues like homophobia, finan-
cial sustainability, and gender equality. “Together we will end AIDS”, whose title is
annoyingly cheerleader-ish, offers some critical information, like the fact that low-
and middle-income countries now invest significantly in their HIV/AIDS response,
while donor countries have not increased much.
Another promising approach would be to expand innovative mechanisms like indi-
rect taxation (airline tickets, mobile phone usage, exchange rate transactions) to
support global health initiatives, including HIV (see below). The larger international
community must continue to support and strengthen existing financial mechanisms,
including the Global Fund and relevant UN organizations.
In 2013, UNAIDS launched the 90/90/90 program under the banner “Treatment for
all”, of having 90% of those with HIV tested, 90% of those tested starting treatment,
and 90% of those on treatment undetectable was not hit in 2020 (81/67/?) and then
upgraded to 95/95/95 in 2021, which has been met by a number of countries. The
95/95/95 program is underway for 2030; we must understand why the 90/90/90
program was not achieved – it is at 86/76/71 today, although, by sub-group, women
have achieved 90/90/90!

The Bill and Melinda Gates Foundation

The largest private philanthropic organization is located in Seattle, US, “focusing on
improving people’s health and giving them the chance” to emerge from “hunger
and extreme poverty.” They have 1,818 employees with an endowment of
$67.3 billion. They have committed in 2022 grants to the tune of $7 billion in 141
countries. Much of these moneys are for non-AIDS-specific works, including
development (reducing poverty and hunger). In health (58% of the total spending),
they fight and prevent enteric and diarrheal diseases, malaria, pneumonia, TB, neg-
lected and infectious diseases, working on integrated health solutions, improving
the delivery of existing tools, and supporting research and development in new inter-
ventions ([Link] They also have adopted an Open Access
policy that enables the unrestricted access and reuse of all peer-reviewed published
research funded, in whole or in part, by the foundation, including any underlying
data sets.

Drugs available from whom and where

FDA’s qualification of generics
Generic drugs are important options that allow greater access to health care. They
have the same high quality, strength, purity, and stability as brand-name drugs.
Generic manufacturing, packaging, and testing sites must pass the same quality
standards as those of brand-name drugs.
For PEPFAR use, all drugs need FDA approval. As of 13 Sep 2023, the FDA had approved
5.13. Global Access to HIV Treatment 249

197 generic drugs for use in the PEPFAR program that are approved in a time as six
weeks. While quality, strength, purity, and stability are guaranteed, administration,
delivery, and correct use are up to local use.
A note: although REMS programs from the FDA or EMA would accept information
on side effects from the Global South (which has up to 6 times the amount of people
on drugs), they probably contribute little to the overall numbers and therefore safety
of these drugs. Mentioned below is VigiAccess from WHO.
FDA inspectors, along with EMA, will continue to perform manufacturer-related
inspections to maintain quality and safety. Enforcement actions from suspension to
licensing closures can be considered.

WHO
HIV, viral hepatitis, and STIs
WHO works on diagnostics (testing) and prevention as well as vaccines and treat-
ments for these diseases. WHO’s 2022–2030 global health sector strategy on HIV
aims to reduce HIV infections from 1.5 million in 2020 to 335,000 by 2030 and
deaths from 680,000 in 2020 to under 240,000 in 2030.

Pre-qualification and quality assurance of antiretroviral products –

a fundamental human right
WHO’s Prequalification Programme conducts evaluation and inspection activities
and builds national capacity for manufacturing and monitoring high-quality
medicines. They have now opened a pharmacovigilance website called VigiAccess
where adverse events due to medicinal products collected by 110 national drug
authorities are housed.
Invitations to manufacturers to submit an expression of interest (EOI) for product
evaluation are issued not only for HIV/AIDS-related products but also for anti-malar-
ial medicines, anti-tuberculosis medicines, influenza-specific antiviral medicines,
and reproductive health products. The WHO List of Prequalified Medicinal Products
is made by both originator and generics companies. Prequalification may be better
described as pre-, ongoing, and post-qualification, as they do inspections at all these
time points. On the list are many drugs for OIs (acyclovir, ceftriaxone, ciprofloxacin,
amongst others). WHO also approves medicines quality control laboratories (QCLs):
57 QCLs are currently prequalified worldwide.

A bridge
Improved treatment in line with scientific evidence and international
standards of care
Médecins Sans Frontières (MSF, Doctors without Borders) are on the front lines in
clinics and health centers in more than 70 countries; their advocacy is not ivory
tower type. On the ground, they work on innovative approaches to tackling the
major health challenges posed by HIV, TB, malaria, flu, neglected tropical diseases,
and emerging pathogens like COVID. They recommend:
• Supporting initiation of ART for all people with HIV. No CD4 count level.
• Dolutegravir over efavirenz, for tolerance as well as prevention.
• Providing access to viral load testing to support adherence and detect treatment
failure earlier, thereby preventing resistance and needless switching to expensive
sub-optimal second-line treatment.
• TPP must not impose restrictive IP protections.
• The World Trade Organization must extend its TRIPS waiver for least developed
countries.
• TB and HCV testing and treatment programs must be better integrated with HIV.
250 ART

How to ensure that the prices of drugs and diagnostics remain reasonable?
The international community has supported policies that will enable funds to stretch
as far as possible to meet needs and contain costs in the short- and long-term by,
amongst other measures, ensuring a continuing supply of drugs.
In accordance with the Doha Declaration on TRIPS and Public Health, governments
can authorize governmental use or compulsory licenses to ensure the generic
production of patented products (as in Brazil and Thailand).
Companies and governments can support the Medicines Patent Pool for antiretro-
viral medicines. This mechanism brings together patents held by different owners
and makes them available to others for generic production and further development
for people in LMIC.

Prices of first-line regimens in low-income countries

The decline in drug prices since 2008 can be attributed to the scaling up of treat-
ment programs, increased competition between a growing number of products
prequalified by WHO, new pricing policies by pharmaceutical companies, and
successful negotiations between foundations like the William J. Clinton Foundation
(CHAI) and major generic manufacturers.

Second-line regimens
Second-line regimens are more expensive than first-line regimens in low- and middle-
income countries. Also, prices paid for second-line regimens can vary significantly
between countries. For people who need to move to a new regimen, whether the
current one is failing or not (after 10+ years on efavirenz), the new recommended
first line of dolutegravir at less than 45$ is a good option. NNRTIs fail at a rate almost
three times higher than the rate of PIs. MSF previously estimated that regimen failure
is “largely under-diagnosed” due to limited lab facilities for viral load testing. This
can only lead to resistance and harder-to-construct post-first-line regimens.

Future Funding
According to KFF, “While donor government contributions to multilateral organi-
zations reached the highest level in 2020, rising by almost US$500 million compared
to the 2019 level (US$2.1 billion), the increase was due to a small set of donors. Only
4 of 14 donors (Germany, Japan, the UK, and the US) increased their multilateral
contributions, while eight (Australia, Canada, Denmark, France, the Netherlands,
Norway, Sweden, and the European Commission) decreased, and two remained flat
(Ireland and Italy). These trends were the same after adjusting for inflation.”
New strategies have to be developed – (RED) is a fund-raising mechanism tied to the
Global Fund that coordinates profits from business sales and has contributed $750 M
to GFATM since 2006. Other proposals have languished – small taxes on currency
transactions (Oxfam’s Robin Hood tax died in 2017), an airline ticket tax (imple-
mented in France and other countries in 2012, but no Unitaid reports since 2013…),
a Global Health charge on alcohol and tobacco consumption (Hill 2012), etc.
It is perhaps more important than ever that we all contribute, whether economically
or advocacy-based, to be able to help end AIDS via prevention as well as by opti-
mally treating everyone.
Europe
The European Union impacts access to medicines for developing countries through
its policies, legislation, and bilateral and regional trade agreements. The EU adopts
measures to improve access to existing medical tools as well as stimulate the research
in resource-limited countries. According to its data, the EC was the 5th largest
contributor to WHO in 2020/2021.
5.13. Global Access to HIV Treatment 251

Eastern Europe & Central Asia: while the disease is becoming better controlled in
most parts of the world, that does not seem to be the case in Eastern Europe.
Convincing political leadership in these countries (esp. Russia) is important since so
few resources are allocated to fighting HIV. The number of people on treatment in
EECA in 2022 is 51%, the lowest in the world, matched only by MENA. There is NO
DATA on kids on treatment (under 15). How is this even possible?
How do we get there? From rhetoric to reality
Successes in controlling the epidemic can be attributed to a comprehensive response
and commitment from all sectors of society, according to on-the-ground experts in
sub-Saharan Africa. Buy-in from the highest political offices is important in creating
policies that place HIV on all national agendas.
At the International AIDS Conference 2023, there was an effort to demonstrate the
importance of including patients and their broader communities in the delivery of
services. We saw, among other things, pediatric/youth testing, mobile phone
messaging, accelerating PrEP services, understanding reasons for disengagement,
social media support, client-initiated appointments (!), local analyses of what works
(incl. community partnerships), national strategic actions for actions to Mpox pre-
vention, long-lasting, and country-led HIV response through strengthening health
systems, and informed consent processes.
The last 10 million
This is not one epidemic with a straightforward answer. There may be some basic
ingredients for “getting there”:
• Cascading implementation structures from national to grassroots level
• Ensuring increasing national government budget allocation to HIV responses while
donors support ongoing gaps (i.e., country ownership)
• Mobilizing all sectors of society to play their part in HIV
• Integrating principles of good governance from the outset to ensure accountability
at all levels.
The number of people needing access to ART is clear – 10 million, give or take. While
amazing strides have happened in the last eight years, do we need to do something
radically different to get the last ten million on therapy and break the never-ending
chain? The most current and useful prevention and treatment strategies are key to
stopping transmission to the most at-risk populations. The pipeline of novel long-
acting and rapid-onset PrEP agents appears robust, including implants, vaginal rings,
and topical inserts (Liu 2023). It is not the 30 million people on treatment who are
transmitting. How to convince these last 10 million? Is there another message, meme,
or TikTok video to convince them? Or another 10 million personalized TikTok videos?
Is CAB-LA the solution? It has been under-implemented, as has the existing PrEP
(TDF/FTC) for years. Is it the lack of political will? Can we bring the condom back?
Raphael Landovitz at CROI 2023, presented on PrEP at the workshop for new inves-
tigators, and reminded us of other methods and possibilities – douches, inserts,
patches, long-acting pills and every-6-months injections. He also reminded us of the
cultural and structural barriers that are parts of this problem, and working with the
end user, what do people want to use? We cannot sit idly by and hope for the best
– we must continue to push that boulder up the hill for as long as it takes so every-
one who needs it has access to prevention including PrEP, treatment, and care as
early and for as long as necessary.
252 ART

Literature
Collaborative Group on HIV Drug Resistance and UK CHIC Study Group. Long-term probability of detecting drug-
resistant HIV in treatment-naïve patients initiating combination antiretroviral therapy. CID 2010, 50: 1275-85.
Gostin L. The unconscionable health gap: a global plan for justice. Lancet 2010, 375:1504-5.
Harrigan RP. HIV drug resistance over the long haul. Clin Infect Dis 2010, 50: 1286-87.
Hill A, Sawyer W. Funding universal access to antiretroviral treatment through a ‘Global Health Charge’ on alcohol
and tobacco consumption: feasibility in the 20 countries with the largest HIV epidemics, International AIDS
Conference, MOAE0306, July 22-27, 2012, Washington DC, USA.
Karim SSA, Barre-Sinoussi F, et al. Threatening the Global AIDS Response – Obstacles to PEPFAR’s Reauthorization.
NEJM DOI: 10.1056/NEJMp2310330 | September 9, 2023.
Landowitz RA. Advances in Biomedical Prevention of HIV. Scott Hammer Workshop for New Investigators and
Trainees. 19 Feb 2023. [Link]
Liu A, Buchbinder S. CROI 2023: Epidemiologic Trends and Prevention for HIV and Other Sexually Transmitted
Infections, Top Antivir Med. 2023 May; 31(3): 468–492, Published online 2023 May 1. PMC10266866, PMID:
37315512.
Ooms G, Hammonds R. Correcting globalization in health: transnational entitlements versus the ethical imper-
ative of reducing aid-dependency. Public Health Ethics 2008; 1: 154-170.
Ravishankar N, Gubbins P, Cooley RJ, et al. Financing of global health: tracking development assistance for health
from 1990 to 2007. Lancet 2009; 373: 2113-2124.
Resch S et al., Funding AIDS programs in the era of shared responsibility: an analysis of domestic spending in 12
low-income and middle-income countries, The Lancet Global Health, 3:e52 – e61.
[Link] accessed 11 Sep 2023.
[Link] accessed 12 Sep 2023.
[Link] accessed 13 Sep 2023.
[Link]
Untangling the web of antiretroviral price reductions, 17th edition, Medecins Sans Frontieres, July 2014,
[Link]
Global HIV/AIDS response. Progress Report 2014. WHO, UNICEF, UNAIDS.
Mellors S, Dybul M, Binagwaho A, et al. How Do We Get There? Country Planning for Maximum Impact,
International AIDS Conference, MOSS01, July 22-27, 2012, Washington DC, USA.

Links (because global access is a moving target, the following are updated regularly and web-based)
[Link]
[Link]
[Link]
M_closes
UNAIDS, How AIDS changed everything
DREAMS, [Link]
[Link] accessed 14 Sep 2023.
TOTALS represent funding specified by Congress in annual appropriations bills and/or identified by agencies for
the Department of State, USAID, CDC, and DoD. In addition, international HIV research activities are supported
by the NIH Office of AIDS Research (OAR) through its annual appropriated budget, but these amounts are not
considered part of PEPFAR. See KFF’s “Breaking Down the U.S. Global Health Budget by Program Area” for addi-
tional information.
[Link]
[Link]
PEPFAR, Fulfilling America’s Promise to End the HIV/AIDS Pandemic by 2030, December 2022.
[Link]
Figure 1 categorization is based on interventions laid out in the PEPFAR Financial Classification Reference Guide,
used for program budgeting. PEPFAR Financial Classifications Reference Guide, March 2023.
KFF. Funding for Key HIV Commodities in PEPFAR Countries; July 2021.
[Link] accessed 13 Sep 2023.
[Link]
[Link]
reductions-can-be-achieved
[Link]
253

6. Viral Resistance and Tropism

E V A W O L F A N D PAT R I C K B R A U N

Consideration of individual resistance data in treatment decisions contributes to

virologic treatment success, both in pretreated and treatment-naïve patients. In
recent years, the prevalence of transmitted resistance-associated mutations (RAMs)
in newly diagnosed PLWH (people living with HIV) has been relatively constant at
10%. The following chapter explains the basics of resistance and tropism testing, the
mechanisms of resistance development, and the resistance profiles of available anti-
retroviral substances.

Blips, low-level viremia, and resistance development

Even on successful ART, viral loads above 50 copies/mL may be sporadically observed,
called viral blips. Blips may reflect biological or statistical variations or maybe assay-
related. Low-level viremia (LLV) is more problematic, i.e., low viral loads between
50 and 200 or 500 HIV RNA copies/mL that occur repeatedly or continuously. LLV
is not rare. According to one review, approximately 4–8% of previously successfully
treated patients develop LLV of 50–200 copies/mL (Ryscavage 2014). Repeated
episodes of detectable viremia suggest ongoing viral replication rather than viral
release from latent reservoirs secondary to immune activation. PLWH with LLV are
at increased risk for developing drug resistance. Between 50 and 100 HIV RNA
copies/mL, the risk of selecting resistant viral variants is about 1–3% and increases
as viral load increases (Prosperi 2011, Braun 2016). The resistance barrier of the sub-
stances used also plays a role.

Resistance development
The rapid emergence of resistant viral variants is caused by the high turnover of HIV
– approximately 10 billion new viral particles are generated daily in untreated patients
– and by the high error rate in reverse transcription of the viral genome (Perelson
2002). Other mechanisms also contribute to the development of resistance or muta-
tions: insufficient (viral infectivity factor-mediated) inhibition of the cellular HIV
restriction factor APOBEC3G can lead to increased G-to-A hypermutation during
reverse transcription, i.e., the transcription of RNA into DNA (Yang 2020). A corre-
spondingly hypermutated proviral DNA usually shows a typical amino acid exchange
at specific resistance positions, such as the mutations E138K, M184I, or M230I in
the RT gene. Hypermutations of TGG to TGA/TAA/TAG can also result in stop codons
leading to replication-incompetent viruses (Fourati 2012).
Although new viral variants (“quasispecies”) are constantly emerging even without
ART, resistance-relevant mutations are selected only in the presence of antiretrovi-
ral drugs. Resistant variants have a selection advantage over wild-type viruses due to
reduced susceptibility and are a major cause of virologic failure. From a virological
point of view, an early start of therapy, as recommended in treatment guidelines
(EACS 2022), reduces the development of viral variants and the emergence of resist-
ance under ART.

Methods of resistance testing

In the early 2000s, genotypic and phenotypic resistance testing have been established
for treatment monitoring (Wilson 2003). With genotypic assays, mutations in the
HIV genome (in comparison to a consensus reference sequence) are detected, and
the resulting resistance profile is interpreted using algorithms based on literature and
254 ART

expertise. Phenotypic resistance assays directly quantify the susceptibility of the viral
population to specific drugs. Analogous to resistance analysis, the tropism testing of
the viral population, which can change during HIV infection (from CCRR5 to
CXCR4), can be performed genotypically or phenotypically. The methods and
specific features of tropism testing are described separately in this chapter.
In genotypic resistance determination, a distinction is made between conventional
genotyping (population sequencing), which generally only detects virus strains com-
prising at least 10 to 20% of the total population, and ultrasensitive sequencing
methods detecting minor virus variants down to ≤1–2% (next generation sequenc-
ing, resp. NGS, or ultradeep sequencing). The clinical relevance of minor viral vari-
ants is discussed below.
Phenotypic resistance analyses are mainly needed during the development of new
drugs. They are used to quantify viral resistance and interpret emerging new muta-
tions in clinical trials. In routine care, they are rarely performed due to the high tech-
nical and time expenditure and associated costs. Moreover, phenotyping is often not
possible at low viremia levels.

Phenotyping basics
Replication capacity is measured in cell culture under the selection pressure of anti-
retroviral substances in increasing concentrations and compared with the wild-type
virus. The drug concentration necessary to inhibit replication of a virus isolate by
50% in cell culture is called IC50 (50% inhibitory concentration). Sensitivity is
expressed as the quotient of measured IC50 and IC50 of a wild-type reference virus.
For interpretation, this quotient – also called resistance factor (RF) or “fold-change”
– is compared with a so-called cut-off value. The cut-off ideally indicates the value
up to which the resistance factor of the HIV isolate can be increased compared to
the wild-type virus without a clinically relevant loss of efficacy.
Table 1: Characteristics of the phenotypic resistance analysis.
Advantages Disadvantages
• Direct, quantifiable measure of the virus’ • Clinical cut-off not available for all drugs
drug susceptibility • Time consuming (several weeks)
• Valid and quantifiable result even in case • Expensive (not covered by health insurance in
of unknown resistance mutations Germany)
(e.g., with new substances) • HIV-1 subtype identification not possible
• Valid result also for complex mutation • Intermediate steps on the way to resistance
patterns with, e.g., resensitization effects formation are not detected
• Resistant populations may remain undetected
due to co-existing, rapidly replicating wild-type
viruses

Technical, biological, and clinical cut-offs (thresholds)

A distinction is made between three thresholds regarding drug susceptibility. The
technical cut-off is a measure of the methodological range of variation. The biological
cut-off measures the natural range of variation in the sensitivity of wild-type virus
isolates. The clinical cut-off indicates the IC50 increase (fold-change) up to which
unrestricted efficacy can still be expected. It is, therefore, the clinically relevant
threshold. Complete resistance to a drug often does not arise abruptly but evolves
gradually by acquiring several amino acid exchanges (especially in the case of drugs
Viral Resistance and Tropism 255

with a high resistance barrier). Ideally, an upper and a lower clinical cut-off are spec-
ified. Above the lower cut-off, the virological response is already reduced; above the
upper cut-off, no virological response is expected. These cut-offs are often missing
for newer drugs due to a lack of data; in these cases, the biological cut-off is used.
Mutations that do not themselves confer drug resistance but provide evidence of
transmitted, evolving, or reverting resistance escape detection by phenotyping.

Basics of genotyping
The HIV genome generally consists of two RNA (ribonucleic acid) strands that contain
the genetic information of the virus. Within the nucleotide sequences of the HIV
genome, three nucleotides (codons) code for a particular amino acid in the protein
sequence. Resistance mutations are described with a number indicating the position
of the respective codon within the genome and two letters. The letter before the
number indicates the amino acid for which this codon encodes in the wild-type virus
at this position. The letter following the number designates the amino acid encoded by
the mutated codon. A change in the nucleotide sequence of a codon, i.e., a muta-
tion, can result in the incorporation of a different amino acid, impairing protein
function and leading to loss of efficacy. For example, the mutation M184V at codon
184 of the RT gene results in an exchange of the amino acid methionine (M) for
valine (V) in the RT enzyme, rendering the virus resistant to RT inhibition by 3TC
or FTC.
So-called “silent mutations” do not result in an amino acid exchange. Only muta-
tions causing an amino acid exchange that also leads to a change in the protein
structure are clinically relevant because this can contribute to the formation of resist-
ance. Beyond that, “lethal” mutations lead to defective protein structures and thereby
interrupt the replication cycle of the virus.

Table 2: Characteristics of genotypic resistance analysis (population sequencing).

Advantages Disadvantages
• Quick to perform (within days) • Indirect measurement of resistance
• Widely used (no S3 lab required) • Detection of variants comprising ≥10–20%
• Detection of all changes in the nucleotide (minor variants with NGS up to 0.1%
sequence and deviations from the reference depending on viral load)
wild-type virus • Complex mutation patterns are often difficult
• Detection of any mutation with either to interpret
evidence of resistance, emerging resistance • Unknown mutations are not considered in
or reverting resistance the interpretation
• HIV-1 subtyping possible • Interpretation systems must be continuously
• In general, reimbursement by health insurance updated

Resistance-associated mutations are detected by direct sequencing of the amplified

HIV genome. Therapeutically relevant is the sequencing of the HIV pol region, which
encodes the viral enzymes protease, reverse transcriptase, and integrase, and the env
region, which encodes the envelope proteins gp41 and gp120. Other gene regions,
such as RNAse H and the gag region, are also relevant to resistance but are not
described further here; they are usually analyzed as part of research projects rather
than routinely. The basis for interpretation is the correlation between genotype,
phenotype, and virologic response. Data are derived from in vitro selection studies,
clinical studies and observations, and numerous duplicate measurements in which
mutations were examined for phenotypic resistance.
256 ART

Viral versus proviral resistance testing

The gold standard of resistance analysis in the presence of detectable viral load in
plasma is the use of HIV RNA of free virions obtained from EDTA plasma. Resistance
testing is also possible from proviral DNA. Although many proviral DNA sequences
are not replication competent (Bruner 2019), proviral DNA testing can be helpful
when viral load is low or undetectable, particularly before a change, e.g., toxicity
reasons or treatment simplification (Allavena 2018). Historically or currently, resist-
ant viral populations can be integrated into cells as provirus. They can be detectable
for years, depending on the duration of treatment failure, the level of viral load, and
other factors such as clonal expansion of cells (Boukli 2015, De La Cruz 2019, Wagner
2012). The agreement between cumulative historical resistance data from viral RNA
in plasma and resistance data from proviral DNA sequencing under suppressive
therapy is approximately 50–60% (Däumer 2019). In a sub-analysis of the LOWER
II study, sequences from the proviral DNA of 96 individuals with multiclass resist-
ance under continuous suppressive therapy were compared intra-individually at
three-year intervals. In only 27% of individuals, a 100% concordance between the
two proviral measurements was observed (Hoffmann 2022). Accordingly, in analy-
ses from proviral DNA, the negative predictive value is of limited value. Treatment
decisions or de-escalation strategies should not be based on proviral resistance data
alone.

Rules-based interpretation systems

Genotypic interpretation systems are often based on rules derived by experts from
literature data and revised once or twice a year. In Germany, the algorithm of HIV-
Grade e.V. is primarily used to interpret resistance mutations (Obermeier 2012).
In addition to an algorithm, the Stanford HIV Drug Resistance Database (HIVdb)
provides a comprehensive database explaining resistance-associated mutations
(Table 3). Commercial resistance test vendors have often implemented interpreta-
tion rules into their systems.

Data-based interpretation systems and virtual phenotype

In contrast to knowledge-based rule systems created by teams of experts, data-based
interpretation systems such as geno2pheno (Beerenwinkel 2003) use machine-learn-
ing techniques such as support vector machines or regression models. The goal is to
predict the phenotype or virological response from genetic information. In this
“virtual phenotype”, a phenotype is assigned to the individual genotypic resistance
pattern without phenotyping. It is based on databases of paired genotyping and
phenotyping.
Table 3: Overview of the most important resistance interpretation systems.
System Interpretation Free Internet:
(version) Access http://
HIV-GRADE (01/2023), Rule-based yes [Link]/grade_new/
Germany
HIV-GRADE HIV-2 Rule-based yes [Link]/HIV2EU/deployed/
(08/2015) [Link]?program=hivalg
HIVdb Version 9.4.1 Rule-based yes [Link]/hivdb/
(06.2023), USA by-mutations/
ANRS HIV-1 (V32), HIV-2 Rule-based yes [Link]
(V33) (10/2022), France
Viral Resistance and Tropism 257

Table 3: Continuation
System Interpretation Free Internet:
(version) Access http://
MGRM GeneSure® MG Rule- and no [Link]
(Monogram Bioscience) data-based
geno2pheno Version 3.4 Data-based yes [Link]
Germany (Virt. Phenotype)

Methods of Tropism Determination

To enter the target cell, HIV needs a so-called co-receptor in addition to the CD4
receptor, namely one of the two chemokine receptors, CCR5 or CXCR4. Depending
on the use of these receptors (“tropism”), viruses are divided into CCR5- or R5-tropic
and CXCR4- or X4-tropic viruses. Viral strains that can use both receptors are called
“dual-tropic”. Since these cannot be distinguished in the tropism test from a mixture
of R5- and X4-tropic viruses, this group is called “dual/mixed” (D/M)-tropic.
Tropism determination is only useful before a planned use of a CCR5 antagonist: to
ensure its effectiveness, the presence of X4-tropic viruses must be excluded. This does
not only apply to viremic patients: Even in cases of prolonged viral suppression and
historically proven CCR5 tropism, a tropism test from proviral DNA may be useful
before switching (even though in these cases, a change in tropism from CCR5 to
CXCR4 is rather unlikely). X4-tropic viruses tend to be detected in proviral DNA
rather than RNA (Verhofstede 2009). In contrast, if X4-tropism has been historically
detected, repeating the test is of little help. Since maraviroc is the only CCR5 antag-
onist used relatively rarely, tropism testing plays a minor role. However, other com-
pounds are in clinical development, such as the humanized antibody Leronlimab
(Jacobson 2010, Dhody 2018), discussed below. As resistance, tropism can be deter-
mined genotypically or phenotypically (Braun 2007, Vandekerckhove 2011).

Phenotypic Tropism Test

Monogram’s Trofile® is the best-known phenotypic tropism test due to its use in
maraviroc pivotal studies. Trofile® ES (Trofile® with enhanced sensitivity) detects
minor virus populations with a sensitivity of 1%. The test is also offered for proviral
DNA at low viral loads <1,000 HIV RNA copies/mL. Another commercial phenotypic
test is Phenoscript® ENV (EuroFins/ VIRalliance). The agreement is 85% (Skrabal
2007). Phenotypic assays are mainly used in the context of studies.

Genotypic tropism test

As with genotypic resistance analysis, advantages include the broad availability and
the rapid results. For subtype B viruses, genotypic and phenotypic analyses were
comparably well associated with virologic response to maraviroc-based therapy
(Poveda 2012, McGovern 2012). Larger discordances were described for non-B sub-
types, particularly for CRF01_AE, CRF02_AG, A, and F. Geno2Pheno and WebPSSM
appear to somewhat overestimate CXCR4 use (Delgado 2011, Mulinge 2013).
Only the V3 region of the gp120 gene, which is crucial for binding, is sequenced.
This determines the viral tropism, even if other gp120 regions, such as V1/V2 and
C4, or substitutions in gp41 are involved. The preferred method at viral loads up to
200 copies/mL is sequencing the V3 loop from proviral DNA. Based on the nucleotide
sequence, tropism is predicted using bioinformatics tools (Garrido 2008).
The coreceptor tool from geno2pheno ([Link] is
widely used, shows good agreement with Trofile® ES, and is primarily used in Europe
258 ART

(Prosperi 2010). In contrast to phenotypic determination, genotypic prediction does

not distinguish between X4-tropic, dual- or mixed-tropic. The result determined with
geno2pheno is the so-called false positive rate (FPR), which indicates the probabil-
ity that an X4 prediction is false. An FPR of 0.1% means X4 tropism and an FPR of
90% means R5 tropism, since the X4 result would be false with a 90% probability.
An FPR of less than 5% is assumed to predict an X4-tropic virus strain and an FPR
of 15% or more is assumed to predict R5-tropic virus (DAIG 2014). These thresholds
also apply to testing from proviral DNA. Maraviroc can be considered at an FPR of
5% to 15%, although residual uncertainty remains. In a study of samples from 101
individuals, a (costly) triple measurement at an FPR of 10% showed a discordance
in tropism prediction in 10 samples. It resulted in reclassification from R5 to X4 in
4 cases (Symons 2012). Of note, single testing is sufficient at an FPR of 20%
(Vandekerckhove 2011).

Mechanisms of action and resistance

NRTIs (nucleos(t)ide reverse transcriptase inhibitors) are administered as prodrugs
and are only effective as triphosphates. Two phosphorylation steps are required for
nucleotide analogs and three for nucleoside analogs. Phosphorylated NRTIs are incor-
porated competitively with natural deoxynucleotide triphosphates (dNTPs) into
proviral DNA. They inhibit further synthesis by the enzyme reverse transcriptase
(RT), thus blocking the extension of proviral DNA and leading to chain termination.
There are two essential biochemical resistance mechanisms (De Mendoza 2002):
Steric inhibition is mediated by mutations that enable the RT enzyme to recognize
structural differences between NRTIs and dNTPs. The incorporation of NRTIs is pre-
vented in favor of dNTPs, for example, in the case of mutations M184V, Q151M,
L74V, and K65R (Naeger 2001, Clavel 2004).
During ATP (adenosine triphosphate)- or pyrophosphate-mediated phosphorylysis,
NRTIs that have already been incorporated are excised from the growing DNA chain.
This is the case with the thymidine analog mutations M41L, D67N, K70R, L210W,
T215Y, and K219Q (Meyer 2000).
The mutation K65R counteracts the excision of already incorporated NRTIs. The
balance of both mechanisms – reduced incorporation by K65R on the one hand and
inhibition of excision by K65R on the other – leads to reduced sensitivity for most
NRTIs but increased sensitivity for AZT (White 2005) and thus resensitization.
NNRTIs (non-nucleos(t)ide reverse transcriptase inhibitors) also inhibit RT but chem-
ically differ from NRTIs. As small molecules, they bind to a hydrophobic pocket close
to the catalytic center of RT. Mutations at the NNRTI binding site of the RT reduce
the affinity of the inhibitors and result in loss of efficacy. While one mutation is
often sufficient for complete resistance in first-generation NNRTIs, mutation pat-
terns are more complex for the less rigid second-generation NNRTIs (Vingerhoets
2010, Molina 2008).
NRTTIs, so-called nucleoside reverse transcriptase translocation inhibitors, block RT
by multiple mechanisms. Islatravir is the first NRTTI in clinical development. RT
uses EFdA triphosphate (TP) and other NRTI-TPs for DNA synthesis in the same way
as dNTP substrates. However, traditional NRTIs lack a 3’-OH group required for DNA
polymerization. Therefore, they act as immediate (obligate) chain terminators after
being incorporated into the nascent DNA chain. On the one hand, since EFdA has
a 3’-OH group, chain termination can still occur. On the other hand, interactions of
the NRTTI at the dNTP binding site itself – even after its incorporation – inhibit
translocation, which in turn inhibits the binding and incorporation of subsequent
Viral Resistance and Tropism 259

nucleotides. Another mechanism of inhibition involves efficient misincorporation

of EFdA by the RT that cannot be removed by excision, thus preventing DNA elon-
gation (Markowitz 2018).
PIs prevent the cleavage of the viral gag-pol precursor protein by the enzyme HIV
protease. This produces virus particles that are not infectious. PI resistance usually
develops slowly, as several mutations usually have to accumulate. A distinction is
made between major and minor mutations.
Major mutations are associated with phenotypic resistance. They include mutations
that are the first to appear under the selection pressure of a drug, as well as muta-
tions (sometimes also called “primary” mutations) that are located in the active site
of the HIV protease and reduce the binding ability of the PI to this enzyme. In some
cases, these mutations also lead to a loss of protease activity.
Minor mutations (“secondary” mutations) are located outside the active site and
usually occur after major mutations. Sometimes, they can compensate for the loss
of viral fitness caused by major mutations (Nijhuis 1999, Wensing 2022).
Integrase strand transfer inhibitors (INSTIs) prevent the integration of the viral
genome, the proviral DNA (after transcription), into the host cell genome. First, the
viral integrase binds to the 3’ends of the proviral DNA in the cytoplasm and forms
the pre-integration complex. Then, the integrase cuts out a dinucleotide at both ends
of the viral DNA, creating new 3’-hydroxyl groups (3’-processing). Strand transfer
occurs in the nucleus, where the integrase joins the end segments of viral DNA to
cellular DNA. Integrase inhibitors prevent strand transfer (therefore also abbreviated
INSTI). They bind to the integrase and migrate into the nucleus along with the pre-
integration complex. In their presence, the integrase molecules can no longer catalyze
the integration of proviral DNA into cellular DNA. Resistance arises by selecting
certain (key) mutations in the integrase gene. Both strand transfer and 3’ processing
can be affected. Different resistance profiles have been described. Accumulation of
additional mutations leads to a further decrease in susceptibility (Jegede 2008).
Entry inhibitors prevent the virus from entering the target cell. HIV binds to the
CD4 receptor with its surface protein gp120 (docking or attachment), which leads
to conformational changes in gp120 and allows the binding of the V3 loop of gp120
with the chemokine receptors of the target cell, CCR5 or CXCR4, respectively.
Interactions of the two heptad repeat regions, HR1 and HR2, and the viral trans-
membrane protein, gp41, result in a conformational change in gp41 that allows the
insertion of gp41 into the cell membrane. The attachment inhibitor (AI) fostem-
savir blocks the HIV envelope protein gp120 after metabolization to temsavir, pre-
venting binding to CD4. Because AIs intervene before binding to the coreceptor,
they can be used regardless of tropism (Li 2013). Ibalizumab, a monoclonal anti-
body, prevents cell entry by binding to the second extracellular domain of the CD4
receptor (Lewis 2017). CCR5 antagonists bind to the CCR5 coreceptor, preventing
interaction with gp120 and, thus, entry into the cell. Tropism determination is
required before use. Resistance mutations can increase the affinity of gp120 to the
CCR5 molecule already bound to the CCR5 antagonist (Woollard 2015). The human-
ized IgG4 monoclonal antibody Leronlimab (PRO-140) also binds to the CCR5 recep-
tor. Unlike maraviroc, which inactivates CCR5 by distorting the molecule’s struc-
ture, Leronlimab binds only at the HIV-binding site but does not interfere with the
function of CCR5 itself. It is also effective with maraviroc-resistant strains but not
with X4-tropic viruses (Jacobsen 2010).
Fusion inhibitors prevent the fusion of the viral membrane with the cell membrane.
T-20 (enfuvirtide) is a synthetic peptide corresponding to the C-terminal HR2 domain
of gp41 and interacts (competitively with HR2) with HR1. This prevents the neces-
260 ART

sary conformational change in gp41 and fusion. Even a single amino acid exchange
in HR1 can significantly limit efficacy.
Capsid inhibitors: The mode of action of capsid inhibitors (including inhibiting
various steps in the replication cycle) is only partially understood. As the first-in-
class capsid inhibitor, lenacapavir binds specifically at the interface between capsid
protein subunits, inhibiting the replication cycle in both the early and late phases
by interfering with capsid assembly or disassembly (Zhuang 2021).
A crucial step takes place in the early phase of replication. Only a few years ago, it
was thought that the capsid destabilizes and dissolves in the cytoplasm. Now it is
known that the capsid is transported in an intact state along the microtubule network
and then imported into the nucleus through the cell pores, followed by complete
uncoating of the capsid, i.e., the capsid envelope breaks into pieces in the nucleus
(Zila 2021). On the one hand, it is postulated that capsid inhibitors hinder the binding
of nuclear import proteins to the capsid, and thus, the transport into the nucleus is
disrupted (Link 2020). On the other hand, the binding of capsid inhibitors is assumed
to impair capsid flexibility. Depending on the capsid inhibitor used, this may lead
to early rupture or stabilization of the capsid, achieved by lenacapavir via binding
to the capsid and converting the nuclear envelope into a rigid but stabilizing form.
However, this disrupts the integrity of the capsid. It is still unclear how and when
the nuclear envelope breakdown occurs after binding the capsid inhibitor in the
nucleus (Li 2021, Selyutina 2022, Li 2023). At a later stage, virus assembly and release
are disrupted. The production of capsid subunits is reduced by interfering with the
gag/gag-pol process (Link 2020).
In the final step of maturation, the binding of capsid inhibitors results in malformed
capsids in the form of tube-like sheaths without integrated pentameric capsomeres
(Kvaratskhelia 2023). However, the antiviral efficacy is 10 times higher in the early
phase than in the late phase of the replication cycle (EC50: 25 pM versus 439 pM)
(Link 2020).

Transmission of resistant strains of HIV

The prevalence of resistance mutations present before therapy varies considerably
from region to region. The standardization of a list of so-called Surveillance Drug
Resistance Mutations (SDRMs) by an international research group made cross-
regional or cross-national comparisons of the transmission of resistance possible
(Bennett 2009). Since then, the prevalence and incidence of individual mutations
have changed. New mutations in the relevant gene regions have emerged, which
should be considered in any list revision (Rhee 2021).
As shown in Figure 1, a trend for an increase in NNRTI resistance and a decrease in
PI resistance can be observed. There is a significant decrease in NRTI resistance.
Transmitted mutations primarily affected NNRTI susceptibility (6.5–6.9%, based on
nevirapine, efavirenz, rilpivirine, and etravirine), whereas <3% of guideline-recom-
mended NRTIs and PIs were affected. For darunavir, the only PI recommended for
first-line therapy, it was only 0.4% (Machnowska 2019). Two- and three-class resist-
ance remained rare, at 1.3% and 0.2%, respectively. Among chronically infected indi-
viduals from the RESINA cohort, the proportion of primary resistance was relatively
stable at approximately 10.7% between 2001 and 2016 (Böhm 2017). NRTIs, PIs, and
NNRTIs were affected in 5.9%, 3.2%, and 3.7%, respectively.
Outside Europe and the US, the prevalence of primary resistance (mainly NRTI and
NNRTI resistance) is much higher. In many countries in Africa, South America, and
Southeast Asia, the proportion of primary NNRTI-resistant viruses (efavirenz or
nevirapine) has been well over 10%. The WHO considers primary resistance a major
Viral Resistance and Tropism 261

Figure 1: Prevalence of transmitted drug resistance (TDR) in the German seroconverter study over time
(Machnowska 2019).

Table 4: Prevalence of primary resistance (%) in untreated patients (selection).

Reference Country/region Period Collective N Prevalence
(study) (%)
Machnowska Germany 1996–2017 Seroconverter 2,715 17.2
2019
Hauser 2017 Germany 2013–2016 ART-naïve 881 10.8
Boehm 2017 Germany 2001–2016 Chronic infected 3,739 10.7
(RESINA)
Visseaux 2019 France 2014–2016 New diagnosed 1,121 10.8
Olsen 2018 Europe/USA/ 1996–2012 ART-naïve 4,717 11.0
Canada (CASCADE)
Margot 2017 Mainly USA and 2000–2013 ART-naïve 6,704 Initial: 5.2
Europe Last: 11.4
(9 clinical studies)

worldwide problem (HIV drug resistance report 2021). The pattern of primary
resistance may change over time due to the introduction of 2nd generation INSTIs
(dolutegravir) as part of first-line ART in treatment guidelines (WHO 2021). Primary
INSTI resistance has rarely been observed in Africa, especially resistance against
second-generation INSTIs such as dolutegravir or bictegravir. Exceptions are HIV
subtype F viruses (e.g., in Uruguay) with the frequently occurring resistance-relevant
polymorphism G163R/K. In the Swiss cohort, only viruses with secondary INSTI
mutations were detected in 1,319 treatment-naive individuals between 2008 and
2014, with one exception (T66I). The proportion of secondary mutations was 2.9%,
with 80% occurring in non-B infections (Scherrer 2016b). Only secondary mutations
were detected in a German cohort, in which 839 isolates from 2013–2016 were exam-
ined (prevalence 2.1%). The L74M and T97A mutations detected were also observed
as polymorphisms before the introduction of INSTI (Hauser 2017). The major INSTI
262 ART

mutation R263K was described in a French cohort of therapy-naïve individuals (Chaix

2016). In the MeditRes HIV cohort (France, Spain, Portugal, Greece, and Italy), the
RT and integrase gene regions of 2,705 therapy-naive individuals between 2018 and
2021 were analyzed. The prevalence of INSTI mutations was 0.23%: T66A, T66I,
E92Q, E138K, E138T, and R263K were each detected once (as a single mutation).
In contrast, the RT mutation M184V/I was detected with a prevalence of 1.03%
(De Salazar 2022).
Despite the currently low transmission of INSTI-resistant viruses, analyzing the inte-
grase gene in therapy-naïve patients may be useful. This applies to patients with
resistance mutations in the RT or protease gene, particularly if the index person has
experienced a treatment failure on an INSTI-containing regimen.
Ultrasensitive methods such as ultradeep sequencing usually detect more resistance
mutations than conventional sequencing methods (Buckton 2011). Clinical rele-
vance, especially when detecting minor resistant viruses in the range of 1–5%, should
always be evaluated in the context of treatment history (Porter 2015).
Transmitted primary resistance can remain detectable for a long time (Pao 2004). In
the German seroconverter cohort, according to population-based Sanger sequenc-
ing, primary NRTI mutations persisted in the plasma of ART-naive PLWH on average
1.0–6.4 years. NNRTI mutations persisted for 1.5–8.0 years and PI mutations for
1.0–4.3 years. Mutations such as M184V that cause loss of fitness are usually the first
to be replaced by wild-type viruses – others, such as K103N, remain detectable for a
longer time in the plasma (Machnowska 2019).

Clinical relevance and guidelines for resistance testing

The clinical relevance of genotypic resistance testing before treatment change was
demonstrated about 20 years ago in prospective studies such as Havana (Tural 2002).
This is also true for phenotypic resistance testing (Cohen 2002). For ethical reasons,
no more studies were designed in subsequent years to investigate the utility of
resistance analysis. Resistance analysis before ART initiation is part of routine
diagnostics.
A retrospective analysis of 10,056 patients who started ART after 1997 showed that
taking resistance into account is essential for sustained treatment success. Patients
who were not treated in accordance with resistance had a 3.1-fold higher risk of treat-
ment failure in the first year. The difference between patients with and without
primary resistance disappeared if all drugs used were fully active (Wittkop 2011).
Data from the Swiss cohort confirm that the relative proportion of individuals with
resistance mutations continues to decrease with new therapies that consider resist-
ance data. Whereas in 2003, resistant viruses were detected in one in three ART-expe-
rienced individuals, this was the case in only one in four in 2013. Monotherapy or
dual therapy mainly was started in the 1990s (Scherrer 2016a).

Resistance testing: When and for whom?

Resistance testing and tropism testing (when a CCR5 antagonist is used) are an
integral part of the European and German guidelines, both in untreated and treated
patients (see Table 5). Resistance testing should be performed if there is a viral load of
>200 HIV-1 RNA copies/mL under ART. With lower viral loads, it may be considered.

The relevance of minor variants

The clinical value of detected minorities is unclear. A meta-analysis (10 studies,
n=985) showed significantly poorer virologic response rates to NNRTI-containing
first-line therapy in the presence of minor resistant viral variants, particularly those
Viral Resistance and Tropism 263

Table 5: German-Austrian Guidelines on HIV Resistance Testing (DAIG 2020).

Recommendation for resistance testing Comments
Previously untreated persons
Primary/recent infection Recommended
Chronic infection, Recommended If not done before
before ART initiation

Treated persons
In case of first therapy Generally recommended (additional Clarification of the causes
failure tropism testing if necessary) of the therapy failure!
Treatment failure Generally recommended before Clarification of the causes
with extensive ART ART switch (additional tropism testing of the therapy failure!
pretreatment may be required, phenotypic testing
may be necessary).
During or after treatment Possibly useful but not mandatory Detection of reversion
interruption to wild-type

with NNRTI resistance (Li 2011). However, NGS data should be interpreted with
caution even for NNRTIs, a class with a lower resistance barrier: In retained baseline
samples from the STaR trial (rilpivirine versus efavirenz in treatment-naïve individ-
uals, each plus TDF+FTC), minor variants were not predictive of treatment failure
(Porter 2015). Another research group investigated whether minor resistant viral
variants also exist more frequently in other gene regions in NNRTI-resistant than in
wild-type viruses; this was not the case (Clutter 2017). Detection of minor variants
is only reproducible above a frequency of 2% (Lee 2020). At low viral load levels of
less than 500 to 1,000 HIV RNA copies/mL, NGS loses its sensitivity advantage
concerning the detection of minor virus populations.

Risk of resistance with pre-exposure prophylaxis (PrEP)?

Before and during PrEP (see chapter Prevention), HIV antibody/antigen tests of the
4th generation must be performed regularly. If HIV infection remains undetected
while on PrEP (with TDF/FTC), development of resistance is otherwise likely. The
overall rate of new infection in PrEP trials was 0.18%, based on all exposed study
participants (Grant 2015, Spinner 2016). In addition, there is also the risk of trans-
mitting resistant viruses. As of early 2017, three cases of confirmed HIV infection on
PrEP with TDF/FTC have been described outside of trials. In two, infection with a
multidrug-resistant virus occurred, and in the third case, a wild-type virus was trans-
mitted despite adequate TDF levels. The cause is unclear. Despite the increasing use
of PrEP with TDF/FTC, resistance development remains a minor problem in clinical
practice (Gibas 2019). In PrEP trials with the long-acting INSTI cabotegravir (see also
chapter ART), the incidence of HIV infection was more frequently associated with
the development of resistance mutations despite higher prevention efficacy com-
pared with daily TDF/FTC (Landovitz 2021).

Interpretation of genotypic resistance profiles

The resistance profiles cited below are only indicative. One of the resistance
interpretation systems mentioned in Table 3, such as HIV-GRADE ([Link]-
[Link]/grade_new/), should be used for treatment decisions.
264 ART

NRTIs
3TC/FTC resistance: inhibition of replication capacity
FTC and 3TC have an almost identical resistance profile – treatment failure is asso-
ciated with the M184V mutation (Borroto-Esoda 2007). This reduces viral replica-
tion capacity by 40–60% (Deval 2004). Under 3TC monotherapy, viral load was still
0.5 log levels below baseline after 52 weeks despite the early appearance of M184V
(Eron 1995). Compared with treatment interruptions, 3TC monotherapy delays
virologic and immunologic deterioration (Castagna 2006). The M184I mutation is
often detected first, which may then be replaced by M184V (Schuurmann 1995) or
persist, depending on concomitant medication (see rilpivirine). In the retrospective
Italian ARCA cohort, the therapeutic success of dual therapies with 3TC was not
affected by the detection of M184V and was better than monotherapy. This implies
that 3TC or probably FTC administration is reasonable despite complete resistance
(Gagliardini 2017).

Relevance of historical and newly selected mutations

Thymidine analog mutations (“TAMs”) include the M41L, D67N, K70R, L210W,
T215Y/F, and K219Q/E mutation. TAMs are selected under AZT and d4T (Larder
1989) and cause gradual cross-resistance to ABC and TDF (Harrigan 2000). Detection
of primary resistant viruses with certain TAMs does not appear to affect first-line
therapy with TDF (Geretti 2016). For ABC and TDF, TAMs are only “re-selected” but
do not emerge.
Under failing ABC-containing therapy, the mutations L74V/I and, less frequently,
the mutation K65R usually occur. Y115F is a specific resistance-associated ABC muta-
tion, but it also affects the efficacy of TDF.
Under TDF, the K65R mutation is primarily selected. It causes intermediate resist-
ance to TDF, ABC, 3TC, and FTC (Miller 2004). In HIV-1 subtype C infection, K65R
is three to four times more likely to be detected under failing TDF-containing therapy
than in other subtypes (White 2016). K65R increases sensitivity to AZT or causes
resensitization to AZT in the case of (few) TAMs (White 2005). Conversely, TAMs
reduce the selection of K65R under regimens with TDF and ABC (Parikh 2007).
Like M184V, K65R (unlike TAMs or L74V/I) reduces viral fitness. Replication capac-
ity decreases to 29% in the simultaneous presence of K65R and M184V (Deval 2004).
Less frequently than K65R, the mutations K70E or K70G have been observed under
failing therapy with tenofovir, especially in combinations with ABC and 3TC
(Delaugerre 2008).
The mutations M184V and L74V, as well as the NNRTI-specific mutations L100I and
Y181C, may exert an antagonistic effect on developing resistance to NRTIs. M184V
causes an IC50 reduction of approximately 50% for AZT. L74V/I results in IC50 reduc-
tion of approximately 70% for AZT and TDF (Underwood 2005). In contrast, M184V,
together with multiple TAMs, can enhance resistance to ABC (Harrigan 2000).
So-called multi-drug resistance (MDR) to all nucleoside analogs is present upon
detection of mutation T69S and an insertion of two or more amino acids (SS, SG, or
SA) between positions 69 and 70. The MDR mutation Q151M causes intermediate
resistance to AZT and ABC, resulting in only a minor loss of TDF, 3TC, and FTC activ-
ity. In combination with mutations at positions 75, 77, and 116, high-level resist-
ance to AZT and ABC and intermediate resistance to TDF arise (Masquelier 2001,
Miller 2004). New emergence of these mutations is rarely observed today, yet these
mutations are found virally and/or provirally in long-term treated individuals with
a history of treatment failure.
Viral Resistance and Tropism 265

Like TDF, TAF is a tenofovir pro-drug. In vitro data suggest that TAF can overcome
NRTI-resistant viral variants with the K65R mutation or up to three TAMs. This effect
may be due to the intracellularly approximately 5-fold higher levels of the active
substance (Margot 2013). However, this effect has not yet been confirmed in vivo.
In two large studies in treatment-naïve patients, the resistance rate under TAF versus
TDF (both plus FTC+elvitegravir/c) was similar, at 1.2% versus 0.9% (Callebaut 2016).
Quantitative sensitivity measurements in large cohorts showed that in NRTI-pre-
treated patients, hypersusceptibility to the first-generation NRTIs is present in up to
29%: the inhibitory concentration is lowered by a factor of 0.3–0.6. In particular,
mutations at positions 215, 208, and 118 play a role (Shulman 2004). However, these
results have not led to new therapeutic strategies.

NNRTIs
First-generation NNRTIs (efavirenz, nevirapine)
Numerous mutations have been described for first-generation NNRTIs. These muta-
tions can occur alone or in combination. Even a single mutation can result in high-
level resistance to nevirapine (NVP) or efavirenz (EFV). For nevirapine, these are
the mutations K101P, K103N/S, V106A/M, Y181C/I/V, Y188C/L, and G190A/E/Q/S.
For efavirenz, these are L100I, K101P, K103N, V106M, Y188C/L, and G190A/E/Q/S
(Melikian 2014). In contrast to V106A, V106M occurs more frequently in subtype C
than B viruses (Grossmann 2004). First-generation NNRTIs should be discontinued
if any of these mutations are detected, to prevent the selection of further mutations
that may affect the efficacy of second-generation NNRTIs such as etravirine or
doravirine.

Second-generation NNRTIs
Compared to first-generation NNRTIs, etravirine (ETR) has a higher resistance
barrier, likely due to flexible binding to the reverse transcriptase. Etravirine is active
against viruses with single NNRTI mutations, such as K103N or G190A. It remains
the only NNRTI that shows efficacy in the presence of Y188L, which indicates
doravirine resistance (Vingerhoets 2010).
In the DUET studies, a total of 17 mutations were found to be relevant. Y181I/V
received the highest resistance score of 3, followed by L100I, K101P, Y181C, and
M230L with 2.5. E138A, V106I, G190S, and V179F were assigned a score of 1.5, and
the remaining mutations of 1. A total score of 0–2 points was associated with a viro-
logic response rate of 74% (best response), 2.5–3.5 points with 52% (intermediate),
and ≥4 points with 38% (reduced response) (Vingerhoets 2010). If the mutations
L100I, K101P, and Y181C/I/V are detected alone, the efficacy of etravirine is already
impaired (Haddad 2010).
Rilpivirine (RPV) is unaffected or barely affected in efficacy by certain NNRTI muta-
tions such as K103N, V106A, or G190A. In vitro, the following mutations were selected:
V90I, L100I, K101E, V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E,
H221Y, F227C, and M230I/L (Azijn 2009). In a study of treatment-naïve individuals
without known NNRTI mutations, most were confirmed in vitro (Molina 2008). There
is high cross-resistance between rilpivirine and etravirine (Melikian 2014).
In the phase 3 ECHO and THRIVE trials, virologic failure was more common in
treatment-naïve individuals on rilpivirine than on efavirenz (10.5% vs. 5.7%),
particularly with high viremia above 100,000 copies/mL (17% vs. 7%). Resistance
mutations were detected more frequently in treatment failure than with efavirenz
(63 vs. 54%). The most common mutations with rilpivirine were E138K (45%), K101E
(13%), H221Y (10%), V189I (8%), Y181C (8%), and V90I (8%) (Rimsky 2012).
266 ART

In the STaR study, NNRTI and/or NRTI resistance developed in 4.3% within one year
on rilpivirine+TDF+FTC, compared with 0.8% on efavirenz+TDF+FTC. The most
common mutations with rilpivirine were Y181C/I, followed by E138K/Q and V90I
(Porter 2014). NRTI mutations in treatment failure were also observed more
frequently with rilpivirine than with efavirenz (68% versus 32%). Under rilpivirine,
this was primarily M184I, and under efavirenz, M184V (Eron 2010, Rimsky 2012).
Resistance testing should also be performed before use due to the naturally occur-
ring E138A polymorphism. E138A occurs in up to 5–7% depending on HIV subtype
and decreases RPV susceptibility by approximately a factor of 2 – comparable to other
mutations at position 138, the effect of which is slightly increased by the M184I
mutation (Xu 2013, Hauser 2018).
In the ATLAS and FLAIR studies on long-acting RPV and cabotegravir, the following
NNRTI mutations were primarily detected in treatment failure: E138A/K/G, K101E,
and M230L (Orkin 2020, Overton 2022). Proviral resistance testing of retained base-
line samples showed that NNRTI mutations were often already detectable at therapy
initiation (Overton 2020). In a pooled analysis of 48-week data from ATLAS, FLAIR,
and ATLAS-2M, HIV-1 subtype A1/A6 and RPV-associated resistance mutations in the
provirus were associated with virologic failure (Cutrell 2021, see cabotegravir). This
underscores the high relevance of considering treatment history with all resistance
data before switching therapy. In case of an incomplete treatment history, a provi-
ral resistance test can be helpful, but its limitations should be considered (see provi-
ral resistance testing).
Doravirine (DOR) has a different resistance profile than previous NNRTIs. It remains
active in the presence of singular NNRTI mutations such as K103N, E138K, Y181C,
and G190A. However, some combinations of these mutations can lead to resistance.
For example, the combination of K103N, Y181C, and V179F led to a resistance factor
of 22 (Saladini 2019). In vitro, resistance development emerges via codon changes at
position 106. An exchange of valine for alanine (V106A) was observed in HIV-1
subtype B, followed by other mutations such as F227L or L234I. In subtype A and
C, both the V106A and V106M pathways were selected. Other mutations, such as
V108I, F227C/I/L, and L234I, were detected with a time lag. The greatest efficacy
loss was seen with Y188L (Feng 2015+2016).
In the Phase 3 DRIVE-FORWARD and -AHEAD studies, the following resistance muta-
tions were detected in 12 individuals (1.6%) by week 144: V75I, A98G, V106I/A/M
V108I, Y188L, H221Y, P225H, F227C, Y318F. The mutations occurred in 10 cases in
combination with V106I/A/M. The following NRTI mutations were detected in 8
individuals: M184V (n=5), M184I (n=1), K65R (n=2), and M41L (n=1). Treatment
failure occurred mainly within the first two years (Martin 2020, Molina 2020+2021a,
Orkin 2021).

Protease inhibitors (PIs)

PIs have a high resistance barrier. In most cases, only several resistance mutations
result in a complete loss of efficacy. The spectrum of mutations is very broad. As
with other antiviral agents, continuation of a failing PI regimen selects additional
mutations that may result in moderate to high cross-resistance. Under classical first-
line therapy with boosted PI and 2 NRTIs, PI mutations are extremely rare, even in
the case of virologic failure. Mutations are more likely to affect NRTIs. Primary resist-
ance to boosted PIs has also been rarely detected (Eron 2006, Molina 2008). Currently,
only darunavir is included in the guidelines for first-line therapy (DAIG 2020).
Viral Resistance and Tropism 267

First-generation PIs
Lopinavir/r (LPV/r; boosted with ritonavir): Under failure, mutations at positions
46, 54, and 82 are primarily selected, but also I50V or V32I in combination with
I47A/V/I (Kempf 2001, Mo 2005). The L76V mutation, which is selected by lopinavir,
fosamprenavir, and darunavir, can lead to resensitization to atazanavir, saquinavir,
or tipranavir (Müller 2004). Viruses with this mutation can be successfully controlled
by the combination of lopinavir (to preserve L76V) and saquinavir (resensitized PI)
despite additional PI mutations (Wiesmann 2011).
Atazanavir/r/c (ATV/r, c; boosted with ritonavir or cobicistat) has a partially unique
resistance profile. In ART-naive patients, unboosted atazanavir mainly selected for
I50L (Colonno 2004). This mutation increases sensitivity to other first-generation
PIs (Weinheimer 2005). With PI pretreatment, I50L emerged in one-third of cases.
The resistance barrier of boosted atazanavir is significantly higher (Gianotti 2005).
Among other mutations, particularly I84V leads to an efficacy loss (Colonno 2004).
In the CASTLE study in therapy-naïve patients, only two cases of PI-resistant virus
were detected, namely M46M/I+N88N/S and V32I+M46I+L90M (Lataillade 2008).

Second-generation PIs
Darunavir/r/c (DRV/r,c; boosted with ritonavir or cobicistat) has a high resistance
barrier and good activity against a broad spectrum of PI-resistant viruses. In vitro
resistance develops more slowly than against lopinavir (De Meyer 2005). The presence
of at least 3/11 resistance-associated mutations (DRV-RAMs) at 10 positions was
associated with a decreased response rate: V11I, V32I, L33F, I47V, I50V, I54L/M, T74P,
L76V, I84V, and L89V (Wensing 2017). Sensitivity is affected to varying degrees: I50V
is in the first place, followed by I54M, L76V, and I84V. This is followed by V32I and
I47V.
Emerging mutations upon treatment failure were V32I, L33F, I47V, I54L, and L89V.
Approximately 50% of these isolates remained sensitive to tipranavir. Detection of
the V82A mutation was positively correlated with treatment response, based on the
POWER/DUET studies, as was E35D (Descamps 2009). A study of approximately
55,000 sequences of PI-naive and 10,500 sequences of PI-experienced individuals
showed a slight increase in accessory DRV-RAMs such as L10F, T74P, and L89V after
2009 (Rhee 2021).
Switch studies, including DRV/r monotherapy studies, have confirmed that boosted
darunavir has a very high resistance barrier. During an observation period of 144
weeks, resistance mutations were detected in only one patient on darunavir
monotherapy in MONET, which did not result in phenotypic resistance (Arribas
2012). The results of the MONET study were confirmed in the PROTEA study. During
a 96-week observation period, there was no treatment failure with the development
of resistance. However, the virologic response was worse, particularly with low CD4
T-cell counts (Girard 2017). Monotherapies are generally not recommended so far.
In the African NADIA trial, patients who had failed first-line NNRTI therapy were
randomized to two NRTIs plus either darunavir/r or dolutegravir. During darunavir,
unlike dolutegravir, there was not a single failure with emerging resistance after two
years (Paton 2022). These data suggest that boosted darunavir has the highest resist-
ance barrier of all approved HIV drugs.
Tipranavir (TPV) is effective against numerous viruses with multiple PI resistances
but is hardly used anymore. In vitro, L33F and I84V were the first mutations to appear,
but they were associated with only a 2-fold decrease in sensitivity (Doyon 2005). A
“weighted” score based on the RESIST data (Scherer 2007) included mutations of an
unweighted score (Baxter 2006) plus five mutations (24I, 30N, 50L/V, 54L, 76V)
268 ART

conferring increased susceptibility. Positive and negative weighting points were

assigned to the mutations, the sum of which results in a weighted tipranavir score.
Of note, the major mutations I47V, I54A/M/V, Q58E, T74P, V82L/T, N83D signifi-
cantly contribute to resistance.

Integrase inhibitors (INSTIs)

Given the increasing use of INSTI-containing regimens, virologic treatment failure
among INSTIs is also becoming more frequent. Nevertheless, transmission of INSTI-
resistant viruses remains rare (see above). Sequence analysis of viruses from therapy-
naïve individuals showed that the integrase gene is highly polymorphic, but the
resistance-relevant positions 143, 148, and 155 are conserved (Rhee 2008).
Raltegravir (RAL): In the STARTMRK study of treatment-naïve patients, the
following integrase mutations were detected after 156 weeks in 4/23 with evaluable
resistance testing in virologic failure: Q148H+G140S, Q148R+G140S,
Y143Y/H+L74L/M+E92Q+T97A, and Y143R (Rockstroh 2013). Three key mutations
or resistance pathways have been described in pretreated patients with treatment
failure on a raltegravir-containing regimen: N155H, Q148K/R/H, and Y143R/C. Other
mutations observed along with N155H were T97A, L74M, E92A/Q, T97A, V151I,
G163K/R, S230R.
In combination with Q148K/R/H, the following mutations were detected: L74M,
E138A/K, G140A/S, and G163R, with mutations prevailing at position 140 (Anstett
2017). The mutations Q148K/R/H and E92Q do not co-occur on the same viral
genome. The occurrence of additional mutations to the key mutations N155H or
Q148K/R/H causes an increase in resistance and, depending on the mutation pattern,
increases the previously reduced viral fitness. This is particularly true for the Q148H
pathway (Hatano 2010). Viruses with N155H plus other secondary mutations are
often replaced by a more resistant and more fit viral population harboring the muta-
tions Q148H+G140S. Therefore, raltegravir should be discontinued once a first key
resistance-associated mutation is detected to avoid compromising the efficacy of
second-generation INSTIs.
The Y143 resistance pathway is specific, with this position interacting directly with
the oxadiazole ring of raltegravir. The most common substitutions at this position
are Y143C and Y143R (Huang 2013). Selection of other mutations, such as L74M,
T97A, E138A, G163R, or S230R, cause an increase in resistance, which may include
substitutions such as Y143K and S (Anstett 2017). More resistant viruses may replace
virus populations with N155H with mutations at position 143 (da Silva 2010). In
viruses with the relatively common HIV-1 subtype CRF02_AG, the G118R mutation
causes raltegravir resistance with a resistance factor of 25 (Malet 2011).
In the presence of (other) resistance mutations, care should be taken not to use
raltegravir as functional monotherapy: In SWITCHMRK, in which virologically
successful lopinavir/r-based ART was either continued or lopinavir/r was replaced
with raltegravir, virologic failure occurred more frequently with raltegravir, likely
due to archived resistance mutations that compromised the efficacy of the NRTI
backbone (Eron 2010). Accordingly, the resistance barrier of raltegravir is lower than
that of a boosted PI or 2nd generation INSTI.
Elvitegravir (EVG): Under failing first-line therapy with elvitegravir/c+TDF+FTC,
the NRTI mutations M184V or M184I occur first, followed by INSTI resistance muta-
tions. In two phase III studies, the following resistance mutations were detected alone
or in combination within the three-year observation period: T66I, T97A, E92Q,
N155H, and Q148R (White 2015). Other mutations such as E138A/K, G140A/C/S/Q
Viral Resistance and Tropism 269

Q148H/K, G163R were observed in cell culture as well as in ART-naïve patients

(Anstett 2017). Given marked cross-resistance between elvitegravir and raltegravir
(White 2015), mutual replacement of these drugs is not recommended in the setting
of treatment failure. Although Y143R is most likely to emerge under raltegravir
(Métifiot 2011), it causes cross-resistance to elvitegravir, particularly with secondary
mutations (Huang 2013). There are sometimes different resistance patterns in viro-
logic failure under raltegravir and elvitegravir. In a phase 3 study, T66I/A (12%) and
E92Q (8%) were the most common under elvitegravir (Molina 2012). T66I pheno-
typically causes resistance to elvitegravir but not to raltegravir. When combined with
E92Q, resistance increases for both; the resistance factor was 18 for raltegravir and
190 for elvitegravir (Van Wesenbeck 2011, Margot 2012). A pilot study evaluated the
switch from successful treatment to TAF/FTC/elvitegravir/c in case of historical
evidence of the M184V/I mutation. Despite initial positive data over 24 weeks (Perez-
Valero 2018), long-term data in a larger collective are lacking. Detection of T97A
alone has no negative impact (Kulkami 2017).
Dolutegravir (DTG) has a higher resistance barrier than raltegravir and elvitegravir.
Resistance mutations emerge in cell culture only after several months, particularly
R263K. In isolates of subtype CRF02_AG, the R263K or G118R mutation was selected.
The latter mutation was also detectable in a subtype C isolate (Canducci 2011,
Quashie 2012). The G118R mutation, which was also detected on raltegravir in
subtype CRF02_AG, causes a threefold reduction in dolutegravir susceptibility. When
reporting resistance factors, it should be noted that the clinical threshold for dolute-
gravir has not been conclusively determined. Monogram gives 4 as the lower clinical
cut-off. Although R263K causes only weak resistance (resistance factor 1.5–2.1), it is
considered specific and may even define its own resistance pathway (Mesplede 2013,
Underwood 2013b).
Analyses of in vitro mutagenesis showed no influence of single primary and second-
ary INSTI mutations on the susceptibility of dolutegravir. Susceptibility is only
affected by combinations of mutations. The highest resistance factors were obtained
with Q148 combinations, depending on the substituted amino acid at the Q148
position. The combination E138K plus Q148K causes high-level resistance with a
resistance factor of 19±8, which was only 2 to 5 for other dual Q148 combinations.
Although the N155H mutation alone does not affect susceptibility, the resistance
factor increases to 2.5±1.2 compared with wild-type virus when E92Q is concomi-
tantly present (Kobayashi 2011).
In ART-naive patients treated with two NRTIs and dolutegravir in each of the phase
3 studies SPRING-2, SINGLE, and FLAMINGO, not a single resistance mutation was
detected (Molina 2014, Raffi 2013), neither against INSTIs nor against the NRTIs
used. In contrast, in a direct comparison between dolutegravir and raltegravir
(SPRING-2), INSTI resistance and NRTI resistance were observed in single cases on
raltegravir-based ART (Raffi 2013). These data demonstrate the high resistance barrier
of dolutegravir-based regimens. However, various monotherapy studies showed that
the resistance barrier of the single substance is not as high as postulated according
to in vitro data. In these studies, early treatment failure occurred in 11/122 individ-
uals. There was no consistent resistance pathway. Subsequent mutations were
detected in 9/11 individuals with virologic failure: 118R and 148H (twice each),
92Q/155H, 97A/155H, 155H/148R, 148K, and 148R once each (Blanco 2017). In the
Domono trial, treatment failure occurred in 8/77 cases after switching to dolute-
gravir. Different mutations were detected in three cases of drug resistance: 155H,
263K, and 230R (Wijting 2017).
In the phase 3 GEMINI (Cahn 2019) trials, in which treatment-naïve patients received
either dolutegravir/3TC or dolutegravir plus TDF/FTC, there was only one treatment
270 ART

failure with development of resistance under dolutegravir/3TC by week 144.

Compliance was questionable in this patient. The mutation M184V was detected
first (week 132), followed by R263R/K (week 144) (Cahn 2020).
More timely than ever is the question of whether dolutegravir/3TC efficacy is com-
promised when M184V is detected. Because a historical or currently documented
M184V/I mutation was an exclusion criterion in the phase 2/3 studies, archived
samples were re-analyzed to detect proviral M184V/I mutations with NGS. In the
ART-PRO study, the presence of M184V did not affect treatment response or blip
rates in 21 individuals (Rial-Crestelo 2021). In the phase 3 SALSA and TANGO trials,
retrospective proviral detection of M184V – albeit low in number – also had no
impact (Ndashimye 2021, Underwood 2022). The prospective SOLAR 3D study has
provided more data regarding the impact of a historical M184V/I mutation. In this
study, 100 individuals on suppressive therapy with a history of treatment failure
(50 with historical M184V/I and 50 without) were switched to dolutegravir/3TC. No
treatment failure was documented in either group until week 48 (Blick 2021).
However, these data do not imply that dolutegravir/3TC can be recommended in
successfully long-term treated patients with proviral or historically proven M184V/I.
Its use remains off-label and is, at best, an option to be discussed in exceptional
situations. In the case of viremia, i.e., when replicative virus with M184V is present,
dolutegravir/3TC should never be given alone from a virologic perspective.
In INSTI-naïve patients of the SAILING study with a history of prior treatment failure,
the mutation R263K was detected in two patients with virologic failure in the first
year (once in HIV subtype B and once in subtype C). The DTG resistance factor was
1.9 (Cahn 2013). Some research groups evaluate R263K as a “dead-end” mutation
because it severely impairs viral fitness. However, this loss of fitness can be reversed
by the E157Q mutation – with a concomitant increase in the resistance level (Anstett
2016). Other in vitro experiments showed that in viruses with R263K, the develop-
ment of NRTI and NNRTI resistance mutations is delayed compared to wild-type
viruses (Oliveira 2014). In SAILING, other resistant viruses were identified between
weeks 48 and 96, including those with the mutations R263K and N155H (Underwood
2015).
The VIKING and SAILING studies demonstrated that dolutegravir with resistance-
adapted concomitant medication can be a good option for multidrug-resistant
viruses. However, the response rate is lower in the case of one or two other INSTI
mutations in the presence of a Q148 mutation. The following mutations newly
emerged at the time of virologic failure in the VIKING-3 trial (week 48): L74L/M/I,
E92Q, T97A, E138K/A, G140S, Y143H, S147G, Q148H/K/R, N155H, and E157E/Q
(Castagna 2014).
Simplified, the resistance level of viruses with Q148 and other dolutegravir RAMs
can be classified as follows: Q148+G140+E138+L74 > Q148+G140+E138 >
Q148+G140+L74 > Q148+G140 > Q148+E138 (Underwood 2013a). On the Q148
resistance pathway, the selection of the T97A mutation enhances resistance about
10-fold (George 2017). According to the VIKING studies, increasing the dolutegravir
dose to 50 mg BID is recommended in cases of suspected or proven resistance.
As described above for darunavir, in the NADIA study, INSTI-naive patients with
viremia and NRTI and/or NNRTI resistance were treated with either a dolutegravir-
or darunavir-based follow-up regimen. In contrast to darunavir, dolutegravir resulted
in the development of resistance in 9 cases, with the patterns differing according to
the concurrent agents. Under AZT/3TC, complex INSTI mutation patterns, includ-
ing G118R and E138K, were primarily detectable, whereas under TDF/3TC, only the
combination M50I and R263K was observed. Data on the HIV subtype that may
influence the resistance pathway are lacking (Paton 2022). These data demonstrate
Viral Resistance and Tropism 271

that in case of detectable viral load and NRTI resistance, viral load should be closely
monitored before switching to DTG + 2 NRTI.
Currently, it is discussed whether other gene regions show changes in therapy failure
without detectable mutations in the integrase gene. For example, in vitro, pheno-
typic INSTI resistance is also seen with alterations in highly conserved regions of the
nef gene (Malet 2017). Whether this is therapeutically relevant remains to be seen.
Bictegravir (BIC), like dolutegravir, has a high resistance barrier. In phase 3 clinical
trials, no resistance mutations were detected in treatment-naïve patients during viro-
logic failure (Gallant 2017, Sax 2017). In the studies GS-1489/1490, no bictegravir
resistance was observed even after five years (Wohl 2022). In rare cases, especially
with comorbidities and adherence problems, resistance mutations such as R263K
may be selected under bictegravir (Stoll 2020).
Since no study data exist on patients with prior INSTI failure, the resistance profile
is currently characterized based solely on in vitro data. A clinical threshold for the
resistance factor has not yet been defined. Data to date show high cross-resistance
to dolutegravir, mediated mainly through the Q148 resistance pathway. In cell
culture, resistance development for elvitegravir, dolutegravir, and bictegravir pro-
ceeded via selection of the R263K mutation, first for elvitegravir, then with a time
lag for bictegravir, and finally for dolutegravir. The mutation M50I was subsequently
selected under bictegravir, T66I under elvitegravir, and S151Y, S119R, and M50I under
dolutegravir. In targeted mutagenesis, phenotypic resistance for bictegravir and
dolutegravir changed slightly or moderately by the mutations above, with an increase
in EC50 by a factor of approximately 3 to 8 (Tsiang 2016). Pre-existing resistance
mutations such as M184V do not appear to affect the efficacy of bictegravir plus
FTC+TAF, based on retrospective analyses of pre-selected study populations (Acosta
2019, Andreatta 2019).
The impact of archived INSTI mutations on bictegravir efficacy was investigated in
a reanalysis of 7 phase 3 studies. One percent of baseline samples had archived
proviral INSTI mutations – specifically E92G, Y143C/H, S147G, Q148H/K/R, N155S,
or R263K +/- secondary substitutions. All 20 cases showed treatment response to
bictegravir (d’Antoni 2022). Again, it should be noted that in these studies, the detec-
tion of INSTI mutations was a priori an exclusion criterion, the observation period
was only one year, and 19 of 20 patients were successfully treated at baseline.
Furthermore, it is unclear whether the detected proviruses were capable of replication.
Cabotegravir (CAB) is biochemically very similar to dolutegravir. In vitro, the fol-
lowing resistance mutations were selected alone or in combination: H51Y, L74M,
E138K, G140S, S147G, S157V, G163R, Q148K/R, and R263K. Resistance selection
occurs more rapidly in vitro under elvitegravir and cabotegravir than under
dolutegravir and bictegravir, indicating a lower resistance barrier (Oliveira 2018).
In the phase 3 switch studies ATLAS, FLAIR, and ATLAS-2M, in which long-acting
(LA) cabotegravir and LA rilpivirine were administered either every 4 or 8 weeks as
intramuscular injections, virologic treatment failure was associated with HIV-1
subtype A1/A6 infection. In ATLAS-2M, treatment failure with the development of
resistance during 152 weeks was observed in 2% (n=11) in the 8-week study arm and
1% (n=2) in the 4-week arm. The INSTI mutations detected in combination with
NNRTI resistance mutations (see rilpivirine) were T97A, E138K, N155H, and Q148R
(Hunter 2021, Overton 2022).
In multivariate analysis, baseline risk factors were HIV-1 subtypes A6 and A1, archived
rilpivirine resistance mutations (in the provirus), and a BMI >30 kg/m2. Detection
of at least 2 of these factors significantly increased the risk of treatment failure. HIV-1
subtype A6, predominant in Russia, differs from subtype A1 at 12 polymorphic
positions, including resistance-associated positions L74I and S119P. These occur more
272 ART

frequently in subtype A6. According to the label, HIV-1 subtype A1 or A6 alone is

not a contraindication. However, those affected should only switch to this new
regimen cautiously after extensive discussion of the risk.
In HPTN-083, in which cabotegravir i.m was administered as PrEP every 8 weeks
(after a 4-week oral lead-in phase), some individuals who became infected with HIV
in the study also developed resistance. In addition to the mutations detected in
ATLAS, the following were detected: E138A, G140A/S, Q148K, and R263K. These were
found early at low viral loads (Landovitz 2021, Marzinke 2021). In accordance with
the marketing authorization restriction, LA therapy with cabotegravir plus rilpivirine
should not be prescribed if INSTI or NNRTI resistance is detected.

Entry inhibitors
CCR5 antagonists such as maraviroc (MVC) should only be used for exclusively
CCR5-tropic viruses. Therefore, a tropism test is required prior to the use of maraviroc.
This therapy is not recommended for CXCR4- or dual-tropic viruses. CCR5-tropic
viruses are detectable in about 80–85% of therapy-naïve patients and about 50–60%
of therapy-experienced patients. Exclusively X4-tropic viruses are rare. The likelihood
of X4-tropic virus populations increases with decreases in CD4 T-cell counts, both
in therapy-naïve and pre-treated individuals (Hunt 2006, Simon 2010).
Two types of resistance to CCR5 antagonists can be distinguished: on the one hand,
the receptor switch from R5- to X4-tropic or dual-tropic viruses, and on the other
hand, the emergence of mutations that enable the virus to use CCR5 molecules for
cell entry even in the presence of CCR5 antagonists. In cases of treatment failure
with maraviroc, a shift from CCR5- to CXCR4-tropic virus has been described in
approximately one-third of cases (Heera 2008). Retrospective studies with more sen-
sitive methods have shown that minor X4 variants were already present in some
individuals before the start of therapy. Occasionally, however, a receptor shift was
also observed in the control arm without maraviroc (Lewis 2007).
Since not every minor X4 virus population necessarily leads to treatment failure, it
is currently unclear when the higher sensitivity of ultradeep sequencing (UDS) has
clinical relevance or at what proportion of X4-tropic viruses the risk for treatment
failure becomes greater. Samples from the A0041029 and Motivate studies were rean-
alyzed by UDS and classified as non-R5 if at least 2% non-R5 viral variants were
detected. Response rates were similarly low for 2–20% of non-R5 viruses compared
to more than 20% of non-R5 viruses (Swenson 2011).
In treatment failure without tropism switch under maraviroc, different mutations
were detected in the V3 loop of the envelope protein gp120 of HIV-1. The resistance
patterns were not uniform; mutations outside the V3 loop were also observed. The
clinical relevance of the individual env mutations is unclear; in some cases, they were
not associated with an increase in IC50. Instead, phenotypic maraviroc resistance was
associated with reduced maximal possible viral inhibition in the dose-response curves
(Mori 2008). This observation suggests that maraviroc-resistant viruses may also
utilize the CCR5 receptor to which maraviroc has already bound (Westby 2007).
Leronlimab (PRO-140) is a humanized CCR5 monoclonal antibody being evalu-
ated in multiple indications (e.g., HIV infection, metastatic triple-negative breast
cancer, or severe respiratory complications associated with COVID-19). To date, the
data from HIV trials is still limited, but the results are nevertheless impressive. Of
42 patients with HIV infection and CCR5-tropic virus only who were switched to
PRO-140 monotherapy (once weekly subcutaneously) on suppressive ART, 16 entered
the extension phase; in 9, PRO-140 therapy was successful for more than two years.
A tropism switch or a significant change in IC50 or IC90 was not observed for either
Viral Resistance and Tropism 273

PRO-140 or maraviroc (Lalezari 2017). In vitro and in vivo, leronlimab shows low
potential for a receptor switch or the development of resistance (Dhody 2018). It is
also effective in maraviroc-resistant strains but not in X4-tropic viruses (Jacobsen
2010, see also chapter 5.3.).
Fostemsavir (FTV) is an attachment inhibitor and is indicated for the treatment
of multidrug-resistant HIV-1 infection. In contrast to existing entry inhibitors, the
active metabolite temsavir binds directly to gp120 of HIV, preventing its binding to
the CD4 receptor. In the BRIGHTE trial, 60% of patients with four-class resistance
achieved durable virologic response beyond week 96 (Ackermann 2021). In particular,
4 positions with the following key mutations/polymorphisms in the gp120 domain
are associated with loss of temsavir efficacy: S375N/H/M/T/I, M426L/I, M434I/K/L/T,
and M475I/L/V. S375N and M426L occurred most frequently (Kozal 2020). There is
no cross-resistance to other entry inhibitors.
The efficacy of temsavir is limited to HIV-1 group M. Thus, it should not be used in
HIV-2 and HIV-1 groups N, O, and P. In HIV-1 group M subtype CRF01-AE, which is
dominant in Southeast Asia, fostemsavir should also not be used due to naturally
occurring resistance. The AE subtype virus has polymorphisms in the gp120 domain
associated with severely reduced activity to temsavir.
Fusion inhibitors: This section is limited to resistance mutations emerging on
Enfuvirtide (T-20)-based treatment. The gp41 gene, which consists of 351 codons,
has positions with very high variability and highly conserved regions. Poly-
morphisms have been observed in all gp41 regions, with the highest variability in
the HR2 region. Primary resistance is very rare (Wiese 2005). Loss of efficacy is mainly
associated with mutations at the T-20 binding site – the HR1 (heptad repeat 1) region
of gp41. HR1 positions 36 to 45 are particularly affected, such as G36D/E/S,
V38A/M/E, Q40H/K/P/R/T, N42T/D/S, N43D/K, or L45M/L. The degree of resistance
is usually higher with double mutations than with singular mutations. In addition,
mutations in HR2 and changes in the viral envelope also influence resistance (Sista
2004). In the absence of selection pressure by T-20, viral replication capacity is
significantly reduced in the presence of HR1 mutations compared to wild type, with
the following ranking: wild type > N42T > V38A > N42T, N43K ≈ N42T, N43S > V38A,
N42D ≈ V38A, N42T. Viral fitness and T-20 susceptibility are inversely correlated
(Lu 2004).

Nucleoside reverse transcriptase translocation inhibitors (NRTTIs)

Islatravir (ISL) is being studied as part of antiviral therapy due to its pharmacolog-
ical properties in diverse formulations and different dose intervals. Islatravir was
effective in vitro against wild-type viruses and most NRTI-resistant viral variants. In
selection studies, islatravir-resistant virus with mutations I142V/T165R/M184V
(resistance factor 22) emerged in vitro after 58 passages, with M184V being the first
mutation selected (RF 7.5) (Markowitz 2018). In a randomized dose-ranging trial in
ART-naïve individuals, no resistance occurred over 144 weeks with the combination
of islatravir plus doravirine, with 3TC additionally included as part of therapy over
the first 24 weeks (Molina 2021b). In MK-8591A-020, a study in ART-naïve PLWH
receiving either B/F/TAF or DOR/ISL, one participant in the DOR/ISL arm with a base-
line viral load above 1 million copies/mL and adherence difficulties showed incom-
plete viral response with the selection of virus harbouring the NNRTI mutations
V106A and P225Y – associated with doravirine resistance – and the NRTI mutation
M184I resulting in a fourfold reduction in susceptibility to islatravir (Rockstroh 2023)
274 ART

Capsid inhibitors
Lenacapavir (LEN) is a long-acting capsid inhibitor with picomolar potency. In vitro,
there was no cross-resistance between lenacapavir and the other antiviral agents
approved to date, including entry inhibitors (Link 2020, Margot 2022a). Viral load
is reduced rapidly (similar to INSTIs), as shown in the CALIBRATE study (Gupta
2022).
In vitro, resistance mutations were identified at 7 positions in the gag gene. The
following mutations and combinations were selected: Q67H (resistance factor, RF 6),
N74D (RF 22), K70N (RF 24), Q67H+N74S (RF 32), Q67H+T107N (RF 62), Q67H+N74D
(RF 1,099), L56I (RF 239), M66I (RF 3,200). Except for the solitary mutation Q67H,
all selected mutations – alone or in combination – lead to a loss in viral fitness (link
2020), although its clinical significance is still unclear. None of the aforementioned
mutations are natural polymorphisms, as shown by an analysis of 1,500 clinical
samples. Accordingly, resistance analysis before the use of lenacapavir is not neces-
sary for HIV-1 subtype B and the non-B subtypes studied (Marcelin 2020).
The resistance barrier does not appear to match that of a second-generation INSTI.
In the phase 1b dose-finding study 4072, 29 HIV patients were treated with
lenacapavir as monotherapy. At day 10, resistant virus with the Q67H capsid
mutation in the gag gene was isolated in 2 patients at the lowest doses (Margot
2022b). In the phase 2 CALIBRATE study, resistance development with the follow-
ing mutations was observed by week 54 in two patients with presumed poor adher-
ence to oral treatment: Q67H+K70R (RF 20, week 10) and Q67H (RF 7, week 54),
respectively (Gupta 2022).
As a representative of a new class of compounds, lenacapavir is an important new
option, especially in patients with resistant viruses. In the CAPELLA study, 83%
achieved viral loads below 50 copies/mL after 52 weeks with lenacapavir and opti-
mized concomitant therapy (n=36). Viruses with gag-associated resistance mutations
were detected in 4 cases during the first 26 weeks: M66I (n=4) in combination with
Q67H/K/N (n=1), K70H/N/R/S (n=1), N74D/H/S (n=3), A105S/T (n=3), or T107A/C/N
(n=1). Functional lenacapavir monotherapy and/or poor adherence were suspected
as reasons for viremia and resistance development (Ogbuaga 2022).

Summary
Sequencing of specific regions of the HIV genome to determine resistance and tropism
is part of the diagnostic standard. Resistance-associated mutations are detected in
about one in ten new HIV infections. Natural polymorphisms also play a role in
some cases. Resistance testing before ART initiation leads to significantly better viro-
logic response rates, and follow-up therapies can be optimized in case of treatment
failure. Professional societies recommend sequencing of the reverse transcriptase,
protease, integrase, and gp41 gene regions, as well as genotypic tropism testing.
Resistance profiles and their interpretation are sometimes very complex. Algorithms
must be continuously updated, and new drug classes must be implemented upon
availability. Phenotypic resistance analysis is used to interpret genotypic resistance
mutations in clinical studies. Defining the cut-offs of resistance factors associated with
clinically relevant resistance is crucial for a valid interpretation of phenotypic results.
A genotypic resistance test from proviral DNA can be a supportive tool in treatment
decision-making, notably in case of therapy changes at low or undetectable plasma
viral load levels and unknown treatment history. However, not all historically
detected mutations are re-detected in the provirus. The clinical relevance of poten-
tial discordances is still unclear.
Viral Resistance and Tropism 275

Increasingly, more sensitive resistance methods such as NGS are being used, which
enable the detection of even minor viral variants. However, the significance of minor
variants concerning individual drugs and drug combinations is still difficult to assess
and should be interpreted in light of the treatment history. Specific thresholds for
the presence of minor variants still need to be defined.
Finally, it should be emphasized that antiretroviral therapy should be started, paused,
or switched only by or in consultation with an experienced HIV care provider.

Substance-specific resistance-associated mutations

The following tables provide a selection of mutations associated with resistance alone
or in combination. The mutation lists do not replace the resistance algorithms used
in clinical practice, such as HIV-GRADE or HIVdb (see Table 3), but serves only as a
guide. They are based on data from the HIV GRADE algorithm ([Link]/
grade_new/), the Stanford HIV Drug Resistance Database ([Link]
and the IAS-USA Drug Resistance Mutations List (Wensing 2022).
Key mutations with the greatest impact in loss of susceptibility are printed in bold;
other mutations (not printed in bold) reduce susceptibility usually in combination
with other mutations.
Further information on the significance and degree of resistance of major and minor
mutations can be found on the website of the HIV Drug Resistance Database
([Link] (2023, version 9.5.0). However, despite good resistance
algorithms and databases, the advice of experts often remains irreplaceable for indi-
vidual treatment decisions.

Table 6a: Mutations associated with NRTI resistance.

M K D H K L Y Q M L T K
41 65 67 69 70 74 115 151 184 210 215 219
AZT L N Insertion R M W YF QE
ABC L REN Insertion V F M V W YF QE
TDF
L REN Insertion E F W YF QE
TAF
3TC
REN Insertion M VIT
FTC

Table 6b: Mutations associated with NNRTI resistance.

L K K V V E V Y Y V G H P F M L Y
100 101 103 106 108 138 179 181 188 189 190 221 225 227 230 234 318
DOR AMIT I CLH SE Y H CLRVI L I F
EFV I P HNST M I CIV CLH ACEQS H CL IL
ETR I EHP I AGKQR DFTL CIV SAE C L
NVP I P HNST AM I CIV CLH ACEQS L
RPV I EP I AGKQRS DIL CIV L I E Y ILV
276 ART

Table 6c: Mutations associated with PI resistance.

L V K L V L M I G I F I A G T L V I N L L
10 11 20 24 32 33 46 47 48 50 53 54 71 73 74 76 82 84 88 89 90
ATV/r IF RMITV I I IFV I V L LY VMTA V CSTA ATFI V S M
DRV/r I I F V V LM S P V V V
LPV/r FIRV MR I I F I VA V L VLAMTS V S V AFTS VA M

Table 6d: Mutations associated with INSTI resistance.

T L E T G F E G Y S Q S N S V R
66 74 92 97 118 121 138 140 143 147 148 153 155 230 260 263
BIC* I Q R AK ACSR HKR FY H R K
CAB IK I*** Q A R AKT ACSR R HKR FRY H R I K
DTG** Q R AKT ACSR HKR FY H R K
EVG IAK GQ A R Y K AS CR G HKR H R I K
RAL I M GQIV A R Y AK ACS CRH HKR HST K
*Based only on in vitro selection data, in vitro mutagenesis resistance data, and phenotypic analyses
of patient samples with INSTI resistance-associated virus populations. **QD; ***in HIV subtype A6

Table 6e: Resistance-associated mutations in the use of entry inhibitors (CCR5 and attachment
inhibitors, respectively).
Medication class Substance Mutations/Comments
CCR5-I MVC Virological failure associated with an increase in
CXCR4-tropic viruses from minor variants. Isolated
mutations are described in the V3 loop of HIV-1 gp120.
AI FTR In particular, key positions in gp120 are associated
with loss of efficacy:
S375N/H/M/T/I, M426L/I, M434I/K/L/T, M475I/L/V;
not recommended for HIV-1 subtype CRF01_AE

Table 6f: Mutations in the capsid gene associated

with resistance to capsid inhibitors.
L M Q K N A T
56 66 67 70 74 105 107
LEN I I HKN HNSR DHS ST ACN
Viral Resistance and Tropism 277

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SECTION 3

AIDS
286

7. Opportunistic infections (OI)

C H R ISTIAN HOFFMAN N

In Western industrialized countries, opportunistic infections (OIs) are now rare.

Incidence today has declined to less than one-tenth compared to the mid-1990s
(Brooks 2009, Buchacz 2017). Antiretroviral therapy has contributed to the change
in the course of OIs. Whereas survival after the first AIDS-defining disease was once
rarely more than three years, people now live with AIDS for thirty years or more.
If the 5-year survival rate after cerebral toxoplasmosis was 7% in 1990–1993, it grew
to 29% in 1994–1996. Since 1997, it has risen to 78% (Hoffmann 2007). Hardly
anyone dies of AIDS anymore.
About 70–90% of people who develop AIDS today are not on antiretroviral treat-
ment at the time of the OI, and a significant proportion are unaware of their HIV
infection. Often, these people present very late and in a serious condition. AIDS
remains life-threatening for this reason alone, and severe PCP does not become less
threatening because the long-term prognosis has improved. The acute danger
remains. It remains crucial to be well-versed in diagnosing and treating OIs.
Despite much progress, not everything has been solved. For example, some
infections, such as PML or cryptosporidiosis, are still barely treatable; others have
resistance problems (TB!). Even today, the mortality of PML is roughly comparable
to non-Hodgkin’s lymphoma (ART-CC 2009). ART does not continually improve
everything immediately; some diseases remain complicated due to immune
reconstitution and atypical courses. We dedicated a subchapter to the immune recon-
stitution syndrome (see IRIS).
In addition, there are always diagnostic problems with many OIs. If you don’t know
the germ, you can’t see it! It is strongly recommended to send examination material to
the reference laboratories and to seek advice in a specialized practice or an HIV center.
The first rule for almost all OIs is that the worse the immune status, the earlier inva-
sive has to be initiated! Do not try to spare the patient unpleasant examinations. If
nothing is found, diagnostics must be repeated. Therapy must be started quickly.
The second rule is that many OIs can usually excluded if the current immune status
is known. Table 1 shows threshold values for CD4 T-cells.
The third rule is that in the case of an OI, ART should be started as soon as possible
if it hasn’t been already. Immune reconstitution is the best protection against recur-
rence. ART is the only hope for infections such as PML or cryptosporidia, for which
no specific therapy exists. No time should be wasted. A rapid start is also crucial for
PCP or toxoplasmosis.
Although OI therapy is not without toxicity and interaction issues – the choice of
antiretroviral agents has increased, and side effects can be dealt with. In ACTG A5164,
282 patients with an acute OI (63% PCP) were randomized to start ART immediately
or after OI therapy cessation (Zolopa 2009). After 48 weeks, significantly fewer deaths
and new AIDS cases had occurred in the immediately treated group. The risk of

Table 1: CD4 thresholds above which certain AIDS diseases are unlikely. The CD4 T-cells only indicate
guideline values; exceptions are possible.
Without limit Kaposi's sarcoma, pulmonary TB, HZV, bacterial pneumonia, lymphoma.
From < 250/μl PCP, candida esophagitis, PML, HSV
From < 100/μl Cerebral toxoplasmosis, HAND, miliary TB
From < 50/μl CMV retinitis, atypical mycobacteriosis, cryptococcosis
Opportunistic infections (OI) 287

switching ART was slightly increased with immediate ART, but not the number of
serious adverse events, hospitalizations, or cases of IRIS. ACTG A5164 thus provides
a clear case for immediate ART initiation in PCP. But is this true for other OIs?
Probably not for all (Lawn 2011). The results of two randomized clinical trials argue
against it; both found unfavorable effects from early ART in cryptococcal meningitis
(Makadzange 2010) and in tuberculous meningitis (Török 2011) – see also ART on
late presenters.
A practical overview is given in the following pages. The literature references are
mostly limited to high-quality reviews and randomized studies. If this is insufficient,
you can download the almost 600-page, constantly updated OI guidelines of the US
NIH: [Link]
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four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Ann Intern Med 2002,
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infections. Curr Opin Infect Dis 2011, 24:34-42.
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288 AIDS

Pneumocystis pneumonia (PCP)

This interstitial pneumonia, which killed a large proportion of patients in the early
years of the HIV epidemic, is caused by pneumocysts. In recent years, knowledge of
this pathogen has made significant progress, primarily through DNA analysis (review:
Thomas 2004). Long traded as protozoa, pneumocysts are now classified as fungi
(Edman 1988). In the 1990s, it became clear that each host, whether rat, monkey,
or human, has its specific pneumocysts. It also became clear that Pneumocystis carinii,
described in 1910 by the Italian Antonio Carini, occurs only in rats. Therefore, the
species affecting humans was renamed from P. carinii to P. jiroveci (after the Czech
parasitologist Otto Jirovec). The term “carinii” was deleted, but the abbreviation PCP
remains (Stringer 2002).
PCP remains among the most common OIs worldwide (Mussini 2008, Buchacz 2016).
Of 270 “late presenters” who presented to a Berlin hospital in 2009–2013, 91 (34%)
had PCP (Tominski 2017). People unaware of their HIV infection are the most likely
to develop it. Among those with known HIV infection, hardly anyone with PCP is
on antiretroviral treatment, and adherence is often lower (Denis 2014).
PCP is dangerous. It often requires mechanical ventilation and still has a mortality
rate of up to 10% (Llibre 2013). Older people have an increased mortality risk,
as do patients with poor arterial blood gases and low hemoglobin (Miller 2010).
Recurrences, once common, are now rare thanks to ART and prophylaxis. Scarring
may leave a tendency for recurrent pneumothoraces. Rarely, PCP may also present
as an immune reconstitution syndrome (see below). Extrapulmonary or disseminated
Pneumocystis infections are now rare.

Clinic
The classic symptom triad consists of dry, irritable cough, subfebrile temperatures,
and slowly progressive exertional dyspnea (ask specifically! respiratory rate?). Unlike
HIV-negative patients with PCP, a subacute course is typical (review: Salzer 2018).
A differentiation from bacterial pneumonia (more productive cough, less dyspnea,
acute high fever, and pain!) is often possible. Often, there is an oral thrush. Weight
loss in the weeks before is also common. If prophylaxis is insufficient (rare),
symptoms may be even more subtle. Weeks, sometimes months, often pass before
the diagnosis is made. As with all interstitial pneumonia, decompensation usually
occurs more rapidly than expected. It is common for those affected to become
abruptly ventilator-dependent after weeks of antibiotic therapy by their primary care
physician (even broad-spectrum antibiotics do not help!). Any case with significant
exertional dyspnea should be hospitalized immediately.

Diagnostics
In case of clinical suspicion (respiratory rate? Abnormal auscultation? Oral thrush?),
a chest X-ray and, if possible, an HR-CT of the lungs should be performed immediately.
Radiographs often show a relatively characteristic picture with butterfly-shaped
(spreading bilaterally from hilars) interstitial drawing proliferation. The early stages
accentuate mid and lower fields, and cystic changes occur. The usually indistinct,
diffuse changes are better seen on HR-CT; other pulmonary infections can be
relatively reliably differentiated (Hidalgo 2003).
However, even if nothing pathological is seen on CT, rapid initiation of therapy is
justified even without a definite diagnosis – especially in the case of the classic triad
of symptoms, low CD4 T-cells, and lack of prophylaxis. Almost always, there is early
partial respiratory insufficiency, which an arterial blood gas analysis should objec-
Opportunistic infections (OI) 289

tify. LDH is often elevated and is of limited use as a progression parameter – it reflects,
albeit imprecisely, the severity of PCP. CRP, on the other hand, usually remains
normal unless there are concurrent infections.
Sputum samples are usually of no help, so bronchoalveolar lavage (BAL) is almost
always required. BAL also diagnoses co-infections (CMV, pneumococci) promptly. It
should be noted that BAL can worsen respiratory insufficiency. Pathogens are still
mainly detected with immunofluorescence tests, and in some laboratories now, also
with very sensitive PCR (Sasso 2016). In most cases, pneumocysts remain detectable
days after initiation of therapy, so do not wait for BAL results. It is recommended to
send material to experienced laboratories and to explicitly inform them of the
suspicion because pneumocysts are easily overlooked.
A new approach is the measurement of beta-D-glucan, a component of the cell wall
in fungi. However, it has yet to be established as a diagnostic marker (Del Corpo
2020).

Therapy
General
If clinically suspected, PCP therapy should be started immediately. Mild PCP (PO2
> 70–80 mmHg) can be treated on an outpatient basis in very mild cases with oral
medication. In collaboration with a competent HIV care service, this is often possible.
If such monitoring is not feasible or respiratory deterioration occurs, immediate
hospitalization is advisable. If ventilation is required, the prognosis is still poor today
(Crothers 2005, Walzer 2008). It is possible that non-invasive techniques (CPAP) if
started early, are more favorable. In particular, pneumothoraces can be prevented
(Confalonieri 2002).
While ART-naïve patients usually waited until PCP was cured before starting ART, a
randomized trial showed the benefits of a rapid start (Zolopa 2009, see above). No
differences were seen in the IDEAL trial, but the case number was small (Schäfer
2019). A retrospective study also showed improved survival when ART was started
while still in the hospital (Morris 2003). Potential cumulative toxicities and allergies
that may lead to discontinuing PCP therapy and ART (Watson 2002) can usually be
avoided.

Medication
The acute therapy for PCP lasts 21 days; the drug of choice is cotrimoxazole, a com-
bination of sulfamethoxazole and trimethoprim. The dosage of 3 x 3 tablets of 960 mg
is only useful in mild cases; it is often moderately tolerated gastrointestinally. There
are case reports on lower doses but no controlled studies (Thomas 2009). In severe
cases, therapy should be inpatient and intravenous. Because of possible deterioration,
probably due to frothy bursting of pneumocysts in the alveoli, 1 mg/kg prednisone
(daily, divided into 1–2 administrations) should always be given for an additional
5–10 days. Don’t be afraid of steroids, especially with poor blood gases! Several reviews
found a benefit (Briel 2016, Wang 2016). In severe PCP, this halves the mortality
risk, with fewer cases requiring ventilation (Briel 2006). Nevertheless, clinical
deterioration during the first week is not uncommon. Initial therapy should be
reconsidered after one week at the earliest and only after excluding co-infections
(CMV!).
Under the high cotrimoxazole doses, blood count, electrolytes, kidney values, and
transaminases should be at least three times a week. In addition to myelotoxicity
and liver and kidney problems, the main problem is drug exanthema, which usually
occurs in the second week of therapy and is often accompanied by drug fever. The
290 AIDS

incidence is up to 30% (Fisk 2009) – check daily for skin changes! One can try to
pause for a day or two in such exanthem, then continue on antihistamines and
steroids at half the dose. Otherwise, cotrimoxazole must be stopped and replaced
with alternative therapies.
All alternatives to cotrimoxazole are less effective. In case of intolerance or known
sulfonamide allergy, pentamidine intravenously is recommended as a second choice,
initially given in a kind of induction therapy (200–300 mg in 500 mL of 5% glucose
or 0.9% NaCl) during the first days, then in half dose from day 6. This therapy is
very toxic; severe derailment of electrolytes and blood glucose (both hyper- and
hypoglycemia) is possible, as well as pancreatitis, cardiac arrhythmias, and renal
failure. Blood glucose, electrolytes, and renal values should be checked daily.
In very mild cases of PCP, purely inhaled therapy with daily pentamidine inhala-
tions (300–600 mg daily for three weeks) may be attempted (Arasteh 1990,
Montogomery 1995). However, experience has not always been positive (Conte 1990,
Soo 1990), and US guidelines discourage inhalation therapy for acute PCP. Instead
of pentamidine, atovaquone suspension or a combination of clindamycin and
primaquine is also possible. However, data exist only for mild to moderate cases
(Hughes 1993, Dohn 1994, Toma 1998). According to a meta-analysis, clindamycin
plus primaquine has the best chance of success after the failure of cotrimoxazole
(Benfield 2008). It appears to be better than pentamidine (Helweg-Larsen 2009), but
there is a risk of hemolytic anemia (rule out G6PD deficiency first!). Caspofungin
also seems to be effective against pneumocysts. Meanwhile, it remains unclear
whether it should be added to initial therapy in severe cases (ventilation). A large
retrospective cohort from China found clinical benefits from combining cotrimox-
azole and caspofungin (Tian 2021), while another did not (Huang 2022).
In recent years, we have rarely used alternatives. Ten days of initial therapy with cot-
rimoxazole can almost always be managed, and things usually improve considerably
by then if exanthema or toxicity force discontinuation between days 10 and 14, the
third week of acute therapy is contested with daily pentamidine inhalations.
However, a sufficiently powered study on this is not in view.

Prophylaxis
People with less than 200 CD4 T-cells/µl (or < 14% of total lymphocyte count) are
at risk and need prophylaxis, ideally cotrimoxazole. Daily administration may be
slightly more effective than thrice weekly (El Sadr 1999). Updosing 14 days is thought
to prevent allergy but is cumbersome (Para 2000). Desensitization is possible for mod-
erate allergy to cotrimoxazole (Leoung 2001); it could certainly be attempted.
Although dapsone and pentamidine inhalation are almost equally effective (Bozzette
1995, Bucher 1997), cotrimoxazole prophylaxis better prevents bacterial infections
such as enteritis and pneumonia (DiRienzo 2002). More importantly, cotrimoxazole
also safely protects against toxoplasmosis. Cotrimoxazole suspension for children
can slowly increase from 12.5, 25, 37.5, 50, and 75 to 100% of the 480 mg tablet
dose over six days for desensitization. In a study of nearly 200 people, this did not
result in severe allergy but did reduce fever and headache. Around three-quarters
were able to “get used to” cotrimoxazole again in this way. However, eight weeks
should pass before re-exposure (Leoung 2001).
Monthly pentamidine inhalations are a well-tolerated alternative. Occasionally, there
is a cough, rarely an asthma attack, and very rarely, a pneumothorax may develop.
Inhalation should be performed with a suitable inhalation system (e.g., Respirgard
II®) and after bronchodilator administration. The loading dose used in the past (3 x
300 mg in the first five days) is no longer widely used. Inhalations are probably less
effective in pulmonary disease. All other options are problematic. Dapsone is poorly
Opportunistic infections (OI) 291

Therapy and prophylaxis of PCP (unless otherwise stated, daily dosages).

Acute therapy Duration: Always at least three weeks
Severe to Cotrimoxazole Cotrim-ratiopharm® 3 x 5–6 amp. at 480 mg IV plus
moderate PCP Decortin H® 40 – 40 – 0 mg (5–10 days, approx. 1 mg/kg)
Mild PCP Cotrimoxazole Cotrim forte® 3 x 3 tab. at 960 mg
Alternatives Pentamidine Pentacarinate® 200–300 mg IV 5 days (4 mg/kg),
then half dose. Mild cases: daily inhalation with 300 mg
Atovaquone Wellvone® suspension 2 x 5–10 mL (2 x 750–1500 mg)
Clindamycin Sobelin® 3–4 x 1 amp. at 600 mg IV plus primaquine
+ primaquine 1 tab. at 30 mg

Prophylaxis From < 200 CD4 T-cells/μl or after a PCP episode

First choice Cotrimoxazole Cotrim® 1 x 1 tab. at 480 mg or
Cotrim forte® 3 x 1 tab. at 960 mg / week
Alternatives Pentamidine Pentacarinate® -inhalation 300 mg 1–2 x / month
Dapsone Dapsone-Fatol® 1 x 2 tab. at 50 mg
Dapsone + Dapsone-Fatol® 1 x 1 tab. at 50 mg plus Daraprim®
pyrimethamine 1 x 2 tab. at 25 mg/wk plus Leucovorin® 1 x 2 tab.
at 15 mg/week
Atovaquone Wellvone® suspension 2 x 5 mL (2 x 750 mg)

tolerated gastrointestinally, is relatively myelotoxic, and often leads to LDH

elevations. LDH, an important diagnostic parameter, is unusable (Ioannidis 1996).
Atovaquone was similarly effective to cotrimoxazole, dapsone, and pentamidine in
two multicenter studies (El-Sadr 1998, Chan 1999) and has since been considered
an alternative. The juice is better tolerated than the tablets (Rosenberg 2001). The
main disadvantage is the high price. Atovaquone is considerably more costly in many
countries than other oral agents (Germany: approx. 1000 euros/month).
PCP prophylaxis can be discontinued while on ART, provided that at least 200 CD4
T-cells/µl have been reached for at least three months (meta-analysis: Costiniuk 2011).
Only occasionally have PCP cases been described after discontinuation at more than
200 CD4 T-cells/µl (Degen 2002, Mussini 2003). If viral load is well suppressed, achiev-
ing 200 CD4 T-cells/µl is probably not necessary. Also, in the large COHERE database,
the risk was extremely low once the viral load was below 400 HIV RNA copies twice
(Atkinson 2021), so prophylaxis can probably be discontinued in these cases.
However, there are no controlled studies. Discontinuation not only reduces side
effects and costs but also prevents resistance.

Resistance, current controversies

Pneumocysts have also been affected by the worldwide use of cotrimoxazole (Martin
1999). Sulfa resistance seems to be increasing (Helweg-Larsen 1999), but a negative
effect on therapy remains unclear (review: Matos 2010). In Europe, resistance has
been rare so far (Suárez 2017).
According to genome analyses, PCP is often a new infection, not a reactivation
(Wakefield 2003). Reservoirs may be asymptomatic PLWH, in whom pneumocysts
are frequently detected, but HIV-negative patients on steroids and those who man-
ifest PCP. Many reports of nosocomial outbreaks exist (Le Gal 2012, Sassi 2012).
However, isolation of PCP cases is not generally recommended (Thomas 2004).
292 AIDS

Pneumocysts do not always cause manifest pneumonia. In many immunocompro-

mised individuals, only “colonization” is present (Ponce 2010, Vargas 2010). This is
now thought to play a role in chronic obstructive pulmonary disease (Morris 2008).
It can also be a reservoir for outbreaks (Le Gal 2012).
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294 AIDS

Cerebral toxoplasmosis
Although the incidence has fallen to less than one-quarter compared with the 1990s
(Abgrall 2001), toxoplasmosis encephalitis (TE) remains the most critical neurologic
OI today. It almost always results from reactivating a latent infection with Toxoplasma
gondii, an intracellular parasite that infects birds, mammals, and humans. Just over
one-third of all humans have antibodies (Wang 2017). However, prevalence varies
considerably, reaching up to 90% in Central Europe. Toxoplasmas have an affinity
for the CNS. Extracerebral manifestations (heart, muscle, liver, intestine, lung) are
rare. People who become ill today are almost always untreated “late presenters.”
TE is potentially life-threatening, and therapy is complicated. Residual neurologic
syndromes with disability (hemiparesis!) or seizure tendencies may remain. In our
cohort study, this was the case in 37% (Hoffmann 2007). It should also be noted that
recurrences occur even after a long time because of intracerebral persistence. With
ART, the prognosis has improved significantly. The 5-year survival rate has increased
to 78% since 1997 (Hoffmann 2007) but seems to have stagnated in recent years.

Clinic
Within a few days, depending on the localization of the foci, focal neurological
deficits such as paresis, speech problems, or sensory disturbances may develop.
Cerebral seizure or febrile psychosyndrome with confusion may also be the first
symptoms. Headache and concurrent fever are also suspicious, whereas meningism
is atypical. Toxoplasma chorioretinitis is an important differential diagnosis of CMV
retinitis in cases of visual disturbances and occurs without encephalitis (Rodgers
1996).

Diagnostics
Above 100 CD4 T-cells/µl, TE is rare; above 200/µl, it is a rarity (Bossi 1998). Below
100 CD4 T-cells/µl, it should always be expected. Any focal neurologic deficit or
seizures in a markedly immunocompromised person should prompt immediate CCT
or MRI of the head. MRI is better and almost always visualizes more foci. Either soli-
tary, multiple (2–5) or numerous foci are found in one-third of each case. There is
annular contrast enhancement and often concomitant edema in about nine out of
ten cases. Occasionally, bleeding may occur.
With all focal findings on CCT or MRI, TE is the most likely diagnosis. The more
foci, the more likely it becomes. Even “atypical” foci are still more common than all
differential diagnoses. Bacterial abscesses or cerebral lymphomas are the most
common, but PML, infarcts, tuberculomas, and cryptococcosis are less common.
Especially in the case of unfavorably located foci, a trial of therapy is warranted
before a brain biopsy. However, a rapid stereotactic brain biopsy cannot be avoided
if symptoms do not improve within a week or worsen.
In the CSF, which does not necessarily have to be examined in the case of clear
radiological findings (several foci with contrast enhancement), there is usually a
moderate pleocytosis and a slightly elevated total protein. Our experience with
toxoplasma PCR from CSF has been relatively poor. The specificity is high, but the
sensitivity is low. A negative result does not exclude TE.
A current serology should be available. Since up to 97% of TE patients have IgG
antibodies, a negative result, which should be repeated in another laboratory if there
is any doubt, makes TE unlikely. Whether IgG titer level is a diagnostic aid has not
been validated. IgM is rarely positive, so it does not help, nor does PCR in blood
(Brittany 2003).
Opportunistic infections (OI) 295

Treatment
Although the current combinations work quite well (resistance has not been
convincingly described), they must be switched in half of the cases because of side
effects – especially allergies. In combination with pyrimethamine, sulfadiazine and
clindamycin are largely equivalent (Dannemann 1992), although with slight
advantages for sulfadiazine (Katlama 1996). Cotrimoxazole may also be considered.
There is no gold standard (Hernandez 2017).
We recommend an oral therapy with sulfadiazine and pyrimethamine. Arguments
favoring clindamycin (instead of sulfadiazine) are sulfonamide allergy and severely
ill patients in whom pill-taking is unsafe. However, the allergy rate with sulfadiazine
is considerable, and there are also recurrent supply bottlenecks. On the other hand,
clindamycin is also allergenic and problematic (pseudomembranous colitis).
A so-called “loading dose” has been advocated for pyrimethamine during the first
days since the first study (Leport 1988). Whether it is necessary is not proven. In
Germany, 100 mg is usually given over three days, followed by 50 mg. Unlike
clindamycin, pyrimethamine is effective even when the blood-brain barrier is intact.
Because of the myelotoxicity of pyrimethamine, which inhibits the conversion of
folic acid to folinic acid, substitution with folinic acid (expensive) is recommended
from the beginning. Folic acid (cheap) is useless because it cannot be converted in
the presence of pyrimethamine (Luft 2000).
Good experience is also reported with intravenous cotrimoxazole, which is dosed
like in PCP (Béraud 2009). In two randomized studies of ocular and cerebral toxo-
plasmosis, respectively, cotrimoxazole was as effective as sulfadiazine/pyrimethamine
(Torre 1998, Soheilian 2005).
If there are intolerances to sulfonamides and clindamycin, atovaquone plus
pyrimethamine is an alternative (Chirgwin 2002). The data are less robust for
azithromycin plus pyrimethamine (Bosch-Driessen 2002).
Acute therapy lasts four to six weeks, possibly longer with alternative therapies.
Improvement is often seen within a few days – cases that have not improved at least
a little clinically after two weeks of adequate therapy are probably not TE (were the
pills taken?). Diagnosis should be in these cases, and a brain biopsy should be quickly
performed. Changing TE therapy makes little sense and only costs time.
ART (no allergenic substances such as abacavir, darunavir/r, NNRTIs) should be
started quickly. A control MRI is useful in stable cases after two weeks at the earli-
est; regressions are often only recognizable after four weeks. In case of increased
intracranial pressure or edema, steroids are used (3–4 x 8 mg fortecortin, only short
period, caveat: aspergillosis!). Maintenance therapy should only be started when the
lesions have regressed by 75%.

Prophylaxis
Exposure prophylaxis: Although it has not been proven that one can be infected
by mere contact with cats, the definitive host of Toxoplasma gondii (Wallace 1993),
cat owners should pay attention to hygiene (gloves in the litter box!). IgG-negative
persons should also avoid eating raw or only briefly roasted meat (especially pork,
beef, and sheep!).
Primary prophylaxis: IgG-positive individuals with less than 100 CD4 T-cells/µl are
recommended cotrimoxazole. Desensitization is possible if an allergy is present (see
PCP). Alternatives such as dapsone plus pyrimethamine are comparably effective but
less tolerated. Primary prophylaxis can be discontinued on ART if CD4 T-cells exceed
200/µl for at least three months.
296 AIDS

Therapy/prophylaxis of cerebral toxoplasmosis

(unless otherwise stated, daily dosages)
Acute therapy Duration: Always at least four weeks
Therapy of choice Sulfadiazine + Sulfadiazin-Heyl® 4 x 2–3 tab. at 500 mg plus
Pyrimethamine Daraprim® 2 x 2 tab. of 25 mg (for 3 days, then halve
dose) plus leucovorin® 3 x 1 tab. of 15 mg/wk
Therapy of choice Clindamycin + Clinda-saar® 4 x 1 amp. at 600 mg IV or 4 x 1 tab. à 600 mg
Pyrimethamine plus Daraprim® 2 x 2 tab. of 25 mg (for 3 days, then halve
dose) plus leucovorin® 3 x 1 tab. of 15 mg/wk
Alternative Atovaquone + Wellvone® suspension 2 x 10 mL (2 x 1500 mg) plus
Pyrimethamine Daraprim® 2 x 2 tab. of 25 mg (for 3 days, then halve
dose) plus leucovorin® 3 x 1 tab. of 15 mg/wk
Maintenance therapy
Like acute therapy Like acute therapy, but half dosages
Discontinuation from > 200 CD4 T-cells/μl > 6 months
(if MRT normal or no contrast enhancement)
Possibly possible Cotrimoxazole Cotrim forte® 1 x 1 tab. at 960 mg
Primary prophylaxis
Standard Cotrimoxazole Cotrim® 1 x 1 tab. at 480 mg
Alternative Dapsone Dapsone-Fatol® 1 x 2 tab. at 50 mg
Alternative Dapsone + Dapsone-Fatol® 1 x 1 tab. at 50 mg plus Daraprim®
pyrimethamine 1 x 2 tab. at 25 mg/wk plus Leucovorin® 1 x 2 tab.
at 15 mg/wk

Secondary prophylaxis: In the absence of immune reconstitution, lifelong

maintenance therapy is required; otherwise, relapse almost always occurs. It usually
consists of halved doses of acute therapy (Podzamczer 2000). Clindamycin, which
does not cross the intact blood-brain barrier, is probably less suitable than sulfadiazine
(Luft 2000). Cotrimoxazole also does not seem as effective as secondary prophylaxis,
but it should be considered because of its simplicity. In any case, higher doses than
for PCP should be used (Ribera 1999, Duval 2004).
Secondary prophylaxis can be discontinued if there is sufficient immune reconsti-
tution (at least three months more than 200 CD4 T-cells/µl) (Benson 2004, Miro
2006). However, a recent MRI should be available. Caution should be exercised in
foci with enhancement, where a tendency to recur persists even after years. Good
CD4 T-cells do not always reflect the quality of the toxoplasma-specific immune
response (Stout 2002, Furco 2008, Lejeune 2011).

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before and during the HAART era. Clin Infect Dis 2001, 33: 1747-55.
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dren: recommendations from CDC, the NIH, and the IDSA. MMWR Recomm Rep 2004, 53(RR-15):1-112.
Béraud G, Pierre-François S, Foltzer A, et al. Cotrimoxazole for treatment of cerebral toxoplasmosis: an observa-
tional cohort study during 1994-2006. Am J Trop Med Hyg 2009, 80:583-7.
Bosch-Driessen LH, Verbraak FD, Suttorp-Schulten MS. A prospective, randomized trial of pyrimethamine and
azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis. Am J Ophthalmol
2002, 134:34-40.
Bossi P, Caumes E, Astagneau P, et al. Epidemiologic characteristics of cerebral toxoplasmosis in 399 HIV-infected
patients followed between 1983 and 1994. Rev Med Interne 1998, 19:313-7.
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Bretagne S. Molecular diagnostics in clinical parasitology and mycology: limits of the current polymerase chain
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Dis 2002, 34:1243-50.
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A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. Ann Intern
Med 1992, 116:33-43.
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era of highly active antiretroviral therapy. AIDS 2004, 18:1342-4.
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with AIDS starting HAART. AIDS 2008, 22:2087-96.
Girard PM, Landman R, Gaudebout C, et al. Dapsone-pyrimethamine compared with aerosolized pentamidine as
primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. N Engl J Med
1993, 328:1514-20.
Hernandez AV, Thota P, Pellegrino D, et al. A systematic review and meta-analysis of the relative efficacy and
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298 AIDS

CMV retinitis
Infections with cytomegaloviruses (CMV) are widespread. In many Western coun-
tries, the infection rates are around 50–70%, in homosexual men even over 90%.
In cases of significant immunodeficiency (below 50 CD4 T-cells/µl), reactivated CMV
infection can lead to retina inflammation (retinitis). CMV retinitis was a common
AIDS disease, causing blindness in up to 30% of affected individuals. Today, it is rare
and seen almost exclusively in late presenters (Jacobson 2000). Inflammatory CMV
retinitis with severe vitritis as IRIS is also possible (see IRIS chapter). In visual dis-
turbances, lesions are almost always already present and are not reversible, even with
adequate therapy. Thus, CMV retinitis remains a dangerous disease even today,
although the prognosis has improved with ART (Salzberger 2005, Thorne 2006).
Other manifestations of disseminated CMV infection are relatively rare (about 15%).
They can affect any organ. Pneumonias, esophageal ulcers, colitides, and encephal-
itides are the most common, but sinusitis also occurs (Jutte 2000). The clinic depends
on the organ affected; the diagnosis can only be made histologically. In the absence of
studies, systemic therapies analogous to CMV retinitis are usually chosen (Whitley 1998).
CMV infection also plays a role in the development of atherosclerosis and immune
activation or immune reconstitution deficiency (reviews: Gianelli 2016, Moss 2019)
– the importance of CMV co-infection is only beginning to be understood.

Clinic
Any peracute or acute visual disturbance such as blurred vision (“snow drift”),
shadows, or spots – especially unilateral – should be a reason to send the patient
immediately to ophthalmology. Today, and not tomorrow. Already symptomatic
CMV retinitis is an emergency – once there is a black spot in the visual field, there
remains a black spot. It is often retinal detachment and macular edema, less com-
monly cataractous changes (Thorne 2006). CMV therapies can usually only stop pro-
gression and cannot reverse anything. Pain in the eye, burning, increased tearing,
and conjunctival irritation are not typical. Many suffer systemic symptoms such as
fever and weight loss.

Diagnostics
The diagnosis of retinitis is made by fundoscopy. The examiner’s experience is
crucial in evaluating the predominantly peripherally located, whitish exudates.
Unfortunately, misdiagnosis, which wastes valuable time (and retina), is not an
exception. If necessary, start with oral valganciclovir and transport the patient to a
center with more experience!
With CD4 T-cells below 100/µl, chorioretinitis due to Toxoplasma gondii is the most
important differential diagnosis. With CD4 T-cells above 100/µl, CMV retinitis is almost
excluded, and other viral infections (HSV, VZV) or even neurosyphilis are more likely.
Sometimes, CMV lesions are confused with cotton wool foci, which are not uncommon
with high HIV viral load. Many small foci without bleeding or exudates are almost
always cotton-wool foci and rarely CMV retinitis. Bilateral infestations also tend to
be the exception. Vitritis beyond an immune reconstitution syndrome is also rare.
CMV serologies (IgG almost always positive, IgM alternating) do not help. A CMV
PCR (formerly also pp65 antigen) in the blood, on the other hand, makes perfect
sense: a negative PCR makes CMV retinitis at least less likely, and the risk of
CMV disease and overall mortality increases with the level of CMV viremia.
Positive PCR is associated with unfavorable prognoses (Nokta 2002, Jabs 2005,
El Amari 2011).
Opportunistic infections (OI) 299

Treatment
Every CMV therapy should be started quickly and monitored very closely by
fundoscopy (once a week, photo documentation!). In the beginning, there is an
intensive induction therapy of two to three weeks, usually with valganciclovir (see
below), until the lesions are scarred. This is followed by reduced-dose maintenance
therapy. All patients should also be started on ART expeditiously. The specific CMV
immune response is thus restorable (Komanduri 1998), and CMV viremia usually
disappears after a few weeks (Deayton 1999, O’Sullivan 1999). In the absence of
symptoms, we would tend not to treat isolated CMV viremia specifically. However,
a (non-randomized) Japanese study showed that “preventive” CMV therapy can
prevent organ manifestations in the presence of low CD4 T-cells and CMV viremia
(Mizushima 2013). Treating only a positive IgM serology (without further diagnostics
or clinic) is expensive and usually an unnecessary risk.

Systemic therapy
The drug of choice is valganciclovir, an orally well absorbable prodrug of ganciclovir.
In a randomized trial, it was as effective as intravenous ganciclovir but also as myelo-
toxic (Martin 2002). Regular blood count checks are vital. Ganciclovir resistance is
rare (Martin 2007).
However, intravenous therapy is usually still favored for acute vision-threatening
lesions. In addition to intravenous ganciclovir, foscarnet can also be used, which
should also be used if valganciclovir is not tolerated. However, foscarnet is nephro-
toxic and can cause very painful penile ulcers. Intensive hydration is necessary. There
are no comparative studies for cidofovir, which is rarely used. The advantage of its
long half-life (given once a week) is offset by its significant nephrotoxicity (Plosker
1999). We saw creatinine increases every second case despite a meticulous infusion
regimen (see Drugs).
A new option could be letermovir (Prevymis®), which targets CMV terminase and
was approved in 2018 in HIV-negative transplant patients (reviews: Chen 2019,
El-Helou 2019). However, there are no data for HIV to date.

Local therapy
Various local therapies have been tested in CMV retinitis (Smith 1998). Although
their use rarely causes complications (infections, bleeding), some drawbacks remain.
For example, intravitreal injections of ganciclovir or foscarnet or implantation of
pellets (Vitrasert®) do not protect against infection in the contralateral eye or
extraocular manifestations (Martin 1999). This is also true for fomivirsen
(Vitravene®), an antisense oligonucleotide to be injected intravitreally, which is also
effective against multidrug-resistant CMV strains (Perry 1999). Local therapies hardly
play a role today.

Prophylaxis
Primary prophylaxis: In prospective studies, no primary prophylaxis has been con-
vincing. There is also no effective vaccination. Therefore, the three-monthly fun-
doscopy is the most crucial prophylaxis with less than 200 CD4 T-cells/µl. If the
immune reconstitution is good, the intervals can be extended. If immune status is
poor, fundoscopy should be performed before ART initiation. Smaller lesions, which
may present as very pronounced inflammatory during immune reconstitution, can
thus be detected in time.
300 AIDS

Therapy/prophylaxis of CMV retinitis (unless otherwise indicated, daily doses)

Acute therapy Duration: Always at least three weeks
Therapy of choice Valganciclovir Valcyte® 2 x 2 tab. of 450 mg (for acute vision-threatening
lesions, choose intravenous alternatives)
Alternative Ganciclovir Cymeven® 2 x 5 mg/kg IV
Alternative Foscarnet Foscavir® 2 x 90 mg/kg IV
Alternative Ganciclovir + Half dosages each as above
Foscavir
Maintenance therapy Discontinuation from > 100–150 CD4 T-cells/μl > 6 months
Therapy of choice Valganciclovir Valcyte® 2 x 1 tab. of 450 mg
Alternative Foscarnet Foscavir® 1 x 120 mg/kg IV on 5 days/week
Alternative Cidofovir Vistide® 1 x 5 mg/kg IV every 14 days (plus probenecid
and hydration as scheduled; see also medication section)
Primary prophylaxis Not recommended

Secondary prophylaxis: After about three weeks of acute therapy, but at the earliest
when the lesions scar, dose-reduced secondary prophylaxis (maintenance therapy)
should be started, preferably with oral valganciclovir (Lalezari 2002). However,
valganciclovir is not only expensive (in Germany, two tablets per day cost about
2000 euros / month) but also as myelotoxic as ganciclovir infusions. Therefore, dis-
continuing secondary prophylaxis as soon as possible is desirable and practical (Jouan
2001). It is recommended by the US guidelines at the earliest after six months of
maintenance therapy and immune reconstitution to above 100–150 CD4 T-cells/µl.
However, we have successfully discontinued valganciclovir even at fewer values,
provided both HIV and CMV PCR in blood were below the detection limit. One study
showed that discontinuation after 18 months of ART/maintenance therapy was safe
at levels as low as 75 CD4 T-cells/µl (Jouan 2001). After discontinuation, ophthal-
mologic monitoring should be performed at least once monthly during the initial
period. Fortunately, the daily infusions of ganciclovir or foscarnet, which used to be
administered via port, pumps, and nursing service for the rest of the patient’s life,
are now history. If recurrences occur under oral valganciclovir, we recommend
re-induction and maintenance therapy with foscarnet.
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Whitley RJ, Jacobson MA, Friedberg DN, et al. Guidelines for the treatment of cytomegalovirus diseases in patients
with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. Arch Intern
Med 1998, 158:957-69.
302 AIDS

Candidiasis
Candidoses are infections with yeast-forming fungi. Of the 150 Candida species
known to date, only about 20 cause disease. The most common strain is C. albicans,
accounting for 60–90% (Review: Patil 2018). Other strains, such as C. tropicalis,
C. glabrata, and C. krusei, are rare, but some respond worse to -azoles. Any candidi-
asis is an important indicator of immunodeficiency and often occurs in the wake of
other OIs. Thus, it provides crucial clues not only to HIV infection but also to other
more serious infections such as PCP – one should be very vigilant, especially in the
presence of fever (not part of candidiasis). Candida esophagitis is AIDS-defining.
With good immune status, other causes of thrush should be considered – alcoholism
and steroid therapy are just two of many. In addition to candidiasis of the oropharynx
and esophagus, vaginitis (although quite common in healthy individuals) is a
common problem in women. Candidemia, on the other hand, rarely occurs in PLWH,
even in those with massive immunodeficiency.

Clinic
The oropharynx is usually affected. Taste disturbances, sometimes a burning sensa-
tion, and whitish, strippable deposits on the buccal mucosa, pharyngeal ring, and
tongue allow visual diagnosis. The tongue alone is rarely affected. Occasionally, there
is atrophic candidiasis with only reddened mucosa.
Thrush esophagitis usually occurs with oropharyngeal involvement but in about 30%
without oral thrush. An inconspicuous pharynx, therefore, does not necessarily
exclude esophagitis. It is often manifested by dysphagia (“food does not slide down”)
and retrosternal pain. Occasionally, there is also nausea, but vomiting rarely occurs.

Diagnostics
In the throat, visual diagnosis is sufficient. A smear is usually not necessary, and the
determination of antibodies or antigens in serum is almost always superfluous.
Typing with culture or even resistance determination (caveat: laboratory uncertain-
ties!) will only cause unnecessary costs and only make sense if a therapy attempt
with fluconazole and itraconazole, respectively, has failed.
Oral candidiasis should not be confused with oral hairy leukoplakia (OHL). Unlike
candidiasis, these whitish, hairy coatings on the lateral margins of the tongue cannot
be scraped off. OHL is not induced by mycoses but by EBV and, although harmless
and not in need of therapy, is an important disease marker for HIV.
Thrush esophagitis can also often be diagnosed clinically. Dysphagia, retrosternal
pain, and an oral thrush make it very likely. Empiric fluconazole therapy saves costs
(Wilcox 1996). Esophagogastroduodenoscopy (EGD) becomes necessary only when
symptoms persist with fluconazole. To differentiate fluconazole-refractory thrush
esophagitis from herpes or CMV esophagitis, specimens should be obtained.

Treatment
If the immune status is still good and the first episode has occurred, topical treatment
with suspensions or lozenges (nystatin, amphomoronal) can be tried first. However,
these are usually not particularly pleasant; systemic therapy is also more effective
and protects against recurrences for longer (Pons 1997).
Fluconazole is the drug of choice; in oral thrush, a one-week oral therapy is sufficient
(Sangeorzan 1994), possibly even a single dose of 750 mg (Hamza 2008). In C. albicans,
-azole resistance has been rare (Sanglard 2002). If thrush persists despite therapy,
a smear should be taken, and the fluconazole dose should be increased to 800 mg
Opportunistic infections (OI) 303

in a second attempt. If thrush esophagitis is present, treatment should be given

immediately for 14 days. Itraconazole, which is still effective in about two-thirds of
cases (Saag 1999), is only considered if another attempt fails and/or non-albicans
strains are detected. Itraconazole suspension is as effective as fluconazole (Graybill
1998) but is burdened by unreliable plasma levels and numerous interactions. We
do not use itraconazole primarily.
Many new antifungal agents have been developed in recent years. However, they
should only be used in cases of apparent fluconazole resistance. There is no evidence
for the superiority of any particular antifungal (Pienaar 2006). Voriconazole is likely
as effective as fluconazole but may not be tolerated well (Ruhnke 1997, Ally 2001).
Posaconazole is also about as effective as fluconazole (Vaszquez 2006). These new
azoles, like amphotericin B, may be considered primarily for multi-azole-resistant
mycoses.
An alternative is mucosal adhesive miconazole tablets (Loramyc®), approved in
Europe (Lalla 2011). However, no comparative studies for PLWH with oral candidiasis
(Vazquez 2010).
The new antifungal class of echinocandins is also effective against most Candida
strains. Substances such as caspofungin, micafungin, or anidulafungin, which can,
however, only be given intravenously, were as effective and tolerable as fluconazole
in randomized trials for thrush esophagitis or invasive candidiasis (Villanueva 2001,
de Wet 2004, Reboli 2007). However, given their cumbersome application, their use
is limited to -azole-resistant strains.
ART should be started if mycosis is present, but at the latest, if there are resistance
problems, since multidrug-resistant strains usually disappear with sufficient immune
reconstitution (Ruhnke 2000).

Therapy/prophylaxis of candidiasis (daily doses)

Acute therapy Duration: 5–10 days
In mild cases Topical Ampho-Moronal® lozenges 4 x 1 or
Nystaderm® Suspension 4 x 1 mL (4 x 1 Pip)
Therapy of choice Fluconazole Diflucan® or Fluconazole CT/Stada® 1 x 1 cap. at 100 mg
for oral candidiasis
Diflucan® or Fluconazole CT/Stada® 1 x 1 cap. at 200 mg
for candida esophagitis
(double dose on the first day)
Alternative Itraconazole Sempera® 2 x 1–2 cap. at 100 mg or
Sempera liquid® 2 x 10–20 mL (1 mL = 10 mg)
Prophylaxis Not recommended

Prophylaxis
A survival benefit has not yet been shown for any Candida prophylaxis (McKinsey
1999, Rex 2000, Goldman 2005). However, in the largest randomized trial, contin-
uous prophylaxis reduced both oral thrush episodes and invasive candidiasis
(Goldman 2005). Incidentally, this study did not confirm the hypothesis that
continuous therapy selects resistant nonalbicans strains (Vazquez 2001). In any case,
azole-resistant candidiasis was not more frequent in the continuous therapy arm.
But every immunosuppressed person should have his or her mouth checked at every
presentation!
304 AIDS

Patients should be urged to change their toothbrushes frequently and carefully clean
dentures. Disinfecting mouth rinses with chlorhexidine 0.12% 1–2 x daily may also
be useful.

Literature
Ally R, Schurmann D, Kreisel W, et al. A randomized, double-blind, double-dummy, multicenter trial of voricona-
zole and fluconazole in the treatment of esophageal candidiasis in immunocompromised patients. Clin Infect
Dis 2001, 33:1447-54.
De Wet N, Llanos-Cuentas A, Suleiman J, et al. A randomized, double-blind, parallel-group, dose-response study
of micafungin compared with fluconazole for the treatment of esophageal candidiasis in HIV-positive patients.
Clin Infect Dis 2004, 39:842-9.
Graybill JR, Vazquez J, Darouiche RO, et al. Randomized trial of itraconazole oral solution for oropharyngeal can-
didiasis in HIV/AIDS patients. Am J Med 1998, 104:33-9.
Hamza OJ, Matee MI, Brüggemann RJ, et al. Single-dose fluconazole versus standard 2-week therapy for oropha-
ryngeal candidiasis in HIV-infected patients: a randomized, double-blind, double-dummy trial. Clin Infect Dis
2008, 47:1270-6.
Lalla RV, Bensadoun RJ. Miconazole mucoadhesive tablet for oropharyngeal candidiasis. Expert Rev Anti Infect
Ther 2011, 9:13-7.
McKinsey DS, Wheat LJ, Cloud GA, et al. Itraconazole prophylaxis for fungal infections in patients with advanced
HIV infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999, 28:1049-56.
Pienaar ED, Young T, Holmes H. Interventions for the prevention and management of oropharyngeal candidia-
sis associated with HIV infection in adults and children. Cochrane Database Syst Rev 2006, 3:CD003940. Review.
Patil S, Majumdar B, Sarode SC, et al. Oropharyngeal Candidosis in HIV-Infected Patients-An Update. Front
Microbiol. 2018 May 15;9:980.
Pons V, Greenspan D, Lozada-Nur F, et al. Oropharyngeal candidiasis in patients with AIDS: randomized com-
parison of fluconazole versus nystatin oral suspensions. Clin Infect Dis 1997, 24:1204-7.
Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med
2007;356:2472-82.
Rex JH, Walsh TJ, Sobel JD, et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 2000, 30:662-78.
Ruhnke M, Adler A, Muller FM. Clearance of a fluconazole-resistant Candida albicans strain after switching anti-
fungal therapy and initiation of triple therapy for HIV infection. Clin Microbiol Infect 2000, 6:220-3.
Ruhnke M, Schmidt-Westhausen A, Trautmann M. In vitro activities of voriconazole (UK-109,496) against flu-
conazole-susceptible and -resistant Candida albicans isolates from oral cavities of patients with HIV infection.
Antimicrob Agents Chemother 1997, 41:575-7.
Saag MS, Fessel WJ, Kaufman CA, et al. Treatment of fluconazole-refractory oropharyngeal candidiasis with itra-
conazole oral solution in HIV-positive patients. AIDS Res Hum Retroviruses 1999, 15:1413-7.
Sangeorzan JA, Bradley SF, He X, et al. Epidemiology of oral candidiasis in HIV-infected patients: colonization,
infection, treatment, and emergence of fluconazole resistance. Am J Med 1994, 97:339-46.
Sanglard D, Odds FC. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical con-
sequences. Lancet Infect Dis 2002, 2:73-85.
Vazquez JA, Peng G, Sobel JD, et al. Evolution of antifungal susceptibility among Candida species isolates recov-
ered from HIV-infected women receiving fluconazole prophylaxis. Clin Infect Dis 2001, 33:1069-75.
Vazquez JA, Skiest DJ, Nieto L, A multicenter randomized trial evaluating posaconazole versus fluconazole for the
treatment of oropharyngeal candidiasis in subjects with HIV/AIDS. Clin Infect Dis 2006, 42:1179-86.
Vazquez JA, Patton LL, Epstein JB, et al. Randomized, comparative, double-blind, double-dummy, multicenter
trial of miconazole buccal tablet and clotrimazole troches for the treatment of oropharyngeal candidiasis: study
of miconazole Lauriad® efficacy and safety (SMiLES). HIV Clin Trials 2010, 11:186-96.
Villanueva A, Arathoon EG, Gotuzzo E, et al. A randomized double-blind study of caspofungin versus ampho-
tericin for the treatment of candidal esophagitis. Clin Infect Dis 2001, 33:1529-35.
Walsh TJ, Gonzalez CE, Piscitelli S, et al. Correlation between in vitro and in vivo antifungal activities in exper-
imental fluconazole-resistant oropharyngeal and esophageal candidiasis. J Clin Microbiol 2000, 38:2369-73.
Wilcox CM, Alexander LN, Clark WS, Thompson SE 3rd. Fluconazole compared with endoscopy for HIV-infected
patients with esophageal symptoms. Gastroenterology 1996, 110:1803-9.
Opportunistic infections (OI) 305

Tuberculosis
C H R ISTIAN H ERZMAN N, GU NAR GÜ NTH ER

Background
Tuberculosis (TB) is one of the most common life-threatening infectious diseases
worldwide. In 2020, approximately 10.6 million people fell ill. About 1.59 million
people died, including 187,000 PLWH (WHO 2022a). The incidence and prevalence
of the disease varies globally but was affected almost universally by the COVID-19
pandemic, as surveillance, diagnostic, and therapeutic services were massively
impaired. Globally reported cases declined significantly in 2020 (5.9 million) and
rebounded modestly in 2021 (6.7 million). The global decline in the incidence of TB
slowed significantly, whereas mortality increased (Figure 1). A global increase in TB
disease is expected in the post-pandemic years (WHO 2022a).
For European countries with low incidence rates, it can be assumed that the refugee
movement from Ukraine will contribute to an increase in incidence in the coming
years. For example, the incidence in 2020 in Ukraine was 70/100,000, compared with
4.8/100,000 in Germany and 8.8/100,000 in Poland. Mainly due to the high rate of
multidrug-resistant tuberculosis in Ukraine (MDR-TB, 33% of all cases), increased
surveillance efforts and diagnostic vigilance are required when tuberculosis is
suspected.
About 6.7% of all new TB cases occurred among PLWH. In Africa and some European
countries, the HIV prevalence among TB patients is exceptionally high. There is a
significantly increased risk of TB disease, especially in those with advanced immun-
odeficiency and ongoing viral replication (Lange 2016). Approximately 76% of
reported TB cases worldwide were tested for HIV in 2021, and 89% of reported cases
with coinfection received antiretroviral therapy (WHO 2022a).
The therapy of PLWH with TB is significantly complicated by its long duration,
frequent side effects, interactions, and poor adherence due to the large number of
drugs. For therapy-naïve individuals without risk of drug resistance (see below), a
combination of rifampicin, isoniazid, pyrazinamide, and ethambutol along with ART
of TDF/3TC or TDF/FTC plus efavirenz, TDF/FTC/efavirenz, or TDF/3TC or TDF/FTC
plus an INSTI at adjusted doses is initially recommended (EACS 2021). If these

Figure 1: Estimated global number of TB deaths with or without HIV infection since 2000. A pandemic-
related increase since 2019. Dashed: WHO target for 2020 (WHO 2022a).
306 AIDS

regimens are not an option, a PI-based regimen such as TDF/3TC(FTC) plus

darunavir/r, atazanavir/r, or lopinavir/r in adjusted dose may also be considered in
combination with rifabutin. Therapy must be adjusted to the results of genotypic
(TB and HIV) and phenotypic (TB) drug sensitivity testing (DST). EACS offers an
online course on HIV and co-infections at [Link].

Interrelationship of HIV and M. tuberculosis

Infections by HIV and Mycobacterium tuberculosis (MTB) synergistically affect the
human immune response. This occurs with continued viral replication (usually in
the absence of effective ART) through reduction of CD4 T-cells or functional loss of
immunocompetence. Even under ART and despite numerically normal numbers,
immune reconstitution remains incomplete in correlation to the CD4 T-cell nadir
(Lange 2003, Lundgren 2015). The pathogenic effect of HIV infection is not limited
to CD4 T-cell function. Even in the early stages of HIV infection, the risk of devel-
oping TB is significantly increased (Sonnenberg 2005).
PLWH have a 21- to 37-fold risk of developing active TB compared with HIV-nega-
tive individuals (Getahun 2010). In addition to low CD4 T-cells, low body mass index,
anemia, diabetes mellitus, and existing viral replication are risk factors. TB can also
lead to immune paralysis and exacerbate the effect of HIV-associated immunodefi-
ciency (Toossi 2003).

Clinical manifestation
In the early stages of HIV infection, TB manifests no differently than in HIV-nega-
tive individuals. Cough, fatigue, fever, night sweats, and weight loss are the most
common symptoms. As immunodeficiency progresses, extrapulmonary (e.g.,
pleurisy, lymphadenopathy, osteomyelitis) and disseminated manifestations such as
meningitis and miliary TB occur (Elliott 1993).
Pulmonary TB is the most common organ manifestation with infiltrations and/or
cavity formation. The upper lobes are most commonly affected. Enlarged hilar lymph
nodes are often a manifestation of HIV infection.
Extrapulmonary TB: The most common manifestation is cervical lymphadenopathy
with enlarged and painful cervical lymph nodes. The lymph nodes may liquify and
form spontaneous fistulae on the cutaneous surface. Smaller abscesses may heal
without surgical intervention; larger abscesses should be drained surgically. Other
forms include pleurisy, pericarditis, abdominal TB, and meningitis. Osteoarticular,
spinal, urogenital, or cutaneous forms of TB also occur; virtually any organ can be
affected.
Miliar-TB (lat. Milium effusum = millet): The chest X-ray shows a nodular pattern
reminiscent of millet grains, which is radiologically indistinguishable from crypto-
coccosis. Radiological changes can often be seen in the meninges, liver, and spleen.

Diagnosis of active tuberculosis and drug sensitivity testing

Suspicion of active TB is based on clinical symptoms and radiological findings (Lange
2004). The gold standard is the cultural detection of MTB from sputum or other spec-
imens, and nucleic acid amplification techniques (NAAT) have become the standard
of initial diagnosis. Blood tests cannot detect active TB (IGRA; see below). Differential
diagnoses include diseases caused by non-tuberculous mycobacteria, solid tumors,
lymphomas, lung abscesses, and sarcoidosis. Less common differential diagnoses
include granulomatosis with polyangiitis, nocardiosis, actinomycosis, rhodococco-
sis, aspergillosis, histoplasmosis, and cryptococcosis.
Opportunistic infections (OI) 307

Radiology: Radiological changes may vary widely, mimic other pneumological

pathologies, or be absent. The more severe the immunodeficiency, the fewer patho-
logic changes are usually found on conventional radiographic thorax (Chamie 2010).
Blurred, streaked infiltrations with cavities, especially in the upper lobes, are typical;
fine-spotted, disseminated (miliary) infiltrates are found in miliary tuberculosis. In
advanced immunodeficiency, pleural effusion without pulmonary infiltrates may
occur early. A CT of the chest should be obtained if in doubt. Pulmonary imaging
is also recommended in cases of extrapulmonary TB. In addition, an ultrasound
should be performed to look for intra-abdominal abscesses, lymphadenopathy, bowel
wall thickening, renal and bladder pathology, and ascites. MRI is superior to CT for
meningitis, radiculitis, and osteomyelitis.
Sputum examination and microscopy: If pulmonary TB is clinically suspected,
2–3 morning sputum samples taken immediately and on the following morning
should be examined. If sputum production is not possible, it can be augmented by
inhalation of hypertonic saline (3%). Microscopic detection of alcohol- and acid-fast
bacilli (AAFB) in sputum is successful in only about 30% of PLWH with pulmonary
tuberculosis – at least 5,000–10,000 mycobacteria/mL must be present for detection.
The specificity of microscopy is also low; they cannot be told apart from non-tuber-
culous mycobacteria (NTM). However, microscopy is still necessary for diagnosing
atypical mycobacterial disease if MTB-specific NAAT remains negative and as a mon-
itoring tool during therapy.
Nucleic acid amplification: Methods for the detection of MTB DNA by nucleic acid
amplification (Xpert® MTB/RIF, Xpert® MTB/RIF Ultra, Truenat® MTB Plus/MTB-Rif
Dx) are diagnostically clearly superior to sputum microscopy and are recommended
by WHO. The time to diagnosis is approximately 2 hours. This allows rapid differ-
entiation of MTB from other acid-fast organisms on microscopy. The sensitivity and
specificity of the Xpert® MTB/RIF Ultra exceed 99% for microscopically positive
sputum samples.
In people living with HIV, the Xpert MTB/RIF Ultra sensitivity is 87%. Even if no
AAFB is detectable in microscopy, but the culture is positive (as is often the case with
HIV), the sensitivity is 77% (Zifodya 2021). The assay is also suitable for diagnosing
extrapulmonary TB, but the sensitivity is lower than for pulmonary TB (Denkinger
2014, Kohli 2021). The Xpert MTB/RIF Ultra significantly increases diagnostic
sensitivity compared to the Xpert MTB/RIF, especially for the diagnosis of TB in CSF
(89%) and pleural effusion (74%) (Kohli 2021). However, in the context of the
improved sensitivity, the number of false positive findings unfortunately also
increases, especially in former TB patients.
The Xpert MTB/RIF Ultra and Truenat MTB-Rif Dx can simultaneously detect
mutations in the rpoB gene that indicate rifampicin resistance with approximately
95% sensitivity (Boehme 2010, Zifodya 2021). False-positive test results can be
expected in countries where rifampicin resistance is relatively rare (e.g., Western
Europe). The Xpert MTB/XDR enables rapid detection of common resistance
mutations to isoniazid, fluoroquinolones, ethionamides, and amikacin.
Lipoarabinomannan assay: This urine test with lateral flow technology is a point-
of-care test recommended by WHO for diagnosing TB in HIV co-infection and severe
immunosuppression. The assay can improve or complement the diagnosis of active
TB, especially in individuals without sputum production and few clinical signs of
TB. A recent Cochrane analysis reported a sensitivity of approximately 40% (Bjerrum
2019). The Fuji company has developed a significantly improved version. However,
a recent evaluation of PLWH showed highly variable results (Szekely 2022).
308 AIDS

Line probe assays (Hain-Lifescience, AID) allow the detection of mutations within
24–48 hours in the mycobacterial genes katG, inhA, rrs, and gyrA/B and others that
are associated with resistance to isoniazid, amikacin, and fluoroquinolones.
Genome sequencing for DST has been established as the new standard for drug sen-
sitivity testing, although its use in primary biological samples like sputum remains
challenging. In 2021, WHO published a catalog of known resistance mutations of
MTB with a grading of clinical relevance (WHO 2021). Currently, Deeplex® Myc-TB,
an assay based on “targeted next-generation sequencing,” analyzes 18 gene targets
for 15 drugs and allows a standardized web-based interpretation of its findings (Jouet
2021). Further assays will be available soon, based on different sequencing tech-
nologies (e.g., Oxford Nanopore Technologies).
Microbiological culture: The diagnostic gold standard is the cultural detection of
M. tuberculosis complex in liquid media (approx. 2–4 weeks) or solid media (approx.
3–5 weeks). If microscopy is negative, a specimen should not be considered culturally
negative for 6–8 weeks. NTMs often grow much faster and are usually diagnosed
within two weeks in specialized laboratories. DST is always required when MTB has been
detected culturally and is now available for most new TB drugs (besides carbapenems).
Bronchoscopy: If both sputum microscopy and NAAT are negative, bronchoscopy
is indicated if TB is still suspected. The investigation of gastric juice is less sensitive.
Bronchial secretions, bronchoalveolar lavage, and transbronchial biopsies can be
analyzed by microscopy, culture, and NAAT. Detecting caseating granulomas or giant
cells in the transbronchial biopsy may further back up the diagnosis of TB. In addi-
tion, MTB-specific immuno-diagnosis using Elispot ([Link]®) from bron-
choalveolar lavage can be performed at specialized centers (Jafari 2018). This proce-
dure identifies more than 90% of all cases of active pulmonary TB. Most differential
diagnoses require bronchoscopic investigation.
Extrapulmonary diagnostic: Biological samples should be obtained from the
affected organ, e.g., heparin blood, urine (three morning samples), cerebrospinal
fluid, pleural, peritoneal, and pericardial fluids. Biopsies of lymph nodes, pleura,
peritoneum, synovium, or pericardium may also be considered. Biopsies should not
be shipped in formalin but in normal saline (NaCl 0,9%) for culture and NAAT. The
sensitivity of molecular tests varies widely; culture remains the gold standard. Details
on the diagnostic quality of molecular tests in different body materials can be found
in a recent Cochrane analysis (Kohli 2021). For lymphadenopathy, needle aspiration
followed by NAAT diagnosis has a high sensitivity for the diagnosis of TB.

Latent infection and preventive therapy

Latent infection with MTB is defined as a positive immune response in the tuber-
culin skin test (TSTTST) or interferon−γ release assay (IGRA) in the absence of active
disease (Mack 2009). Immunodiagnostics are part of TB prevention. After the active
disease has been excluded, IGRA or TST should be used to identify PLWH at the
highest risk of developing active disease (Getahun 2015). Immunoassays do not dis-
tinguish between active and latent disease, i.e., they are not helpful in diagnosing
active TB. IGRAs are more specific than skin testing. The [Link]® test appears to
be less dependent on CD4 T-cell count (Rangaka 2007) than the IFN−γ response of
the QuantiFERON®-TB Gold test (Leidl 2010). However, the higher specificity is not
associated with a higher positive predictive value for the development of active TB.
Few studies have evaluated progression rates to active TB in PLWH based on TST and
IGRA (Aichelburg 2009, Sester 2014). Viral loads above 50 copies/mL and positive
TST are the greatest risk factors for developing TB (Sester 2014). Progression from
Opportunistic infections (OI) 309

latent to active disease is prevented by preventive therapy (Sester 2014). The “number
needed to treat” to prevent one case of active TB in TST-positive HIV patients is below
10, and TST is superior to IGRAs. However, many cases that later develop TB are not
detected by either TST or IGRAs (Sester 2014). New approaches are aiming for assays
with higher positive predictive values. For example, transcriptome-based gene
signatures (such as RISK 6/RISK 11) are currently evaluated for their predictive value,
but also for triage and treatment monitoring (Hamada 2022).
To prevent TB, administration of six to nine months of INH (300 mg) plus pyridoxine
(25 mg) is recommended in PLWH with positive TST or IGRA. Alternatively,
rifampicin or rifabutin may be administered for four months (EACS 2022). Once-
weekly administration of rifapentine 900 mg and INH 900 mg for 12 weeks was non-
inferior to 600 mg INH for nine months (Sterling 2016). Rifapentine 600 mg and
isoniazid 300 mg daily for one month are good alternatives. However, rifapentin is
not approved by the EMA and is therefore unavailable in Europe (EACS 2022).
Children living with HIV likely benefit from preventive INH administration, but this
recommendation is not strong (Zunza 2017).

Infection Control
Most people fall ill a short time after infection. Therefore, infection control is vital
in contact with actively ill people (Horsburgh 2010, Houben 2011). Contact isola-
tion from the moment of diagnosis until effective treatment according to DST has
been established as particularly important in HIV co-infection (Escombe 2008).
Transmission of MTB appears to decrease sharply in a short time after initiation of
effective treatment (Dharmadhikari 2014). However, the absence of MTB growth in
culture is probably still the best indicator that patients are no longer contagious. For
pulmonary TB, initial weekly sputum microscopy and evaluation of MTB growth in
culture are useful (Schaberg 2022).

Treatment
Treatment of susceptible TB consists of a combination of the first-line drugs
rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB). RIF is
the most potent drug. Standard therapy consists of a two-month initiation phase
with RIF, INH, PZA, and EMB, followed by a four-month maintenance phase with
RIF and INH (WHO 2022b). Molecular DST (e.g., Xpert® MTB/Rif Ultra and Xpert®
MTB/XDR) with a diagnostic interval of approximately 2 hours should rapidly
provide information on the most important genotypic resistance mutations. DST for
additional second-line drugs from primary material (e.g., GenoType MTBDRplus
VER2.0 and MTBDRsl VER2.0, Deeplex Myc-TB) should be available within a few
days to adjust therapy as needed.
Since 2022, WHO recommends the combination of rifapentine, isoniazid, moxi-
floxacin, and pyrazinamide for four months, which was not inferior to the previous
standard regimen (WHO 2022b). As rifapentin is not approved by the EMA, this
regimen is challenging to implement in European practice. Results were replicated
in a subgroup of PLWH on efavirenz-based ART (Pettit 2022). Further, the rifampicin
dosing should be optimized, with up to 35 mg/kg appearing safe and more effective
(Boeree 2015). Dosages, side effects, and drug interactions of the major TB drugs are
listed in Table 1. The duration of therapy in PLWH is the same as in non-infected
persons (WHO 2022). There is insufficient evidence to justify prolonged therapy in
disseminated TB, except for CNS manifestations. There is a survival benefit for TB
meningitis when steroids are used in patients without HIV infection. Unfortunately,
data are lacking for co-infected individuals (Prasad 2016).
310 AIDS

Table 1: Anti-TB drugs, side effects, and interactions.

Drug Daily dose Common side effects Comments
Rifampicin (RIF) 10 mg/kg Hepatitis, anemia, Numerous interactions:
oral, IV > 50 kg: 600 mg lymphopenia, fever, (see Table 2), monitoring of
< 50 kg: 450 mg discoloration of urine, liver function, possibly safe
nephritis, rash up to 35 mg/kg (Boeree
2015), avoiding alcohol
consumption
Isoniazid (INH) 5 mg/kg, Hepatitis, polyneuropathy, Avoid d4T, ddI
oral, IV maximum psychosis Avoid alcohol consumption
300 mg/day Liver failure: replacement
combine with with levofloxacin
vitamin B6
Ethambutol (EMB) 15 mg/kg Neuritis optica (contra- Monthly screening of visual
oral, IV (15–20 mg/kg) indicated in the presence acuity and color vision
of pre-existing optic Antacids decrease
nerve damage) absorption
Pyrazinamide (PZA) 25 mg/kg Hepatitis, hyperuricemia, Treat hyperuricemia only
oral (20–30 mg/kg) gout if symptomatic
Amikacin (Am) 15 mg/kg Ototoxicity, nephrotoxicity Audiometry, monitoring of
IV/IM max 1 g/day renal function, avoid during
pregnancy
Cycloserine (CS) 15 mg/kg CNS side effects (in the Enhances CNS side effects
oral (0,75–1 g/day) first few weeks): of INH and protionamide
Dizziness, psychosis
Levofloxacin (LFX) 750–1,500 mg/day CNS side effects (headache, Not approved for children
oral, IV (15 mg/kg) dizziness, sleep disturbances),
Achilles tendon rupture (rare),
QT prolongation
Linezolid (LZD) 600 mg/day Frequent: thrombocytopenia, Mostly 600 mg
oral, IV anemia, polyneuropathy
Moxifloxacin (MFX) 400 mg/day See levofloxacin, acute liver Activity similar to
oral/IV failure (very rare) levofloxacin, 800 mg can
also be used if necessary
Prothionamide (PTO) 15 mg/kg Nausea, vomiting (especially Monitoring of liver values,
oral (0.75–1 g/day) with PAS), hepatotoxicity, if necessary, gradual dosage
CNS side effects
Rifabutin (RFB) 150–300 mg/day Hepatitis, anemia, lympho- Weaker CYP 450 inducer
oral or 3 x 150 mg/week penia, thrombocytopenia than RIF, therefore preferred
in combination Fever, urine discoloration, with ART (see Table 2)
with PI nephritis, uveitis, rash
Bedaquiline (BDQ) 400 mg 2 x daily Nausea, QT prolongation Rifampicin halves plasma
oral for 2 weeks, then levels, EFV reduces plasma
200 mg per day levels, in combination with
QT-prolonging drugs, ECG
monitoring, monitoring
liver values
Opportunistic infections (OI) 311

Table 1: Continuation
Drug Daily dose Common side effects Comments
Delamanid (DLM) 100 mg 2 x daily Nausea, vomiting, Not in combination with
oral dizziness, QT prolongation rifampicin
Clofazimine (CFZ) 100 mg/d Skin discoloration, pruritus, Combination with
oral photosensitivity, nausea, QT-prolonging drugs:
QT prolongation ECG monitoring
Avoid direct sunlight
Meropenem/ 1–2,000 mg Exanthema, nausea, Only active in combination,
amoxicillin- 3 x daily i.v. leukocytopenia, data still limited
clavulanic acid plus 125 mg thrombocytopenia
(MPM; AMX-CLV) clavulanic acid,
e.g., as amoxicillin/
clavulanic acid
875 mg+125 mg
Pretomanide Pretomanide In combination often Study data in combination
200 mg daily neuropathy and anemia with MXF, BDQ, and LZD
(initial dose 600 mg
recommended)
Paraamino- 4–6 g 2 x daily Nausea, diarrhea, vomiting
salicylic acid

Therapy of resistant tuberculosis (MDR/XDR-TB)

Resistance to RIF and INH defines MDR-TB (multidrug resistance) and requires
second-line drugs. If additional resistance to fluoroquinolones is present, pre-XDR
(extensively drug-resistant) TB is present; if additional resistance to linezolid or
bedaquiline is present, XDR-TB is present.
The treatment options for MDR/rifampicin-resistant TB (RR-TB) have changed con-
siderably in recent years. Ideally, therapy based on up-to-date drug susceptibility
testing should be initiated with at least four, preferably five, effective drugs. NAAT-
based methods and genome sequencing gain importance in resistance testing. Experts
should interpret sequencing results as there are still uncertainties about the extent
to which genotypic resistance is associated with phenotypic resistance.
Two clinical trials have documented high efficacy with significantly shorter dura-
tion of therapy of only six months and reduced toxicity with new combinations:
the combination of bedaquiline, linezolid, pretomanid (TB PRACTECAL) and
moxifloxacin for MDR-TB and bedaquiline, linezolid and pretomanid (ZeNIX-TB)
for pre-XDR/XDR-TB (Conradi 2022). Based on available data, WHO has recom-
mended using these treatment regimens since May 2022. The recommendation also
addresses PLWH despite low case numbers to date. In principle, expert advice is
recommended for MDR/XDR tuberculosis, and therapy should be carried out at an
experienced center.

Timing of ART and TB therapy

Three large clinical trials (SAPIT, CAMELIA, and STRIDE) have investigated the best
timing for ART initiation in TB (Abdool Karim 2011, Blanc 2011, Havlir 2011). In
particular, patients with low CD4 T-cell counts benefit from early initiation; those
with less than 50/µl should receive antiretroviral treatment no later than two weeks
after initiation of TB therapy (EACS 2022). However, in TB meningitis, even with
312 AIDS

low CD4 T-cells, a postponement of 8 weeks is reasonable (see below). Pregnant

women should also receive prompt antiretroviral treatment to avoid vertical trans-
mission.

Combination of ART and TB therapy

Under RIF-containing therapy, ART consists of efavirenz 600 or 400 mg daily, each
combined with TDF+FTC or TDF+3TC. Raltegravir 400 mg or 800 mg BID in com-
bination with TDF/FTC or TDF/3TC is considered an alternative, as is dolutegravir.
However, the latter requires a dose adjustment to 2 x 50 mg (EACS 2022). Based on
the ENCORE trial, efavirenz is often given as 400 mg daily. ART must be adjusted to
resistance levels. Table 2 shows the required dose adjustments for rifampicin and
rifabutin. Interactions are manifold, mainly due to RIF-associated induction of
cytochrome P450 3A4/5.

Table 2: Recommendations for co-administration of ART with rifampicin/rifabutin.

Drug Dose adjustment Comments
Lopinavir/r Rifabutin 150 mg daily only if no alternative is
If rifabutin is unavailable, available: hepatotoxicity,
lopinavir/r 400/400 mg 2 x daily diarrhea
(super-boosting) TDM recommended for PIs
Darunavir/r Rifabutin 150 mg daily
Atazanavir/r Rifabutin 150 mg daily
Efavirenz Rifampicin 600 mg 1 x daily TDM after 2 weeks
(probably also 400 mg safe)
Rifabutin 450 mg
Nevirapine No co-administration with rifampicin
Etravirine No co-administration with
rifampicin or rifabutin
Rilpivirine Rifabutin 300 mg daily and Rilpivirine levels drop
double the rilpivirine dose by 80%
Raltegravir 400 or 800 mg 2 x daily TDM for raltegravir
Elvitegravir/Cobicistat No co-administration with rifampicin,
with caution: rifabutin 150 mg daily
Dolutegravir Rifampicin 50 mg 2 x daily
Rifabutin 300 mg daily
Bictegravir No co-administration with
rifampicin and rifabutin
Cabotegravir oral Administration is possible with
rifabutin, not with rifampicin/rifapentine
Cabotegravir/ No co-administration with rifampicin,
rilpivirine rifabutin, rifapentine
NRTIs (incl. TAF) Standard ARV dosing for rifampicin Triple NRTI is not
and rifabutin recommended
Maraviroc Rifampicin 600 mg every 12 h AUC reduction 63%
Comment: There are no recommendations for dosage adjustment of rifampicin
Opportunistic infections (OI) 313

Rifabutin (150 mg/d) can also be combined with boosted PIs after dose adjustment.
However, increased neutropenias have been observed with atazanavir/r (Zhang 2011).
With the recommended rifabutin dose of 150 mg daily, watch out for possible uveitis
and/or neutropenia (EACS 2022). Tenofovir does not interact with RIF (Droste 2005),
and TAF 25 mg daily can probably be given with rifampicin. Efavirenz (standard
dose) can be combined with rifabutin (450 mg daily) (EACS 2022).
The INSPIRING trial showed good tolerability and efficacy of dolutegravir 2 x 50 mg
with rifampicin (Dooley 2019). NRTI-only therapy (AZT, ABC, 3TC ± TDF) may be
considered in the absence of alternatives and low viral load (< 100,000 copies/mL)
until therapy with RIF is completed. Rilpivirine is not recommended with rifabutin
and rifampicin. Etravirine may be given in combination with rifabutin 300 mg OD,
but not with rifampicin. Bedaquiline should not be combined with CYP3A4
inhibitors or inducers (efavirenz). Lopinavir/r increases bedaquiline levels but appears
to be safe. Dolutegravir and nevirapine are potential partners for bedaquiline.
Delamanid has few relevant interactions with antiretroviral agents but should not
be combined with rifampicin (Mallikaariun 2016), and pretomanid should not be
combined with efavirenz. In any case, regular consultation of the Liverpool Drug
Interactions Database ([Link]) is recommended.
The key to success is good adherence, hampered by the high tablet load and numer-
ous side effects. This is why WHO recommends DOT (directly observed therapy) for
all TB patients.

Immune Reconstitution Syndrome (IRIS)

When ART and TB therapy are started simultaneously, there is a high risk of TB-IRIS
(immune reconstitution inflammatory syndrome). TB-IRIS may occur in about 15%
of patients with severe immunodeficiency (Meintjes 2008). A distinction is made
between paradoxical and unmasking IRIS. In paradoxical IRIS, active TB initially
responds well to therapy but deteriorates within the first three months after ART
initiation with lymphadenopathy, pulmonary infiltrates, serous effusions, or CNS
symptoms. Differential diagnosis must exclude side effects, infections, poor adher-
ence, malignancies, and resistance. The cause is thought to be an exaggerated TH1
immune response against mycobacterial antigens (Bourgarit 2006). In unmasking
IRIS, active TB develops within three months, which was previously subclinical
(Meintjes 2008); symptoms are first triggered by immune reconstitution.
People with severe immunodeficiency should be monitored closely. Because of the
high IRIS-associated mortality in TB meningitis, ART should not be started until eight
weeks after initiating TB therapy (Törok 2011). ART and TB therapy should be
continued despite IRIS (EACS 2022). Steroids may be useful. In the only randomized
trial of IRIS to date, 1.5 mg/kg prednisolone for two weeks followed by 0.75 mg/kg
for an additional two weeks showed benefit (Meintjes 2010) in terms of inpatient
treatment days and outpatient resources. In a more recent study, steroids were
helpful, provided ART was started within 30 days of TB therapy initiation in case of
fewer than 100 CD4 T-cells/µl: 40 mg and then 20 mg prednisolone for two weeks
each reduced the incidence of TB IRIS by more than 50% (Meintjes 2019).

Side effects
For the most common side effects, see Table 1. INH should always be given with
vitamin B6 (pyridoxine) to prevent peripheral polyneuropathy. Color vision should
be assessed before and during therapy with EMB because of possible optic nerve
damage. EMB and PZA must be dose-adjusted in renal insufficiency. Liver injury is
common and usually resolves after discontinuation (drug-induced liver injury, DILI).
Management can follow the South African HIV Society guidelines (Jong 2013). Liver
314 AIDS

enzymes, creatinine, electrolytes, and blood counts should be monitored during TB

therapy (initially weekly, later monthly). Hyperuricemia often occurs under PZA but
usually does not require treatment. Mild polyarthralgia can be treated with
allopurinol or nonsteroidal analgesics.
In the treatment of M/XDR-TB, linezolid is associated with high toxicity in a dose-
dependent manner. Given peripheral neuropathies, anemias, and optic nerve
neuropathies, treated patients should be screened regularly for side effects and
managed in experienced centers. Arthralgias can also be induced by rifamycins. The
combination of nephrotoxic substances should be avoided. Current guidelines only
allow amikacin as an aminoglycoside, with close monitoring of renal function (Brust
2018). In addition, monthly audiometry should be performed.
Based on the DELIBERATE trial, the administration of bedaquiline and delamanid
with dolutegravir appears relatively safe (Dooley 2019). Both can cause QTc
prolongation, which requires regular ECG monitoring, especially when combined
with fluoroquinolones and clofazimine (WHO 2019). Pretomanid does not cause QT
time prolongation and can be administered with INSTIs. More data are needed,
particularly on the toxicity of the new short regimens for MDR/XDR-TB. Affected
individuals with severe side effects should be hospitalized, and TB medications should
be discontinued until adverse effects have resolved.
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316 AIDS

Atypical mycobacteriosis (MAC)

Atypical mycobacterioses are most often understood as synonymous with
Mycobacterium avium complex (MAC) infections. MAC is by far the most common
pathogen; however, a variety of other atypical mycobacteria can cause similar clinical
pictures, such as M. celatum, M. kansasii, M. xenopi, or M. genavense. MAC bacteria
can be detected in diverse animal species, soil, water, and food. Exposure prophy-
laxis is not possible, and isolating affected patients is not advisable. At the same
time, MAC may be detectable in the sputum or stool of asymptomatic individuals
(colonization); almost only patients with less than 50 CD4 T-cells/µl become ill
(Horsburgh 1999). Meanwhile, the infection is rare in industrialized countries
(Karakousis 2004). The clinical picture has changed significantly – the formerly
almost always chronic disseminated disease, found in many “wasting” cases, has
become a primarily localized infection, which occurs under ART almost only in the
course of an immune reconstitution syndrome. However, the disease may remain
threatening and show very unusual manifestations.

Clinic
Symptoms of disseminated MAC infection are non-specific. Fever, weight loss, and
diarrhea with less than 100 CD4 T-cells/µl should always suggest atypical mycobac-
teriosis. Abdominal pain also occurs. Far more common than disseminated are now
localized MAC infections, especially in the form of lymph node abscesses. We have
seen abscesses in cervical, inguinal, and abdominal lymph nodes, some forming
fistulas and healing very slowly after surgical opening. Any abscess developing during
ART (in severe immunodeficiency) is suspicious for MAC! Osteomyelitides are also
possible as localized forms, especially in the vertebral bodies and joints (seen: knee,
hand, fingers).

Diagnostics
Diagnosis is difficult in the disseminated form. Blood cultures (heparin blood) should
always be sent to a reference laboratory. Although atypical mycobacteria usually grow
more rapidly than TB bacteria, it may take weeks to culture and differentiate from
tubercle bacilli. If anemia is present, bone marrow aspiration is often successful. If
detected in stool or sputum, but also in BAL, there is usually only colonization: in
the absence of general symptoms, therapy can be dispensed. This also applies to
Mycobacterium kansasii (Kerbiriou 2003). In the laboratory, alkaline phosphatase (AP)
is typically elevated – high AP in the presence of poor immune status is always sus-
picious for MAC. MAC infection should also be considered in the presence of anemia
and constitutional symptoms. Cytopenia, especially anemia, often indicates bone
marrow involvement. Sonographically, the liver and spleen are enlarged. Lymph
nodes are also often enlarged but are notable less for their size than numbers (Gordin
1997). Differential diagnoses include TB or lymphoma. In the localized forms, mate-
rial should always be obtained directly; detection from abscess punctate is usually
successful.

Treatment
The treatment of a culturally proven MAC infection is complex. Analogous to TB,
one drug alone is not sufficient. Since 1996, many have favored a combination of
macrolide (clarithromycin or azithromycin), rifabutin, and ethambutol (Shafran
1996). This used to be given for life; now, it should be continued for at least six
Opportunistic infections (OI) 317

months until the CD4 T-cell increase exceeds 100/µl on ART. After some data sug-
gested that rifabutin could be omitted (Dunne 2000), the randomized ACTG 223
trial showed a survival benefit with the triple combination of clarithromycin,
rifabutin, and ethambutol over clarithromycin and ethambutol or rifabutin, and
mortality rates were halved in the triple arm (Benson 2003).
However, rifabutin should be discontinued after several weeks and clinical improve-
ment because of its large interaction potential. For clarithromycin, the dose should
not exceed 2 x 500 mg. In two randomized trials, the number of deaths was
significantly increased at higher doses for unexplained reasons (Chaisson 1994, Cohn
1999). Equally effective as clarithromycin is azithromycin, which also interacts less
with cytochrome p450 enzymes (Ward 1998).
Therapy should be monitored in disseminated disease by regular blood cultures,
which should be negative after 8 weeks at the latest. In localized forms, the response
is better assessed clinically. Any MAC therapy carries a high potential for side effects
and interactions. Concomitant medications, including ART, must be closely reviewed
– it is not uncommon for dose adjustments to be required, and contraindications
exist (see chapter Drug). Reserve drugs such as amikacin or levofloxacin are needed
only in exceptional cases. In all atypical mycobacterioses, the resistance situation
should be investigated.
In localized MAC disease, we usually stop therapy when the abscess resolves – usually,
this takes a few months. In individual cases, steroids may be helpful temporarily.
However, there are no separate recommendations in localized MAC infections.

Therapy/prophylaxis of MAC infections (unless otherwise indicated, daily doses)

Acute therapy
Therapy of choice Clarithromycin + Klacid retard® 2 x 1 tab. at 500 mg plus
Ethambutol + Myambutol® 1 x 3 tab. at 400 mg plus
possibly Rifabutin Mycobutin® 1 x 2 tab. at 150 mg
Alternative Azithromycin + Ultreon® 1 x 1 tab. at 600 mg plus
Ethambutol + Myambutol® 1 x 3 tab. at 400 mg plus
possibly Rifabutin Mycobutin® 1 x 2 caps. at 150 mg
Maintenance therapy Like acute therapy but without rifabutin
Discontinuation from > 100 CD4 T-cells/μl > 6 months
Primary prophylaxis If CD4 T-cells are persistently below 50/μl, consider
Discontinuation from > 100/μl > 3 months
Therapy of choice Azithromycin Ultreon® 1 x 2 tab. at 600 mg/week
Alternative Clarithromycin Klacid retard® 2 x 1 tab. at 500 mg

Prophylaxis
In the United States, for clarithromycin, azithromycin, and rifabutin, large placebo-
controlled trials have shown that primary prophylaxis significantly reduces MAC
mortality in severely immunocompromised individuals (Havlir 1996, Nightingale
1992, Pierce 1996, Oldfield 1998). In Europe, MAC infections are less common. Partly
because of concerns about compliance and resistance developments, few individuals
in Europe receive primary MAC prophylaxis for this reason. Azithromycin should
be considered from below 50 cells/µl if ART options are limited. Weekly adminis-
tration is patient-friendly and, according to a Cochrane analysis, the prophylaxis of
choice (Uthman 2013).
318 AIDS

Primary prophylaxis and maintenance therapies (see above) can be discontinued if

CD4 T-cells exceed 100/µl (El Sadr 2000, Shafran 2002, Aberg 2003). Partial viral
suppression may be sufficient for MAC-specific immune reconstitution (Havlir 2000).
Cures under immune reconstitution are possible (Aberg 1998).
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seminated Mycobacterium avium complex disease in AIDS patients: excess mortality associated with high-dose
clarithromycin. Clin Infect Dis 1999, 29:125-33.
Dunne M, Fessel J, Kumar P, et al. A randomized, double-blind trial comparing azithromycin and clarithromycin
in the treatment of disseminated Mycobacterium avium infection in patients with HIV. Clin Infect Dis 2000,
31:1245-52.
El-Sadr WM, Burman WJ, Grant LB, et al. Discontinuation of prophylaxis for Mycobacterium avium complex
disease in HIV-infected patients responding to ART. N Engl J Med 2000, 342:1085-92.
Gordin FM, Cohn DL, Sullam PM, Schoenfelder JR, Wynne BA, Horsburgh CR Jr. Early manifestations of dis-
seminated Mycobacterium avium complex disease: a prospective evaluation. J Infect Dis 1997, 176:126-32.
Havlir DV, Dube MP, Sattler FR, et al. Prophylaxis against disseminated Mycobacterium avium complex with
weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996, 335:392-8.
Havlir DV, Schrier RD, Torriani FJ, et al. Effect of potent antiretroviral therapy on immune responses to
Mycobacterium avium in HIV-infected subjects. J Infect Dis 2000, 182:1658-63.
Horsburgh CR Jr. The pathophysiology of disseminated Mycobacterium avium complex disease in AIDS. J Infect
Dis 1999, Suppl 3:S461-5.
Karakousis PC, Moore RD, Chaisson RE. Mycobacterium avium complex in patients with HIV infection in the era
of highly active antiretroviral therapy. Lancet Infect Dis 2004, 4:557-65.
Kerbiriou L, Ustianowski A, Johnson MA, Gillespie SH, Miller RF, Lipman MC. HIV type 1-related pulmonary
Mycobacterium xenopi infection: a need to treat? Clin Infect Dis 2003; 37: 1250-4.
Nightingale SD, Byrd LT, Southern PM, et al. Incidence of Mycobacterium avium-intracellulare complex bac-
teremia in HIV-positive patients. J Infect Dis 1992, 165:1082-5.
Oldfield EC 3rd, Fessel WJ, Dunne MW, et al. Once weekly azithromycin therapy for prevention of Mycobacterium
avium complex infection in patients with AIDS: a randomized, double-blind, placebo-controlled multi-center
trial. Clin Infect Dis 1998, 26:611-9.
Pierce M, Crampton S, Henry D, et al. A randomized trial of clarithromycin as prophylaxis against disseminated
Mycobacterium avium complex infection in patients with advanced AIDS. N Engl J Med 1996, 335:384-91.
Shafran SD, Singer J, Zarowny DP, et al. A comparison of two regimens for the treatment of Mycobacterium avium
complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine,
and ciprofloxacin. N Engl J Med 1996, 335:377-83.
Shafran SD, Mashinter LD, Phillips P, et al. Successful discontinuation of therapy for disseminated Mycobacterium
avium complex infection after effective antiretroviral therapy. Ann Intern Med 2002;137:734-7.
Uthman MM, Uthman OA, Yahaya I. Interventions for the prevention of mycobacterium avium complex in adults
and children with HIV. Cochrane Database Syst Rev 2013 Apr 30;4:CD007191.
Ward TT, Rimland D, Kauffman C, Huycke M, Evans TG, Heifets L. Randomized, open-label trial of azithromycin
plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia
in patients with HIV infection. Clin Infect Dis 1998, 27:1278-85.
Opportunistic infections (OI) 319

Herpes simplex
Herpes simplex virus (HSV) infections are a common problem, and chronic courses
are possible, especially in cases of significant immunodeficiency (below 100 CD4
T-cells/µl). There are two viruses:
HSV-1 is transmitted through mucosal contact (kissing) and causes itchy perioral
blisters on the lips, tongue, palate, or oral mucosa.
HSV-2 is sexually transmitted and causes herpetiform lesions on the penis, vagina,
vulva, and anus. The lesions significantly increase the risk of transmission of HIV
(Freeman 2006, see Prevention).
In severe cases, other organs may be affected. These include esophagus (ulcers), CNS
(encephalitis), eye (keratoconjunctivitis, uveitis), and respiratory tract (pneumonitis,
bronchitis). In these cases, and if persistent for more than four weeks, HSV infection
is considered AIDS-defining.

Clinic, diagnostics
The vesicles itch and burn. Oral involvement may impair food intake. In genital or anal
infestation (proctitis!), urination and defecation can be painful. Extensive lesions are
possible in severe immunodeficiency. Regional lymph nodes are often swollen.
The clinic of disseminated herpes infections depends on the organs affected.
In the case of oral, genital, or perianal infestation, visual diagnosis is often sufficient.
In case of doubt, a swab can be taken, which must be transported quickly to the
laboratory in a virus culture medium. Resistance testing in refractory lesions is also
possible. Organ manifestations are usually diagnosed histologically. In HSV
encephalitis, diagnosis is difficult because CSF often is not helpful. Serologies are
only informative if negative (rare), making HSV infection unlikely.

Treatment
Any therapy is more effective the sooner it is started. If the immune status is good
and the lesions are only discrete, topical administration of acyclovir may be sufficient.
Penciclovir cream (Vectavir®) is probably as effective (Chen 2000) and reportedly
somewhat less irritating but significantly more expensive.
Systemically, the nucleoside analog acyclovir remains the drug of choice. It inhibits
the DNA polymerase of herpes viruses. Resistance is rare, even 40 years after market
introduction (Levin 2004). Acyclovir is well tolerated and effective against HSV-1
and HSV-2. Intravenous treatment should be used in severe cases and organ
manifestations. Because CNS levels are lower than in plasma, the dose should be
increased in the presence of encephalitis. Renal values should be monitored during
intravenous administration of acyclovir.
Equivalent alternatives are valaciclovir and famciclovir (Ormrod 2000, Conant 2002),
which need to be taken less often with better oral availability but are more expen-
sive and not approved in immunosuppression. They should be used only when
acyclovir is not effective. We have had good experience with famciclovir, a prodrug
of penciclovir (Vinh 2006). For uncomplicated genital lesions, two days of 500 mg
of famciclovir may be sufficient, provided there is no immunodeficiency (Bodsworth
2008). Brivudine (approved only for HZV) should no longer be used.
320 AIDS

Treatment/prophylaxis of HSV infection (daily doses)

Acute therapy Duration: 7–14 days
First choice Acyclovir Aciclovir ratiopharm® 5 x 1 tablets of 400 mg
Severe cases Aciclovir p.i.® 3 x ½–1 amp. of 500 mg (3 x 5–10 mg/kg) IV
Alternatives Valaciclovir Valtrex® 3 x 2 tablets at 500 mg
Alternatives Famciclovir Famvir® 3 x 1 tablet at 250 mg
Prophylaxis Not recommended

In exceptions, especially in refractory lesions, therapy with foscarnet for several weeks
may be useful. New drugs such as pitrelivir, which inhibits another enzyme of herpes
viruses, helicase, were quite promising in initial larger studie, but are not yet approved
(Wald 2014+2016). Phase III trials began in 2020. The same is true for therapeutic
vaccines, and several companies have initiated clinical studies (Bernstein 2017).
In the case of painful mucocutaneous lesions, a local anesthetic is useful.
Unfortunately, the proven tetracaine solution (Herviros®) has been withdrawn from
the market, but some pharmacies can prepare something comparable.

Prophylaxis
Primary prophylaxis with HSV drugs is not usually recommended. An early meta-
analysis, according to which the risk of both HSV and HZV disease decreased by
more than 70% and even mortality decreased under acyclovir (Ioannidis 1998), is
nowadays probably to be put into perspective. For persistent recurrences, low
continuous doses of acyclovir or valaciclovir (DeJesus 2003, Warren 2004) may be
useful. However, sub-clinical HSV reactivations are unlikely to be adequately
prevented in this way (Johnston 2012). Vaccination studies are still in the early stages
and are only partially protective (Belshe 2012).

Interactions between HIV and herpes simplex

Genital HSV infections increase the risk of contracting HIV almost threefold (Freeman
2006, see Prevention). In recent years, extensive randomized studies showed that HSV
therapy interestingly also reduces the HIV viral load: with acyclovir by 0.33 logs
(Ludema 2011), on higher doses or valacyclovir even slightly more (Mugwanya 2011,
Perti 2013, Vanpouille 2015). Even the progression of HIV infection can be slowed
(Reynolds 2012). Although the antiviral effect clearly cannot prevent HIV transmis-
sion, these observations have breathed new life into HSV and especially acyclovir
therapy (Vanpouille 2009+2015). An “ancient drug” such as acyclovir has become
interesting again: it may be possible to develop new derivatives based on it, whose
antiviral potency is better with good tolerability with respect to HIV.

Literature
Belshe RB, Leone PA, Bernstein DI, et al. Efficacy results of a trial of a herpes simplex vaccine. N Engl J Med 2012,
366:34-43.
Bernstein D, Wald A, Warren T, et al. Therapeutic Vaccine for Genital Herpes Simplex Virus-2 Infection: Findings
From a Randomized Trial. J Infect Dis. 2017, 215:856-64.
Bodsworth N, Bloch M, McNulty A, et al. 2-day versus 5-day famciclovir as treatment of recurrences of genital
herpes: results of the FaST study. Short-Course Herpes Therapy Study Group. Sex Health 2008, 5:219-25.
Chen XS, Han GZ, Guo ZP, et al. A comparison of topical application of penciclovir 1% cream with acyclovir
3% cream for treatment of genital herpes: a randomized, double-blind, multicentre trial. Int J STD AIDS 2000,
11:568-73.
Conant MA, Schacker TW, Murphy RL, et al. Valaciclovir versus aciclovir for herpes simplex virus infection in
HIV-infected individuals: two randomized trials. Int J STD AIDS 2002, 13:12-21.
Opportunistic infections (OI) 321

DeJesus E, Wald A, Warren T, et al. Valacyclovir for the suppression of recurrent genital herpes in HIV-infected
subjects. J Infect Dis 2003; 188: 1009-16.
Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus two infection increases
HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006,
20:73-83.
Ioannidis JP, Collier AC, Cooper DA, et al. Clinical efficacy of high-dose acyclovir in patients with HIV infection:
a meta-analysis of randomized individual patient data. J Infect Dis 1998, 178:349-59.
Johnston C, Saracino M, Kuntz S, et al. Standard-dose and high-dose daily antiviral therapy for short episodes of
genital HSV-2 reactivation: three randomised, open-label, cross-over trials. Lancet 2012, 379:641-7.
Levin MJ, Bacon TH, Leary JJ. Resistance of herpes simplex virus infections to nucleoside analogues in HIV-infected
patients. Clin Infect Dis 2004, 39 Suppl 5:S248-57.
Ludema C, Cole SR, Poole C, Chu H, Eron JJ. Meta-analysis of randomized trials on the association of prophy-
lactic acyclovir and HIV-1 viral load in individuals coinfected with herpes simplex virus-2. AIDS 2011, 25:1265-9.
Mugwanya K, Baeten JM, Mugo NR, et al. High-dose valacyclovir HSV-2 suppression results in greater reduction
in plasma HIV-1 levels compared with standard dose acyclovir among HIV-1/HSV-2 coinfected persons: a ran-
domized, crossover trial. J Infect Dis 2011, 204:1912-7.
Ormrod D, Scott LJ, Perry CM. Valaciclovir: A review of its long-term utility in the management of genital herpes
simplex virus and cytomegalovirus infection.
Perti T, Saracino M, Baeten JM, Johnston C, Diem K, Ocbamichael N, Huang ML, Selke S, Magaret A, Corey L,
Wald A. High-dose valacyclovir decreases plasma HIV-1 RNA more than standard-dose acyclovir in persons coin-
fected with HIV-1 and HSV-2: a randomized crossover trial. J AIDS 2013, 63:201-8.
Reynolds SJ, Makumbi F, Newell K, et al. Effect of daily aciclovir on HIV disease progression in individuals in
Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: a randomised, double-blind placebo-con-
trolled trial. Lancet Infect Dis 2012, 12:441-8.
Safrin S. Treatment of acyclovir-resistant herpes simplex virus infections in patients with AIDS. J Acquir Immune
Defic Syndr 1992, Suppl 1:S29-32.
Vanpouille C, Lisco A, Margolis L. Acyclovir: a new use for an old drug. Curr Opin Infect Dis 2009, 22:583-7.
Vanpouille C, Lisco A, Grivel JC, et al. Valacyclovir Decreases Plasma HIV-1 RNA in HSV-2 Seronegative Individuals:
A Randomized Placebo-Controlled Crossover Trial. Clin Infect Dis 2015, 60:1708-14.
Vinh DC, Aoki FY. Famciclovir for the treatment of recurrent genital herpes: a clinical and pharmacological per-
spective. Expert Opin Pharmacother 2006, 7:2271-86.
Warren T, Harris J, Brennan CA. Efficacy and safety of valacyclovir for the suppression and episodic treatment of
herpes simplex virus in patients with HIV. Clin Infect Dis 2004, 39 Suppl 5:S258-66.
Wald A, Corey L, Timmler B, Magaret A, et al. Helicase-primase inhibitor pritelivir for HSV-2 infection. N Engl J
Med 2014, 370:201-10.
Wald A, Timmler B, Magaret A et al. Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding
in Patients With Frequent Recurrences: A Randomized Clinical Trial. JAMA 2016, 316:2495-2503.
322 AIDS

Herpes zoster
Zoster is the reactivation of a previous infection with varicella (chickenpox), which
persists in the spinal ganglia for life. Zoster episodes are observed even with relatively
good immune status and, despite recent declines in incidence (Moanna 2013), are
still common enough to be considered an indicator disease for HIV infection.
Typically, zoster presents as IRIS (Martinez 1998). With increasing immunodeficiency,
the risk of generalization increases (Zou 2022). In addition to the typical involve-
ment of one or more dermatomes, there is also complicated involvement of the eye
(when the trigeminal branch is affected, “zoster ophthalmicus” with involvement
of the cornea) and ear (“zoster oticus”). Necrotizing zoster retinitis is feared. Other
complications include meningoencephalitis, myelitis, and involvement of other
cranial nerves (Brown 2001, Zou 2022).

Clinic
There are often prodromes with headache, feeling of sickness and photophobia,
which are rarely accompanied by fever. At the affected sites, there is often initially
only hypersensitivity, which changes to itching and/or pain within a few hours or
days. The pain may precede the skin lesions by several days. These often present as
segmental (always unilateral!) redness with herpetiform blisters in the area of one
or more dermatomes. The lesions are ulcerative, often hemorrhagic, and gradually
dry up. They should be kept dry and clean to prevent bacterial superinfection.
Unpleasant pain syndromes remain in 20%, especially when multiple dermatomes
are affected. Such zoster neuralgia can be assumed if the pain persists for more than
a month (Gnann 2002).

Diagnostics
In cutaneous cases, visual diagnosis is usually sufficient. However, the diagnosis may
be misjudged in atypical localization (extremities!) and complicated cases. If you are
unsure you can send a swab from a blister to the laboratory. An immunofluorescence
assay is probably more reliable. VZV encephalitis can only be detected by CSF diag-
nostics or PCR. In case of peracute hearing disorders, zoster oticus should be con-
sidered, which is not necessarily recognizable from the outside – either look into the
ear yourself or go to the ENT department! For visual disturbances – quickly go to the
ophthalmology department!

Treatment
Monosegmental zoster can be treated on an outpatient basis with oral acyclovir.
Rapid onset is essential. Systemic therapy is always required, and dosages are higher
than for HSV. Drying up the lesions is accelerated by a zinc mixture, which simul-
taneously relieves the pain: put on gloves! Initially, the lesions are highly infectious,
and unvaccinated persons without a history of chickenpox, especially pregnant
women, should avoid contact with persons with herpes zoster. Analgesics (novamin-
sulfone, tramadol) should not be spared. Complicated, multisegmental, or facial
zoster episodes are usually a case for intravenous therapy. Valaciclovir and famci-
clovir are alternatives to acyclovir. Whether zoster neuralgia occurs less frequently
remains controversial (Li 2009, McDonald 2011). These agents have hardly been
tested for HIV, are not approved for use in immunocompromised patients, and are
significantly more expensive. Acyclovir resistance is rare (Saint-Leger 2001) and can
Opportunistic infections (OI) 323

be treated with foscarnet. Brivudine (Zostex®) should no longer be used because of

unclear deaths (especially in combination with chemotherapies).
The therapy of zoster neuralgia is complex. Carbamazepine or gabapentin is only
partially effective, and steroids are not useful (Gnann 2002). Lidocaine patches
(Versatis®), applied to the painful area, have been approved in Europe since 2007.
Due to possible local skin irritation, the lesions should have resolved. The effect often
takes days to appear (Garnock-Jones 2009).

Prophylaxis
Live varicella vaccination with Zostavax® has since been replaced by a likely more
effective vaccine (Shingrix®). Shingrix® was approved in 2018 for HIV patients over
age 50. This also applies to those with a history of zoster, although data are scarce
here. Some safety interval (6 months) should be maintained from a zoster episode.
Two vaccinations 2–6 months apart are necessary. Otherwise, vaccination success is
compromised. Shingrix® causes relatively frequent local reactions and, although
primarily moderate, myalgias, fatigue, and headache (Review: Short 2019).
In case of negative serology and varicella exposure (highly infectious!), hyper-
immunoglobulin (2 mg/kg IV) can be given. Low-dose continuous therapy is only
considered for persistent recurrences. In a randomized trial, zoster episodes were
prevented by acyclovir (Barnabas 2016).

Treatment/prophylaxis of VZV infection (daily doses)

Acute therapy Duration: At least 7 days
First choice Acyclovir Aciclostad® 5 x 1 tablets at 800 mg
Severe cases Aciclovir p.i.® 3 x 1–2 amp. of 500 mg (3 x 10 mg/kg) IV
Alternatives Valaciclovir Valtrex® 3 x 2 tablets at 500 mg
Alternatives Famciclovir Famvir® 3 x 2 tablets at 250 mg
Prophylaxis Not recommended

Literature
Barnabas RV, Baeten JM, Lingappa JR. Acyclovir Prophylaxis Reduces the Incidence of Herpes Zoster Among HIV
Individuals. JID 2016;213:551-5.
Brown M, Scarborough M, Brink N, et al. Varicella zoster virus-associated neurological disease in HIV-infected
patients. Int J STD AIDS 2001, 12:79-83.
Garnock-Jones KP, Keating GM. Lidocaine 5% medicated plaster: a review of its use in postherpetic neuralgia.
Drugs 2009, 69:2149-65.
Li Q, Chen N, Yang J, et al. Antiviral treatment for preventing postherpetic neuralgia. Cochrane Database Syst
Rev 2009, 2: CD006866.
Martinez E, Gatell J, Moran Y, et al. High incidence of herpes zoster in patients with AIDS soon after therapy with
PIs. CID 1998, 27:1510-3.
McDonald EM, de Kock J, Ram FS. Antivirals for management of herpes zoster including ophthalmicus: a sys-
tematic review of high-quality randomized controlled trials. Antivir Ther 2012, 17:255-64.
Moanna A, Rimland D. Decreasing incidence of herpes zoster in the highly active antiretroviral therapy era. Clin
Infect Dis 2013, 57:122-5.
Saint-Leger E, Caumes E, Breton G, et al. Clinical and virologic characterization of acyclovir-resistant varicella-
zoster viruses isolated from 11 patients with AIDS. Clin Infect Dis 2001, 33:2061-7.
Short MD, Fergus C. Which patients should receive the herpes zoster vaccine? JAAPA 2019, 32:18-20.
Zou J, Krentz HB, Lang R, et al. Seropositivity, Risks, and Morbidity From Varicella-Zoster Virus Infections in an
Adult PWH Cohort From 2000-2020. Open Forum Infect Dis 2022, 9(8):ofac395.
324 AIDS

Progressive multifocal leukoencephalopathy

PML is a severe demyelinating disease of the central nervous system. It is caused by
the JC virus (JCV), a simply constructed polyomavirus distributed worldwide. JCV
was named after the initials of the patient John Cunningham, from whom it was
first isolated in 1971 (Major 1992). Thus, JC has nothing to do with Jakob-Creutzfeldt
syndrome, as is often erroneously assumed. Given worldwide seroprevalence rates
of up to 80%, latent persistent infection with a normally apathogenic JCV archetype
is assumed. Kidney and bone appear to be important reservoirs. Only when the
cellular immune response is impaired, reactivation reactivation or transformation of
the archetype into the JCV that ultimately triggers PML occur. The difference between
archetype and PML-JCV lies in the non-coding regulatory region of the viral DNA.
Since this region looks different in each PML case, it is assumed that the pathogenic
JCV strains are not transmitted but evolve in the respective host – over the years –
from the apathogenic variants (Pavlovic 2015).
It seems inevitable that JCV enters the CNS via leukocytes and primarily affects oligo-
dendrocytes and, thus, the myelin sheath cells. Their destruction is macroscopically
manifested as multifocal demyelination. The white matter of the cerebral hemi-
spheres is predominantly affected, but also the cerebellum and partly the gray matter.
PML is a classic opportunistic infection. It can occur in hematologic diseases and
during therapy with monoclonal antibodies such as rituximab, efalizumab, and espe-
cially natalizumab (Misbah 2017). However, people living with HIV are still the most
commonly affected.
Severe immunodeficiency is common but not obligatory – CD4 T-cells are below
100/µl at manifestation in about 75% but above 200 CD4 T-cells/µl in 5–10%
(Gasnault 2008). The decline in incidence is not as steep as for other OIs; it is about
one-third from the pre-ART era (Engsing 2009). After cerebral toxoplasmosis, PML
is the second most common neurological OI in HIV (Antinori 2001).
The prognosis used to be very poor without ART – the time from first symptoms to
death was between 3 and 6 months. In most cases, the patients died of secondary
complications after being bedridden for weeks. Under ART, slower courses and even
complete remissions are possible (Albrecht 1998). In 1,427 PML patients in France,
one-year survival increased from 20% before 1996 to 54% in 1996–2004 (Gasnault
2008). However, relatively lower rates have been reported in Spain or Denmark (Falco
2008, Engsing 2009). Complete remissions are most likely to be observed in inflam-
matory PML in the setting of IRIS (Du Pasquier 2003, Hoffmann 2003, Tan 2009).
The level of CD4 T-cells and the strength of the JCV-specific immune response are
of prognostic relevance; in contrast, the level of JCV viral load does not play a role
(Khanna 2009, Marzocchetti 2009). PML remains the OI with the highest mortality
today (ART-CC 2009).

Clinic
The clinic offers a broad spectrum due to the differently localized demyelinating
foci, but it still shows some characteristics. For example, in addition to cognitive dis-
orders ranging from mild concentration disorders to dementia, focal neurological
deficits are typical. Most common are mono- or hemiparesis, language deficits, and
visual deficits – we have seen several cases of blindness. The deficits may begin as
discrete coordination deficits and rapidly progress to significant disability. Epileptic
seizures are possible. Sensory disturbances, fever, and headache are rare and are more
suggestive of cerebral toxoplasmosis.
Opportunistic infections (OI) 325

Diagnostics
If there is a clinical suspicion of PML, this should be objectified quickly. CCT shows
the (hypodense) lesions only inadequately. MRI is much more sensitive in terms of
both number and size of lesions. It reveals mostly signal-intense foci in T2 weight-
ing and in the FLAIR sequence, which are hypointense in T1 weighting and usually
remain without gadolinium enhancement or mass effect. However, inflammatory
courses with sometimes marked enhancement are possible under ART (see immune
reconstitution syndrome). Typically, the gray matter is spared – this is, after all, a
“leuko”-encephalopathy. The lesions are almost always asymmetric.
Differentiation from cerebral toxoplasmosis or lymphoma is usually possible with
MRI. The vast, planar lesions over an entire hemisphere often seen in textbooks are
not obligate. All PML starts small – discrete, localized, solitary lesions do not preclude
the diagnosis. PML can be localized anywhere in the brain without predilection sites.
Foci are often parieto-occipital or periventricular, but the cerebellum may also be
affected. Differentiation from HHV-6 infection (Caserta 2004) or HIV-related
leukoencephalopathy (Langford 2002) is challenging.
Therefore, the clinical radiological diagnosis is not conclusive. An examination of
the cerebrospinal fluid is essential. Here, the nonspecific signs of inflammation are
usually absent, provided no coinfections exist. However, the total protein is usually
slightly elevated. Conversely, pleocytosis is rarely present, and more than 100/3 of
cells tend to argue against PML. CSF should be tested for JCV or sent to a laboratory
experienced in JCV. Newer PCR techniques have a sensitivity of about 80% with a
specificity of well over 90%.
The diagnosis is very likely in case of clinical radiological suspicion and positive
JCV-PCR. A brain biopsy is then unnecessary. However, a negative PCR does not
exclude PML with certainty. The level of JCV viral load varies widely and does not
correlate with the extent of lesions (Eggers 1999, Garcia 2002, Bossolasco 2005).
Many people with PML have low or undetectable JCV viral load in CSF on ART
(Bossollasco 2005). Here, stereotactic brain biopsy may still be necessary in individ-
ual cases. A sophisticated diagnostic algorithm has been published (Berger 2013).

Treatment
To date, there is no effective therapy. Foscarnet, interferon, immunostimulators,
steroids, and chemotherapies with camptothecin/topotecan or cytosine arabinoside
(Hall 1998) are ineffective. Even the nucleotide analog cidofovir, approved for CMV
retinitis and initially attributed positive effects, showed no clinical benefit in a meta-
analysis of 370 patients (De Luca 2008).
The serotonergic receptor 5HT2AR is a receptor for JC viruses to infect human glial
cells (Elphick 2004); thus, the blockade could be a therapeutic target. Case studies
exist for neuroleptics such as risperidone and mirtazapine that block serotonergic
receptors (Verma 2007, Focosi 2008, Cettomai 2009). Controlled studies are lacking.
Mefloquine, which was already held in hope after in vitro data (Brickelmeier 2009)
and positive case reports, failed to provide any evidence of an effect in a random-
ized trial (Clifford 2013). Another approach is pembrolizumab, which showed some
effect as a checkpoint inhibitor in a small uncontrolled case series (Cortese 2019).
Most case reports are published in HIV-negative cases (review: Corey 2022).
However, many experts are currently rather pessimistic about effective PML thera-
pies in the coming years (Pavovic 2015, Du Pasquir 2019), not only because of the
lack of animal models, the rarity of the disease, and the rapid progression of primarily
comorbid patients, which usually make controlled trials impossible – it also remains
326 AIDS

questionable whether systemic therapies will be able to reach concentrations to stop

the extraordinarily high replication of JCV in the brain which is seen in patients
with PML.
It remains an absolute priority to optimize ART in every PML. Restoration of the
JCV-specific immune response is a crucial determinant of outcome (Khanna 2009,
Marzocchetti 2009, Gasnault 2011). Numerous research groups have confirmed our
early observation (Albrecht 1998) that prognosis improves significantly with ART)
(Clifford 1999, Berenguer 2003, Khanna 2009, Gasnault 2011). In view of an in vitro
demonstrated synergism of HIV and JCV, HIV should be maximally suppressed. While
progressive courses are also possible, ART remains the only hope. The common
opinion is that primarily antiretrovirals should be used that can penetrate CNS
(see chapter Neurology). This has not been proven, nor has the use of intensive ART
regimens (Gasnault 2011).

Therapy/prophylaxis of PML
Acute therapy
ART The main goal is maximum HIV suppression and immune reconstitution!
Integrate substances that penetrate CNS if possible
Experimental Nothing to recommend outside of trials, possibly risperidone, mirtazapine,
possibly pembrolizumab as a clinical cure trial?
Prophylaxis Not available. Exposure prophylaxis is also not available

Literature
Albrecht H, Hoffmann C, Degen O, et al. HAART significantly improves the prognosis of patients with HIV-asso-
ciated progressive multifocal leukoencephalopathy. AIDS 1998, 12:1149-1154.
Antinori A, Ammassari A, Giancola ML, et al. Epidemiology and prognosis of AIDS-associated progressive multi-
focal leukoencephalopathy in the HAART era. J Neurovirol 2001, 7:323-8.
Antiretroviral Therapy Cohort Collaboration (ART-CC). Variable impact on mortality of AIDS-defining events
diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal. Clin
Infect Dis 2009, 48:1138-51.
Berenguer J, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoen-
cephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003, 36: 1047-52.
Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN
Neuroinfectious Disease Section. Neurology 2013, 80:1430-8.
Berger JR, Levy RM, Flomenhoft D, et al. Predictive factors for prolonged survival in AIDS-associated progressive
multifocal leukoencephalopathy. Ann Neurol 1998, 44:341-9.
Bossolasco S, Calori G, Moretti F, et al. Prognostic significance of JC virus DNA levels in cerebrospinal fluid of
patients with HIV-associated progressive multifocal leukoencephalopathy. Clin Infect Dis 2005, 40:738-44.
Brickelmaier M, Lugovskoy A, Kartikeyan R, et al. Identification and characterization of mefloquine efficacy against
JC virus in vitro. Antimicrob Agents Chemother 2009, 53:1840-9.
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328 AIDS

Bacterial pneumonia
Bacterial pneumonia occur even with relatively good immune status (above 200 CD4
T-cells/µl); the association with immunodeficiency is not compelling, and the decline
in incidence is more moderate with ART than with other OIs. AIDS-defining
conditions are exclusively repeated, radiologically (and) culturally proven acute
pneumonia (more than one in the past 12 months). A distinction should be made
between community-acquired and nosocomial-acquired pneumonias. For the
former, a detailed history (travel? animal contacts?) should be obtained. Nosocomial
pneumonias are often caused by hospital germs (Klebsiellae, Staphylococcus or
Pseudomonas) (Franzetti 2006). Therapy should be adapted to the local resistance
situation and experience (Gant 2000, Vogel 2000).
The local pathogen spectrum of community-acquired pneumonia does not differ
significantly from that of uninfected people. The most common pathogens are
pneumococci and hemophilus influenza, also in PLWH. In younger people,
mycoplasma plays a role. Klebsiellae, Staphylococcus aureus, and Pseudomonas aeroginosa
should be noted; legionella is rare. Intravenous drug users are at higher risk. Nicotine
abuse, alcohol abuse, and pre-existing pulmonary disease are other risk factors (Grau
2006, De 2013); in the SMART study, treatment breaks and nicotine abuse were risk
factors (Gordin 2008). Nicotine abstinence significantly reduces the risk (Bénard
2010). Low CD4 T-cells and liver cirrhosis are risk factors for severe courses (Manno
2009, Madeddu 2010).

Clinic/Diagnostics
Acute, usually high fever and cough with sputum are typical. Breathing is painful
due to the accompanying pleurisy, whereas pronounced dyspnea is rare. Auscultation
of the infiltrates almost always differentiates it from PCP. If you hear something, it
is not PCP! The chest x-ray confirms the diagnosis. CRP is clearly elevated, LDH is
usually normal. Blood cultures should be taken several times before starting therapy
and at temperatures above 38.5 degrees. The main problems with blood culture are
the duration of diagnosis (24–48 hours) and relatively low sensitivity. However,
culture is the only method that allows resistance testing. Using a sputum sample,
the etiology can be determined in about half of the cases, but its usefulness is
controversial (Cordero 2002). This also applies to pneumococcal antigen detection
in urine and diagnostics for other specific pathogens. S3 guidelines recommend base-
line pathogen diagnostics with at least two blood culture pairs, a urine antigen test
for Legionella, and sputum examination in all patients hospitalized for moderate to
severe pneumonia. If processing within 2–4 hours for Gram stain and culture is not
possible, sputum examination is dispensable (Ewig 2016).

Treatment
In principle, the treatment of bacterial pneumonia is similar to that of HIV-negative
cases. Therapy should be started empirically and quickly; sputum and blood cultures
should not be awaited. Cases with poor immune status below 200 CD4 T-cells/µl
should be hospitalized (Madeddu 2010). This also applies in cases of high fever (above
39.5 degrees), poor compliance, signs of organ failure, CNS disturbances (confusion),
or disturbances of vital signs (tachypnea, tachycardia, hypotension), and older age
(above 65 years). The guidelines also use a simplified CRB-65 score (C = Confusion,
R = Respiratory rate > 30/min, B = Blood pressure: Systolic/diastolic below
90/60 mmHg, 65 = Patient is at least 65 years old). This ranges from 0 (no factor) to
Opportunistic infections (OI) 329

4 (all positive), and admission is recommended at a score of 1. In more recent guide-

lines, age is no longer a criterion; only respiratory rate, blood pressure, O2 saturation
(92% as a limit), and consciousness are factors to be taken into account.
Adequate hydration should always be ensured. Supportive therapies with mucolytics
such as N-acetylcysteine or antitussives are controversial. With sufficient antibiotic
therapy, improvement can be expected within 48–72 hours. With clinical response,
5–7 days is usually sufficient. The “use up the pack” paradigm is gone; the new par-
adigm is “as short as possible.” If fever persists, especially in cases of significant
immunodeficiency, reconsider therapy after 72 hours at the latest. It should be noted
that the current first-line therapies are not effective against Pseudomonas aeruginosa.

Medication
The guidelines distinguish between mild (CRB-65= 0, O2 saturation > 90%), moderate
(1–2), and severe pneumonia (3–4, acute respiratory failure and/or severe sepsis),
each of which requires different therapies (Ewig 2016). The pathogen spectrum is
largely identical for moderate and severe pneumonia – the combinations for severe
pneumonia (intensive care unit!) are primarily aimed at reducing possible gaps in
efficacy.
For mild pneumonia, aminopenicillin is considered the first choice. Some practi-
tioners favor those with beta-lactamase inhibitors (BLIs), such as clavulanic acid,
which expands the spectrum of activity to include BL-forming S. aureus, H. influenzae,
and enterobacteria. Quinolones are considered an alternative in penicillin allergy
cases, but the indication has been significantly limited due to (rare) skin and liver
reactions. Oral cephalosporins are no longer recommended (underdosed), as is
roxithromycin.
Macrolides such as azithromycin or clarithromycin may be considered in mild cases
but only in patients without co-morbidities – whether HIV infection qualifies as one
(the guidelines do not list it separately, unlike heart failure, CNS disease, or COPD)
remains unclear and should be decided on a case-by-case basis. Macrolides have

Empirical treatment of community-acquired bacterial pneumonia (daily doses, selection)

Outpatient (mild) Duration: 5 days
First choice Amoxicillin + Clavulanic acid Augmentan® 3 x 1 tab. at 875/125 mg
Alternative Clarithromycin Klacid PRO® 2 x 1 tab. of 500 mg
Alternative Azithromycin Azithromycin® 1 x 1 tab. at 500 mg
Alternative Moxifloxacin Avalox® 1 x 1 tab. of 400 mg
Hospitalized
Intermediate Amoxicillin + clavulanic acid Augmentan® 3 x 1 infusion vials at 2.2 g
Severe plus macrolide 3 days plus azithromycin® 1 x 1 tab. of 500 mg
or Klacid PRO® 2 x 1 tab. at 500 mg
Intermediate Ceftriaxone Rocephin® 1 x 1 infusion vials of 2 g IV
Severe plus macrolide 3 days plus azithromycin® 1 x 1 tab. at 500 mg
or Klacid PRO® 2 x 1 tab. of 500 mg
Severe Piperacillin + Tazobactam Tazobac® 3 x 1 infusion vials of 4.5 g IV
+ macrolide 3 days plus azithromycin® 1 x 1 tab. at 500 mg
or Klacid PRO® 2 x 1 tab. of 500 mg
Prophylaxis Vaccination (pneumococcal Sequential: first Prevenar13® and after
polysaccharide) 6 months with Pneumovax 23® IM
330 AIDS

advantages for atypical pathogens such as mycoplasma, chlamydia, and Legionella.

However, macrolide-resistant pneumococci are increasing in Europe (Germany:
approximately 14%). There are gaps in effectiveness with hemophilus strains.
Moderate and severe pneumonia should be treated as an inpatient and intravenously.
The combination with macrolides is recommended in principle, although the data
is insufficient.

Prophylaxis
Pneumovax® vaccination is recommended above 200 CD4 T-cells/µl but is probably
protective below that level (Penaranda 2007). The 13-valent conjugate vaccine
Prevenar 13® is said to have better immunogenicity but has a narrower spectrum.
Many guidelines recommend a sequence of first Prevenar13® and, after 6 months,
Pneumovax® (see Vaccinations).
Literature
Barakat LA, Juthani-Mehta M, Allore H, et al. Comparing clinical outcomes in HIV-infected and uninfected older
men hospitalized with community-acquired pneumonia. HIV Med 2015;16:421-30.
Bénard A, Mercié P, Alioum A, et al. Bacterial Pneumonia among HIV-infected patients: decreased risk after tobacco
smoking cessation. ANRS CO3 Aquitaine Cohort, 2000-2007. PLoS One 2010, 5:e8896.
Cordero E, Pachon J, Rivero A, et al. Usefulness of sputum culture for diagnosis of bacterial pneumonia in HIV-
infected patients. Eur J Clin Microbiol Infect Dis 2002, 21:362-7.
De P, Farley A, Lindson N, Aveyard P. Systematic review and meta-analysis: influence of smoking cessation on
incidence of pneumonia in HIV. BMC Med 2013, 11:15.
Ewig S, Höffgen G, Kern WK et al. Behandlung von erwachsenen Patienten mit ambulant erworbener Pneumonie
und Prävention – Update 2016. Pneumologie 2016; 70: 151-200.
Franzetti F, Grassini A, Piazza M, et al. Nosocomial bacterial pneumonia in HIV-infected patients: risk factors for
adverse outcome and implications for rational empiric antibiotic therapy. Infection 2006;34:9-16.
Gant V, Parton S. Community-acquired pneumonia. Curr Opin Pulm Med 2000, 6:226-33.
Gordin FM, Roediger MP, Girard PM, et al. Pneumonia in HIV-infected persons: increased risk with cigarette
smoking and treatment interruption. Am J Respir Crit Care Med 2008, 178:630-6.
Grau I, Pallares R, Tubau F, et al. Epidemiologic changes in bacteremic pneumococcal disease in patients with
human immunodeficiency virus in the era of highly active antiretroviral therapy. Arch Intern Med 2005;165:1533-40.
Madeddu G, Fiori ML, Mura MS. Bacterial community-acquired pneumonia in HIV-infected patients. Curr Opin
Pulm Med 2010 Feb 11.
Manno D, Puoti M, Signorini L, et al. Risk factors and clinical characteristics associated with hospitalization for
community-acquired bacterial pneumonia in HIV-positive patients according to the presence of liver cirrhosis.
Infection 2009, 37:334-9.
Penaranda M, Falco V, Payeras A, et al. Effectiveness of polysaccharide pneumococcal vaccine in HIV-infected
patients: a case-control study. Clin Infect Dis 2007;45.
Rimland D, Navin TR, Lennox JL, et al. Prospective study of etiologic agents of community-acquired pneumonia
in patients with HIV infection. AIDS 2002, 16:85-95.
Vogel F, Worth H, Adam D, et al. Rationale Therapie bakterieller Atemwegsinfektionen. Empfehlungen einer
Expertengruppe der Paul-Ehrlich-Gesellschaft für Chemotherapie e.v. und der Deutschen Atemwegsliga.
Chemotherapie Journal 2000, 1:3-23.
Opportunistic infections (OI) 331

Cryptosporidiosis
Cryptosporidiosis is a parasitic, fecal-orally transmitted intestinal disease. Crypto-
sporidium parvum and hominis are the most relevant among the numerous species of
these intracellular protozoa. Both immunocompetent and immunocompromised
individuals may be affected (review: Checkley 2015). Since their first description in
1976, cryptosporidia have been among the most important diarrheal pathogens
worldwide; in children, they are considered the second most important causative
agent of severe diarrhea after rotaviruses. The primary sources of infection are
animals, contaminated water, and food. The incubation period is about 10 days.
While diarrhea in PLWH with more than 200 CD4 T-cells/µl usually disappears after
a few days, cryptosporidiosis can become chronic, with massive water and electrolyte
losses in cases of immunodeficiency below 50/µl (Colord 1996). The chronic – not
acute – disease is AIDS-defining.

Clinic
The watery diarrhea can be so severe that it leads to death via electrolyte loss and
dehydration. Twenty defecations per day are not uncommon. Tenesmus usually
persists, often causing nausea and vomiting. However, there is great variability in
symptoms. Fever is usually absent. Occasionally, there is bile duct involvement with
elevated bile enzymes. Pancreatitis is also possible.

Diagnostics
The laboratory must be explicitly informed of the suspicion when the stool samples
are sent. Otherwise, cryptosporidia are usually overlooked. If the laboratory has
experience, a stool sample is usually sufficient for detection by immunofluorescence
microscopy. Antibodies or other diagnostic methods are of no help. Differentially,
all diarrheal germs can be considered.

Therapy
With good immune status, diarrhea is self-limiting; ART often leads to a cure if poor
immune status is improved (Carr 1998, Miao 2000). In addition, loperamide and/or
Tinctura opii simplex (opium) should be given. If this is unsuccessful, other diar-
rheal agents, possibly including Sandostatin®, should be tried. Care should be taken
to ensure good hydration – infusions are occasionally necessary.
All specific therapies are suboptimal (review: Diptyanusa 2021). We have had some
good experiences with nitazoxanide (Alinia®, Cryptaz). This anthelmintic was
effective in a small randomized trial (Rossignol 2001). Nitazoxanide was approved
in the United States in 2005 for cryptosporidium-associated diarrhea in immuno-
competent individuals; it can be imported. There is no approval for AIDS patients,
and it was without effect in HIV-positive children with cryptosporidia in a double-
blind randomized trial (Amadi 2009). Rifaximin (Xifaxan®) is a non-absorbable
rifampicin derivative approved as a diarrheal agent in the United States. There are
case reports of people with AIDS (Gathe 2008).
Paromomycin (Humatin®), a non-absorbable aminoglycoside antibiotic, had a
beneficial effect on diarrhea in small, uncontrolled studies (White 2001). However, in
a double-blind randomized trial, there was no advantage over placebo (Hewitt 2000).
There may, however, be some effect in combination with azithromycin (Smith 1998).
332 AIDS

Therapy/prophylaxis of cryptosporidiosis (daily doses)

Acute therapy
Symptomatic Loperamide + Imodium® 2–6 x 1 cap. at 2 mg or
Opium tincture Imodium solution® 2–6 x 10 mL and/or
Tinctura opii simplex 1% = 4 x 5–15 drops
Symptomatic Octreotide Sandostatin Injection Solution® 2–3 x 1 Amp à 50 μg SC
(increase dose only slowly)
Experimental Nitazoxanide Cryptaz™ 2 x 1 tab. at 500 mg
Experimental Rifaximin Xifaxan™ 2 x 2 tab. of 200 mg
Experimental Paromomycin + Humatin Pulvis® 3 x 1 tab. at 1 g plus
azithromycin Ultreon® 1 x 1 tab. of 600 mg
Prophylaxis Exposure prophylaxis: Do not drink tap water

Prophylaxis
There is no recognized prophylaxis, although rifabutin and clarithromycin were pro-
tective in retrospective studies (Holmberg 1998). It is more important not to drink
tap water in countries with hygiene problems. Contact with human and animal feces
should be avoided. Cryptosporidia are resistant to most disinfectants. However, stan-
dard hygiene measures (gloves) are sufficient in the hospital. Patients do not need
to be isolated, but it is better not to place them with immunocompromised persons.
Literature
Amadi B, Mwiya M, Musuku J, et al. Effect of nitazoxanide on morbidity and mortality in Zambian children with
cryptosporidiosis: a randomised controlled trial. Lancet 2002, 360:1375-1380.
Amadi B, Mwiya M, Sianongo S, et al. High dose prolonged nitazoxanide treatment is ineffective for cryp-
tosporidiosis in HIV positive Zambian children: a randomised controlled trial. BMC Infect Dis 2009, 9:195.
Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1 associated microsporidiosis and cryp-
tosporidiosis with combination antiretroviral therapy. Lancet 1998, 351:256-61.
Checkley W, White AC Jr, Jaganath D, et al. A review of the global burden, novel diagnostics, therapeutics, and
vaccine targets for cryptosporidium. Lancet Infect Dis 2015, 15:85-94.
Colford JM Jr, Tager IB, Hirozawa AM, et al. Cryptosporidiosis among patients infected with HIV. Factors related
to symptomatic infection and survival. Am J Epidemiol 1996, 144:807-16.
Diptyanusa A, Puspa Sari I. Treatment of human intestinal cryptosporidiosis: A review of published clinical trials.
Int J Parasitol Drugs Drug Resist 2021, 17:128-138.
Gathe JC Jr, Mayberry C, Clemmons J, Nemecek J. Resolution of severe cryptosporidial diarrhea with rifaximin
in patients with AIDS. J AIDS 2008, 48:363-4.
Griffiths JK. Treatment for AIDS-associated cryptosporidiosis. J Infect Dis 1998, 178:915-6.
Hewitt RG, Yiannoutsos CT, Higgs ES, et al. Paromomycin: No more effective than placebo for treatment of cryp-
tosporidiosis in patients with advanced HIV infection. Clin Inf Dis 2000, 31:1084-92.
Holmberg SD, Moorman AC, Von Bargen JC, et al. Possible effectiveness of clarithromycin and rifabutin for cryp-
tosporidiosis chemoprophylaxis in HIV disease. JAMA 1998, 279:384-6.
Miao YM, Awad-El-Kariem FM, Franzen C, et al. Eradication of cryptosporidia and microsporidia following suc-
cessful antiretroviral therapy. J Acquir Immune Defic Syndr 2000, 25: 124-9.
Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective ran-
domized, double-blind, placebo-controlled study of Nitazoxanide. J Infect Dis 2001, 184:103-6.
Smith NH, Cron S, Valdez LM, Chappell CL, White AC Jr. Combination drug therapy for cryptosporidiosis in
AIDS. J Infect Dis 1998, 178:900-3.
White AC, Cron SG, Chappell CL. Paromomycin in cryptosporidiosis. Clin Inf Dis 2001, 32:1516-7.
Opportunistic infections (OI) 333

Cryptococcosis
Infections caused by the yeast Cryptococcus neoformans are rare in Europe. They are
more common in the US, Africa, and Southeast Asia and are among the most impor-
tant AIDS-defining diseases worldwide (review: Rajasingham 2017). C. neoformans is
likely transmitted by inhalation. Bird droppings are an important reservoir of
pathogens. Pulmonary infection is occasionally not apparent in immunocompetent
individuals; in HIV, it is usually the onset of disseminated disease. The CNS is the
leading site of manifestation besides the lungs after hematogenous dissemination.
However, isolated skin manifestations and lymphadenitis also occur, and more rarely,
osseous or urogenital involvement.
Cryptococcosis almost always occurs in the presence of massive immunodeficiency.
Of 114 patients in Germany, 87% had fewer than 100 CD4 T-cells/µl, with a median
of 30/µl (Weitzel 1999). Cryptococcosis is also relatively commonly seen in the setting
of IRIS. If left untreated, it is fatal – causing approximately 15% of all AIDS deaths
worldwide (Rajasingham 2017). Treatment is complicated, lengthy, and recom-
mended only as an inpatient. Recurrences used to be common (at least 15%) but are
now less frequent due to ART.

Clinic
The CNS manifestation with an encephalitic picture is the most frequent (approx.
80%). Headache, fever, and increasing disturbances of consciousness (confusion)
within a few days are typical. Sometimes, there are also gait, hearing or visual
disturbances, and paresis, especially of the cranial nerves. The intracranial pressure
is almost always elevated. Meningeal irritation symptoms are usually absent. In the
setting of IRIS, the clinic is often atypical and characterized by abscesses (Manfredi
1999). In pulmonary involvement, there are symptoms of atypical pneumonia with
nonproductive cough and chest pain. Skin lesions may initially resemble molluscs
that later confluence into ulcerative lesions.

Diagnostics
Cryptococcosis is acutely life-threatening; there is no time to lose. In case of any
suspicion (positive cryptococcal antigen!), lungs (HR-CT!) and CNS (MRI head!)
should be examined quickly. The spectrum in HR-CT of the lung is varied: scattered,
small foci, as in TB, are possible, as are sharply demarcated infiltrates reminiscent of
bronchopneumonia. Cavernous formations, even bronchiectasis, occur. An attempt
should be made to identify the causative agent by BAL. MRI of the head is often
unremarkable, in contrast to toxoplasmosis and cerebral lymphoma, and single or
multiple mass lesions (“cryptococcomas”) are rare. Nevertheless, intracranial pressure
is elevated at 50–70%. Fundoscopy (papilledema?) and MRI should be quickly
followed by CSF puncture. It almost always brings the diagnosis with an ink
preparation. Even in the case of pulmonary or other localization, the CSF must be
examined to exclude CNS involvement. cryptococcal antigen in the blood (titer
> 1:8) is a suitable parameter and should always be determined, especially if CD4
T-cells are low below 100/µl (Jarvis 2011). In asymptomatic individuals with posi-
tive antigen, meningitis is already present in one-third (Wake 2017), and they should
be treated promptly. Blood cultures are also often positive. In cutaneous infestations,
the diagnosis is usually made only by biopsy.
334 AIDS

Treatment
In the case of CNS involvement, several antimycotics must be combined acutely.
Fluconazole alone is not sufficient, even in high doses. In large randomized trials
from Africa, mortality in the first few weeks was as high as 40–60% (Longley 2008,
Makadzange 2009, Beardsley 2016). Combinations prevent resistance and allow
induction therapy to be shortened to two weeks.
Historically, a triple combination of amphotericin B, flucytosine, and fluconazole
has often been used for several weeks in cases of CNS infection; complete remission
can be achieved in about 80% (Weitzel 1999). Liposomal amphotericin (Ambisome®)
is probably somewhat more effective than conventional amphotericin B – apart from
lower toxicity (Leenders 1997, Hamill 1999).
Recently, the results of the large AMBITION study were published (Jarvis 2022). In
this study, a single dose of high-dose liposomal amphotericin (10 mg/kg) on day 1
plus 14 days of flucytosine (100 mg/kg per day) and fluconazole (1,200 mg per day)
was compared with the standard therapy recommended by the WHO since 2018.
This consisted of a combination of amphotericin-B (1 mg/kg per day) plus flucytosine
(100 mg/kg) for 7 days, followed by fluconazole (1200 mg per day) for an additional
7 days. Clinically, the arm with the single dose Ambisome® was not inferior, and
toxicity was even reduced, so this combination has already found its way into some
guidelines (Ngan 2022).
Induction therapy is followed after to weeks by at least eight weeks of maintenance
therapy with high-dose fluconazole (400–800 mg per day); for subsequent second-
ary prophylaxis for at least one year, the dose may be reduced to 200 mg.
When amphotericin B is unavailable, the combination of flucytosine and flucona-
zole is better than fluconazole alone (Nussbaum 2010). Fluconazole should be given
as an infusion, especially in confused individuals. Therapy is also very toxic with
Ambisome® -containing combinations. Daily monitoring of renal and liver enzymes,
blood counts, and electrolytes is recommended during induction therapy. Other
azoles (except voriconazole, studies ongoing) have poor liquid tolerance and should
be avoided.
The optimal timing of ART is challenging, due to a high risk of IRIS. Several major
African studies showed that IRIS incidence and mortality decrease when waiting at
least four weeks (Makadzange 2010, Bisson 2013, Boulware 2014). Thus, starting cryp-
tococcal therapy and ART at the same time should be avoided. ART should not contain
TDF (renal failure) and substances with high interaction potential (no boosting
agents).
In case of isolated pulmonary involvement (CSF negative!) or other extracerebral
manifestations, we treat without flucytosine. A positive cryptococcal antigen test
without a clinic would be treated with fluconazole only.
The success of therapy is monitored clinically and with repeated lumbar punctures.
After two weeks, the CSF is usually negative (Saag 2000). If so, the patient can be
switched to maintenance therapy. The sooner the CSF is negative, the better the
prognosis (Bicanic 2009, Chang 2012). If intracranial pressure is elevated, therapeutic
CSF punctures may be useful (Rolfes 2014), sometimes even CSF drainage (Graybill
2000), both of which are possible (Xu 2022). Steroids are harmful and should be
avoided (Beardsley 2016).
Opportunistic infections (OI) 335

Treatment/prophylaxis of cryptococcosis (if not otherwise specified, daily doses); for application, see
Drug chapter. Wait at least 4 weeks before starting ART!
Acute therapy Duration: Always at least two weeks
Therapy of choice Amphotericin B Amphotericin B® 1 x 0.5–0.75 mg/kg or
AmBisome® 1 x 3 mg/kg (also consider single dose
1 x 10 mg/kg) plus
+ Fluconazole Diflucan® 3 x 1 inf. vial of 400 mg IV or
Diflucan® or Fluconazole CT/Stada 3 x 2 cap. at 200 mg
plus
+ Flucytosine Ancotil® 4 x 1 inf. vial of 250 mL (2.5 g) IV
(= 100–150 mg/kg distributed over 4 individual doses)
Maintenance therapy
Therapy of choice Fluconazole Diflucan® or Fluconazole CT/Stada 2 x 2 cap. of 200 mg
for 8 weeks, then 1 x 1 cap. at 200 mg for one year,
discontinue only after > 200 CD4 T-cells/μl > 6 months
and negative cryptococcal antigen
Primary prophylaxis Not recommended

Prophylaxis
Exposure is hardly preventable. Primary prophylaxis is not recommended because
there was no survival benefit, even in endemic areas such as Thailand (McKinsey
1999, Chariyalertsak 2002). In a study from Uganda of 1,519 PLWH with negative
cryptococcal antigen and less than 200 CD4 T-cells, of 19 episodes, 18 occurred with
placebo, and only one with fluconazole, but overall survival was not improved
(Parkes-Ratanshi 2011).
Secondary prophylaxis or maintenance therapy consists of fluconazole, which is
significantly more effective than itraconazole (Saag 1999). Fluconazole can be
discontinued upon immune reconstitution (> 100 CD4 T-cells, viral load three
months below the limit of detection) and after at least six months of maintenance
therapy (Aberg 2002, Kirk 2002, Vibhagool 2003, Mussini 2004). Before this, the
cryptococcal antigen should be checked (Mussini 2004). If the antigen is positive,
which is associated with an increased risk of recurrence, especially with high titers
(Lortholary 2006), it is better to continue therapy.

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Aberg JA, Price RW, Heeren DM, Bredt B. A pilot study of discontinuing antifungal therapy for disseminated cryp-
tococcal disease in patients with AIDS, following immunologic response to ART. J Infect Dis 2002, 185:1179-82.
Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis.
N Engl J MedEJM 2016;374:542-54.
Bicanic T, Muzoora C, Brouwer AE, et al. Independent association between rate of clearance of infection and clin-
ical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin Infect
Dis 2009, 49:702-9.
Bisson GP, Molefi M, Bellamy S, et al. Early Versus Delayed Antiretroviral Therapy and Cerebrospinal Fluid Fungal
Clearance in Adults With HIV and Cryptococcal Meningitis. Clin Infect Dis 2013, 56:1165-73.
Boulware DR, Meya DB, Muzoora C, COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryp-
tococcal meningitis. N Engl J Med 2014, 370:2487-98.
Chang C, Dorasamy A, Elliot J, et al. HIV+ Patients with CM Who Attain CSF Sterility Pre-cART Commencement
Experience Improved Outcomes in the First 24 Weeks. Abstract 955, 19th CROI 2012, Seattle.
Chariyalertsak S, Supparatpinyo K, Sirisanthana T, et al. A controlled trial of itraconazole as primary prophylaxis
for systemic fungal infections in patients with advanced HIV infection in Thailand. Clin Infect Dis 2002, 34:277-84.
336 AIDS

Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with
AIDS and cryptococcal meningitis. Clin Infect Dis 2000;30:47-54.
Hamill RJ, Sobel J, El-Sadr W, et al. Randomized double blind trial of Ambisome and amphotericin B in acute
cryptococcal meningitis in AIDS patients. 39th ICAAC 1999, San Francisco; Abstract 1161.
Jarvis JN, Lawrence DS, Meya DB, et al. Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal
Meningitis. N Engl J Med 2022, 386:1109-1120.
Jarvis JN, Percival A, Bauman S, et al. Evaluation of a novel point-of-care cryptococcal antigen test on serum,
plasma, and urine from patients with HIV-associated cryptococcal meningitis. Clin Infect Dis 2011, 53:1019-23.
Kirk O, Reiss P, Uberti-Foppa C, et al. Safe interruption of maintenance therapy against previous infection with
four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Ann Intern Med 2002,
137:239-50.
Leenders AC, Reiss P, Portegies P, et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B
both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 1997,
11:1463-71.
Longley N, Muzoora C, Taseera K, et al. Dose response effect of high-dose fluconazole for HIV-associated crypto-
coccal meningitis in southwestern Uganda. Clin Infect Dis 2008, 47:1556-61.
Lortholary O, Poizat G, Zeller V, et al. Long-term outcome of AIDS-associated cryptococcosis in the era of com-
bination antiretroviral therapy. AIDS 2006, 20:2183-91.
Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for con-
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HAART era. Case reports and literature review. Mycopathologia 1999, 148:73-8.
McKinsey DS, Wheat LJ, Cloud GA, Itraconazole prophylaxis for fungal infections in patients with advanced HIV
infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999, 28:1049-56.
Mussini C, Pezzotti P, Miro JM, et al. Discontinuation of maintenance therapy for cryptococcal meningitis in
patients with AIDS treated with HAART: an international observational study. Clin Infect Dis 2004, 38:565-71.
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Going? Drugs 2022, 82:1237-1249.
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Opportunistic infections (OI) 337

Salmonella septicemia
Infection with non-typhoidal Salmonella species, which usually cause only enteritis
in healthy individuals, can result in severe septicemia in immunocompromised
individuals (Jacobs 1985). The most important reservoir of pathogens is food,
especially poultry. Recurrent, non-typhoidal Salmonella septicemias are AIDS-defin-
ing. In central Europe, they are rare and account for less than 1% of all AIDS cases
(Burckhardt 1999). In contrast, in southern Europe or Africa, salmonella species are
the most common pathogens detected in blood cultures (Gordon 2008). In addition
to septicemia, osteomyelitis, empyema, lung abscesses, pyelonephritis, or meningitis
have been described (Albrecht 1992, Nadelman 1985). Recurrences have become less
frequent with ART (Hung 2007).

Clinic/Diagnostics
The patients are often seriously ill. Chills and high fever are usually present, but
diarrhea is not always present. If not treated in time, septic shock may occur. Blood
cultures are primarily used to isolate the enteritis salmonella strains S. enteritides
and S. typhimurium. The typhoid and paratyphoid fever pathogens, S. typhi and
S. paratyphi, occur only rarely.

Treatment/Prophylaxis
Ciprofloxacin is the drug of choice. In most cases, one-week intravenous adminis-
tration is sufficient. In Asia, resistance rates are sometimes as high as 30% (Hung
2007); cefotaxime or ceftriaxone can then be considered. Oral maintenance therapy
for 6–8 months should not be discontinued too early (Hung 2001). Previously, life-
long relapse prophylaxis is no longer required. Primary prophylaxis is not recom-
mended; food hygiene rules should be followed (see Travel Medicine). As with shigella
(see Dermatology), outbreaks among MSM have not been observed.
Treatment/prophylaxis of salmonella sepsis (daily doses)
Acute therapy 7–14 days
Therapy of choice Ciprofloxacin Ciprofloxacin 2 x 1 infusions of 200 mg IV
Alternative Ceftriaxone Rocephin® 1 x 1 infusions of 2 g IV
Prophylaxis Against recurrences
Ciprofloxacin Ciprofloxacin 2 x 1 tab. at 500 mg (6–8 months)

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338 AIDS

Immune Reconstitution Syndrome (IRIS)

In 1997, PLWH who developed unusual CMV retinitis (Jacobsen 1997) or abscessing
MAC infections (Race 1998) a few weeks after ART initiation was reported for the
first time. The common feature was a pronounced inflammatory component – early
on. Therefore, a syndrome was postulated in which an infection or disease already
latent before therapy was more adequately fought by the restoring immune system
(review: Walker 2015). This “immune reconstitution inflammatory syndrome” (IRIS)
is defined as a worsening of an infectious or inflammatory event that is temporally
related to ART initiation. In addition to activation of the cellular immune response,
changes in the cytokine network are also involved in the pathogenesis of IRIS – but
apparently, the mechanisms differ depending on the disease and genetic profile (Price
2001, Shelbourne 2005).
A viral load drop of at least one log is required as a response criterion, and the
symptoms must not be explainable by side effects, therapy failure, or non-adherence.
A distinction must be made between subclinical infections that are unmasked during
ART (“unmasking IRIS”) and infections that were already clinically evident at the
start of ART, and that paradoxically worsen during therapy (“paradoxical IRIS”). IRIS
is not limited to infections; the spectrum includes autoimmune diseases and
malignancies. Thus, IRIS today is a panopticon of bizarre case reports with only one
thing in common: unexpected, clinically usually impressive problems occurred under
newly started, effective ART. The ART regimen does not matter: the hypothesis that
INSTIs increase the risk of IRIS, which was repeatedly raised for a while, has not been
proven true (Zhao 2022).
How common is IRIS? In the absence of a definition, the figures vary. We consider
a frequency of 5–10% realistic with less than 200 CD4 T-cells/µl. Very low CD4
T-cells, a high viral load before starting therapy, a rapid decline under ART seem to
be predictors, and an elevated CRP before starting ART. If only cases infected with
mycobacteria or cryptococci before ART initiation are considered, IRIS rates of 30%
and more are observed (Müller 2010).
Atypical mycobacterial IRIS: For MAC, the number of published cases with fistu-
lous lymphadenitis, cutaneous or muscular abscesses, osteomyelitis, nephritides, or
meningitis exceeds the citable range. Lymph node abscesses usually occur in the first
few weeks. IRIS cases with Mycobacterium xenopi or kansasii have also been described
(Chen 2004, Phillips 2005).
TB-IRIS: In four large randomized trials of ART-naïve patients with TB, the IRIS rate
was 18% (Namale 2015). These cases initially worsen dramatically under tubercu-
lostasis and ART-mediated immune reconstitution. Meningitis, and in some cases,
excessive lymph node swelling with often nonspecific histology, complicate the
course. The administration of prednisolone was very effective in a placebo-controlled
study and should be considered (Meintjes 2010+2012). Mortality in TB-IRIS is then
not increased, except for tuberculous meningitis (Török 2009).
CMV-IRIS: In CMV retinitis, IRIS will be expected in about one-third (Müller 2010).
Inflammatory CMV retinitis with vision-threatening vitritis, papillitis, and macular
edema is considered a distinct syndrome and differs significantly from classic CMV
retinitis (Jacobson 1997, Karavellas 1999). Neovascularization threatens visual acuity
even after healing (Wright 2003). Analogous to MAC, the CMV-specific response was
also shown to improve most in cases of vitritis (Mutimer 2002, Stone 2002).
Inflammatory CMV manifestations are not limited to the retina but can also affect
other organs.
Opportunistic infections (OI) 339

PML-IRIS: The clinic of “IRIS-PML” is often initially more fulminant than in classic
PML. Also atypical is contrast enhancement, which gradually regresses over time.
There is a more favorable prognosis, and a complete cure is possible (Hoffmann 2003,
Du Pasquier 2003). There are positive case reports on steroids acutely (Nuttall 2004,
Tan 2009).
Cryptococcal IRIS: Besides MAC/TBC and CMV, cryptococci are probably the most
essential IRIS pathogens (Haddow 2010). In co-infected individuals, the incidence is
up to 20% (Sungkanuparph 2009, Müller 2010). MRI usually shows choriomeningitis
with marked enhancement into the choroid plexus. Cryptococcal antigen in CSF is
positive, but culture remains negative. CSF pressure is often remarkably high
(Shelburne 2005). Because cryptococcal IRIS has a high mortality rate, ART should
always be delayed by several weeks and never start simultaneously (Boulware 2014).
Other infections: The IRIS panopticon also has various case examples on hand, such
as leishmanioses (Badaró 2015), histoplasmoses (De Lavaissière 2008), penicillioses
(Ho 2010), coccidioidomycoses (Mu 2017), pneumocysts (Mok 2014), toxoplasmoses
(Martin-Blondel 2011, van Bilsen 2017), or herpes infections (Tobian 2014). Episodes
of herpes zoster and relapses of hepatitis B or C also appear to occur on ART, especially
in the first few weeks (Martinez 1998, Behrens 2000, Chung 2002, Manegold 2001).
HHV-8-associated Kaposi’s sarcoma may initially worsen significantly on ART (Bower
2005, Feller 2008). Furthermore, exacerbations of molluscum, warts, folliculitis, or
dermatoses have been reported (Handa 2001, Lehloenyia 2006, Pereira 2007, Iarikov
2008). There are reports on parvoviruses and leprosy (Nolan 2003, Couppie 2004,
Watanabe 2011).
Other diseases: IRIS has long been attributed not only to OI but also to autoimmune
diseases such as Graves’ disease, lupus erythematosus, Sweet and Reiter syndrome,
Guillain-Barré syndrome, and acute porphyria, gout, sarcoidosis, to name a few
(Behrens 1998, Bevilacqua 1999, Fox 1999, Mirmirani 1999, Makela 2002, Neumann
2003, Sebeny 2010, Rasul 2011). Two cases of Peyronie’s disease, a penile fibromatosis,
have been reported (Rogers 2004).
Consequences
Patients who start ART with less than 200 CD4 T-cells/µl (and a high viral load simul-
taneously) should be observed carefully during the first weeks. Vigilance is required
primarily for those who refused ART for a long time but now feel physically “weak”
(subfebrile?) and want to start ART “after a longer period of consideration.” In this
case, there is often already a latent infection. The worse the immune status and the
longer it has been poor, the higher the risk of IRIS. Although studies show that
inflammatory parameters such as CRP, D-dimers, or cytokines such as IL-6 or IL-7,
among others, are predictive of IRIS or OI (Rodger 2009, Porter 2010, George 2017),
this has not yet found its way into routine diagnostics.
X-ray thorax, abdominal ultrasonography, and fundoscopy, on the other hand, are
part of the standard program before ART initiation. Prophylaxis cannot prevent MAC-
IRIS (Phillips 2002+2005), nor can the administration of maraviroc (Sierra-Madero
2014). In contrast, when present, steroids should not be spared, particularly for
mycobacterioses. In a randomized trial, prednisolone showed a clear clinical benefit
(Meintjes 2018). In contrast, steroids are probably of no benefit in viral-induced IRIS
(Meintjes 2012).
In any case, clinicians should be prepared for atypical localizations and courses of
opportunistic infections. There is nothing that does not exist, and nothing is the
same anymore. IRIS does not mean that ART has failed. The prognosis is usually
good, and mortality is not increased (Park 2006).
340 AIDS

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Stout JE, Lai JC, Giner J, Hamilton CD. Reactivation of retinal toxoplasmosis despite evidence of immune response
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342 AIDS

Wasting Syndrome
Classic wasting syndrome is defined as an involuntary weight loss of at least 10% of
the original body weight that occurs concurrently with persistent diarrhea (at least
two bowel movements per day for more than 30 days) or weakness and/or fever
without an identifiable infectious cause. Thus, wasting syndrome is a diagnosis of
exclusion. Formerly a common sight in every HIV center, classic wasting syndrome
has become rare in Europe and the United States. However, weight loss remains an
independent mortality factor (Tang 2002), and every person with HIV should be
weighed regularly! Affected persons with classic wasting syndrome are often very
debilitated. Their risk of opportunistic infections is significantly increased (Dworkin
2003). Cognitive abilities are also reduced (Dolan 2003).

Diagnostics
First, opportunistic infections (TB, MAC, crypto-, and microsporidia) should be
excluded or treated. If nothing can be found, such different reasons remain, such as
metabolic disorders, hypogonadism, malnutrition, and malabsorption syndromes
(overview: Grinspoon 2003), which can be combined. The medical history remains
vital: What is the diet, are there diets? Is there depression, drug use, eating disorders?
What ART is being taken? There are often smooth transitions to antiretroviral-
induced lipoatrophy (history of AZT, d4T, ddI?). Under interferon, (reversible) severe
weight loss is also common (Garcia-Benayas 2002). Next, hypogonadism should be
ruled out (measurement of testosterone). Several simple tests are available for
malabsorption syndromes. For now, it makes sense to determine albumin, TSH, and
cholesterol. Further tests, such as the D-xylose absorption test or small intestine
biopsies, are only valuable for gastroenterologists. Also, tests like DEXA, densitom-
etry, and bioelectrical impedance analysis should only be used in centers where
experience with wasting syndrome in AIDS exists.

Treatment
Nutritional counseling and exercise are helpful, if possible, but successful only up
to a point. Parenteral nutrition only helps in absorption disorders (Kotler 1990,
Melchior 1996). An ART that avoids AZT and possibly even nucleoside analogs is
essential (see Nuke-Sparing). Drugs have limited success and are often problematic.
Megestrol acetate, a synthetic progestogen approved in Europe as Megestat® for
advanced breast cancer, also has a benefit in wasting syndrome due to its appetite-
stimulating effect (Von Roenn 1994, Mulligan 2006). Due to the steroid-typical side
effects (including hypogonadism), we do not consider its use to be useful.
Dronabinol (THC), the main active ingredient in marijuana, has been approved as
a narcotic in several European countries since 1998. However, legislation and regu-
lation of medicinal products containing cannabinoids vary across EU countries,
leading to different accessibility to these products. In any case, the effect on wasting
is moderate at best (Beal 1995, Badowski 2016) and probably even weaker than that
produced by megestrol acetate (Timpone 1997).
Hypogonadism is a common problem in the wasting syndrome. When testosterone
levels are depressed, substitution is effective in terms of weight gain and quality of
life (Grinspoon 1998). Testosterone 250 mg IM every 3–4 weeks is given; generic
drugs are available. The effect lasts even with long-term use (Grinspoon 1999). In
women, one should be cautious with androgens. Other anabolic steroids such as
oxandrolone or nandrolone may be more effective than testosterone (Gold 2006,
Opportunistic infections (OI) 343

Sardar 2010) but are likely fraught with more side effects, primarily affecting the liver
(Corcoran 1999). Positive effects have also been reported for the anabolic steroid
oxymetholone (Hengge 2003), although significant transaminase elevations are
sometimes observed.
Side effects and costs also limit the use of growth hormones, and nothing is known
about long-term use (Schambelan 1996). However, according to a meta-analysis,
there is evidence that growth hormones are more effective than anabolic steroids or
testosterone in wasting syndrome (Moyle 2004). Major side effects are glucose
elevations, arthralgias, myalgias, and peripheral edema, which respond to discon-
tinuation or dose reductions (review: Gelato 2007).
Literature
Badowski ME, Perez SE. Clinical utility of dronabinol in the treatment of weight loss associated with HIV and
AIDS. HIV AIDS (Auckl) 2016. 8:37-45.
Beal JE, Olson R, Laubenstein L, et al. Dronabinol as a treatment for anorexia associated with weight loss in
patients with AIDS. J Pain Symptom Manage 1995;10:89-97.
Corcoran C, Grinspoon S. Treatments for wasting in patients with the acquired immunodeficiency syndrome.
NEJM 1999, 340:1740-50.
Dolan S, Montagno A, Wilkie S, et al. Neurocognitive Function in HIV-Infected Patients With Low Weight and
Weight Loss. JAIDS 2003; 34: 155-64.
Dworkin MS, Williamson JM. AIDS wasting syndrome: trends, influence on opportunistic infections, and sur-
vival. J AIDS 2003; 33: 267-73.
Garcia-Benayas T, Blanco F, Soriano V. Weight loss in HIV-infected patients. N Engl J Med 2002, 347: 1287-8.
Gelato M, McNurlan M, Freedland E. Role of recombinant human growth hormone in HIV-associated wasting
and cachexia: pathophysiology and rationale for treatment. Clin Ther 2007; 29:2269-88.
Gold J, Batterham MJ, Rekers H, et al. Effects of nandrolone decanoate compared with placebo or testosterone on
HIV-associated wasting. HIV Med 2006, 7:146-55.
Grinspoon S, Corcoran C, Anderson E, Hubbard J, Basgoz N, Klibanski A. Sustained anabolic effects of long-term
androgen administration in men with AIDS wasting. Clin Infect Dis 1999, 28:634-636.
Grinspoon S, Corcoran C, Askari H, et al. Effects of androgen administration in men with the AIDS wasting syn-
drome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 129:18-26.
Grinspoon S, Mulligan K. Weight loss and wasting in patients infected with human immunodeficiency virus. Clin
Infect Dis 2003; 36: S69-78.
Hengge UR, Stocks K, Faulkner S, et al. Oxymetholone for the treatment of HIV-wasting: a double-blind, ran-
domized, placebo-controlled phase III trial in eugonadal men and women. HIV Clin Trials 2003; 4:150-63.
Kotler DP, Tierney AR, Culpepper-Morgan JA, Wang J, Pierson RN Jr. Effect of home total parenteral nutrition on
body composition in patients with AIDS. J Parenter Enteral Nutr 1990;14:454-458.
Melchior J, Chastang C, Gelas P, et al. Efficacy of 2-month total parenteral nutrition in AIDS patients: a controlled
randomized prospective trial. AIDS 1996;10:379-384.
Moyle GJ, Daar ES, Gertner JM, et al. Growth hormone improves lean body mass, physical performance, and
quality of life in subjects with HIV-associated weight loss or wasting on highly active antiretroviral therapy.
J Acquir Immune Defic Syndr 2004;35:367-75.
Mulligan K, Zackin R, Von Roenn JH, et al. Testosterone supplementation of megestrol therapy does not enhance
lean tissue accrual in men with HIV-associated weight loss: A randomized, double-blind, placebo-controlled mul-
ticenter trial. J Clin Endocrinol Metab 2006 Nov 7.
Sardar P, Jha A, Roy D, Majumdar U, et al. Therapeutic effects of nandrolone and testosterone in adult male HIV
patients with AIDS wasting syndrome (AWS): a randomized, double-blind, placebo-controlled trial. HIV Clin Trials
2010, 11:220-9.
Schambelan M, Mulligan K, Grunfeld C, et al. Recombinant human growth hormone in patients with HIV-asso-
ciated wasting: a randomized, placebo-controlled trial. Ann Intern Med 1996, 125:873-882.
Tang AM, Forrester J, Spiegelman D, et al. Weight loss and survival in HIV-positive patients in the era of highly
active antiretroviral therapy. J AIDS 2002, 31: 230-6.
Timpone JG, Wright DJ, Li N, et al. The safety and pharmacokinetics of single-agent and combination therapy
with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. AIDS Res Hum Retroviruses
1997, 13:305-15.
Von Roenn JH, Armstrong D, Kotler DP, et al. Megesterol acetate in patients with AIDS-related cachexia. Ann
Intern Med 1994, 121:393-399.
Wanke CA, Silva M, Knox TA, et al. Weight loss and wasting remain common complications in individuals infected
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344 AIDS

Rare opportunistic infections (OIs)

C H R I S T I A N H O F F M A N N A N D G E R D F ÄT K E N H E U E R

In the following, OIs that hardly occur in Central Europe or have become very rare
due to ART will be described. These affect PLWH more often than immunocompetent
patients, are more severe, and recur more frequently. Only three infections, namely
histoplasmosis, isosporiasis, and coccidioidomycosis, are AIDS-defining.

Aspergillosis
Aspergilloses are not AIDS-defining, although the CD4 T-cell count is almost always
below 50/µl (Mylonakis 1998). The primary manifestation is the lungs (pneumonia,
tracheobronchitis). CNS and renal or hepatic abscesses also occur (Hunt 2000,
Mylonakis 2000). Steroids and severe neutropenia are risk factors. Aspergillus fumi-
gatus is the most common pathogen (> 90%).
The most severely ill complain of fever, cough, dyspnea, and chest pain. Hemoptysis
is often present. The diagnosis can only be made reliably by biopsy. A serum antigen
test for galactomannan may support the tentative diagnosis. Detection of Aspergillus
in pulmonary secretions is considered circumstantial but is often colonization-
related. The chest x-ray usually shows nonspecific changes or is unremarkable. The
diagnostic method of choice is HR-CT, which shows pulmonary infiltrates that typ-
ically contain air pockets or are blurred (halo sign) (Ullmann 2018).
Voriconazole is the therapy of choice; it was better than conventional amphotericin
B in a randomized study (Herbrecht 2002). The daily dose is 2 x 4 mg IV/kg (loading
dose: 2 x 6 mg/kg day 1, switching to oral therapy with 2 x 200 mg from day 7). It
has the advantage of effectively penetrating the brain parenchyma (Schwartz 2005), but
visual disturbances occur in about 20% and often (reversible) liver elevations. Thera-
peutic monitoring with target levels 1–5,5 mg/l is recommended (Ullmann 2018).
Alternatives to voriconazole include isavuconazole (Cresemba®), at a daily dose of
3 x 200 mg i.v. for 2 days, followed by 1 x 200 mg IV or per os (Maertens 2016), lipo-
somal amphotericin B (3 mg/kg/d), caspofungin, or posaconazole. Combinations are
probably no better (Garbati 2012). Steroid therapies should be discontinued if
possible, and any affected individual should receive antiretroviral therapy promptly.
The duration of therapy with antimycotics depends on the clinical course; before
discontinuation, no activity should be detectable in the CT thorax.
Literature
Garbati MA, Alasmari FA, Al-Tannir MA, et al. The role of combination antifungal therapy in the treatment of
invasive aspergillosis: a systematic review. Int J Infect Dis 2012, 16:e76-81.
Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus vs amphotericin B for primary therapy of inva-
sive aspergillosis. NEJM 2002, 347:408-15.
Hunt SM, Miyamoto RC, Cornelius RS, Tami TA. Invasive fungal sinusitis in the AIDS. Otolaryngol Clin North
Am 2000, 33:335-47.
Maertens JA, Raad II, Marr K, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould
disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-infe-
riority trial. Lancet 2016, 387(10020):760-9.
Mylonakis E, Barlam TF, Flanigan T, Rich JD. Pulmonary aspergillosis and invasive disease in AIDS: review of 342
cases. Chest 1998, 114:251-62.
Mylonakis E, Paliou M, Sax PE, et al. Central nervous system aspergillosis in patients with HIV infection. Medicine
(Baltimore) 2000, 79:269-80.
Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome in central nervous system aspergillosis, using voricona-
zole treatment. Blood 2005, 106:2641-5.
Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al. Diagnosis and management of Aspergillus diseases. Clin Microbiol
Infect 2018, 24 Suppl 1:e1-e38.
Yoganathan K. Long-term suppressive therapy for pulmonary aspergilloma in an immunocompromised man with
AIDS. Is it always necessary? Int J STD AIDS 2009, 20:434-6.
Opportunistic infections (OI) 345

Bacillary angiomatosis
Bacillary angiomatosis (BA) was already described in PLWH in the 1980s (review:
Maguiña 2000). It is caused by the two species Bartonella henselae and Bartonella
quintana (formerly “Rochalimaea”). Cats are the primary host for Bartonella henselae,
and cat fleas are the vector. Various pathogen reservoirs are discussed for Bartonella
quintana, and people from socially deprived backgrounds, especially people experi-
encing homelessness, frequently become ill (Gasquet 1998). In North and South
America, BA is probably more common; in Brazil, antibody prevalence was 38%
(Lamas 2010). In a study of 382 febrile PLWH in San Francisco, bartonella was the
cause of fever in 18% (Koehler 2003).
BA is an important differential diagnosis in cases of unclear skin proliferations. The
vascular skin proliferation can occur solitary but is usually multiple and is clinically
(and histologically!) confused with Kaposi’s sarcomas or even hemangiomas as
cherry-red or purplish nodules. Dry, hyperkeratotic changes reminiscent of psoriasis
also occur. In addition to the skin, the skeleton is also affected in about 25%, with
osteolytic, painful foci (AP elevation!). In a case collection of 21 patients, the skin
was involved in 19, bone in 5, and liver in 4 (Plettenberg 2000). Lymph nodes,
muscle, CNS involvement, and eye, gingiva, and gastrointestinal tract manifestations
have also been reported.
Diagnosis is difficult. The Gram-negative pathogens can only be visible from biopsy
material using Warthin-Starry silver staining. If you do not do a Warthin-Starry silver
stain, you will not diagnose BA! Pathologies should be advised of the suspicion as
this stain is not routine. PCR is also possible.
Therapy consists of at least four weeks of erythromycin, 4 x 500 mg/die (Maguiña
2009). Recurrences are common, so some experts favor at least three months of
therapy. Clarithromycin and doxycycline are also reported to be effective, the latter
being considered the treatment of choice for CNS involvement.
Because cats are important carriers, US guidelines recommend not keeping them as
pets. If it “has to be”, the cat should be older than one year and healthy. Scratch
injuries should be avoided.
Literature
Cockerell CJ, LeBoit PE. Bacillary angiomatosis: a newly characterized, pseudoneoplastic, infectious, cutaneous
vascular disorder. J Am Acad Dermatol 1990, 22:501-12.
Gasquet S, Maurin M, Brouqui P, Lepidi H, Raoult D. Bacillary angiomatosis in immunocompromised patients.
AIDS 1998, 12:1793-803.
Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacil-
lary angiomatosis-peliosis. N Engl J Med 1997, 337:1876-83.
Koehler JE, Sanchez MA, Tye S, et al. Prevalence of Bartonella infection among HIV-infected patients with fever.
Clin Infect Dis 2003, 37:559-66.
Lamas CC, Mares-Guia MA, Rozental T, et al. Bartonella spp. infection in HIV positive individuals, their pets and
ectoparasites in Rio de Janeiro, Brazil: serological and molecular study. Acta Trop 2010, 115:137-41.
LeBoit PE, Berger TG, Egbert BM, Beckstead JH, Yen TSB, Stoler MH. Bacillary angiomatosis: the histopathology
and differential diagnosis of a pseudoneoplastic infection in patients with HIV disease. Am J Surg Pathol 1989,
13:909-920.
Maguiña C, Guerra H, Ventosilla P. Bartonellosis. Clin Dermatol 2009, 27:271-80.
Plettenberg A, Lorenzen T, Burtsche BT, et al. Bacillary angiomatosis in HIV-infected patients—an epidemiologi-
cal and clinical study. Dermatology 2000, 201:326-31.
Pons I, Sanfeliu I, Nogueras MM, et al. Seroprevalence of Bartonella spp. infection in HIV patients in Catalonia,
Spain. BMC Infect Dis 2008, 8:58.
Stoler MH, Bonfiglio TA, Steigbigel RB, et al. An atypical subcutaneous infection associated with AIDS. Am J Clin
Pathol 1983, 80:714-718.
346 AIDS

Histoplasmosis
Histoplasma capsulatum is a dimorphic mold that lives primarily in moist soil and,
despite its name, does not have a capsule. Endemic areas include the southern and
Midwestern United States, Central America, and Africa. Histoplasmosis remains a
severe and important OI in these regions (Ocansey 2022) and is a rarity in Northern
Europe.
If the microconidia (spores) are inhaled, they can cause granulomatous disease in
the lungs of immunocompetent individuals. In PLWH (85–95% have less than 100
CD4 T-cells/µl), infection leads to a life-threatening illness with dry cough, fever,
dyspnea, and feeling sick (Gutierrez 2005, Mora 2008). Miliary TB or PCP are impor-
tant differential diagnoses. Disseminated courses also occur, where the pathogen can
be detected in bone marrow or liver (Albrecht 1994). Skin (ulcers), oropharynx, or
CNS may also be involved (Scheinfeld 2003, Wheat 2005, Antonello 2011). Hepato-
splenomegaly is usually present (Mora 2008).
Histoplasmosis is an AIDS-defining disease. Analogous to cryptococci, the pathogen
can be detected relatively reliably in the blood with an antigen test. In the labora-
tory, LDH, AP, and transaminases are sometimes significantly elevated.
Itraconazole (2–3 x 200 mg/day) can be given in milder cases, arguably better than
fluconazole (Wheat 2002). In all other cases, liposomal amphotericin (3 mg
Ambisome®, 3 mg/kg/day for 14 days) is recommended, which is less toxic and
possibly more effective than amphotericin (Johnson 2002). It can be switched to
itraconazole after 7–10 days if stabilized. Acute therapy lasts 12 weeks, after which
itraconazole is given at half dose (1 x 200 mg) as secondary prophylaxis. Note inter-
actions, especially with ritonavir and efavirenz (Andrade 2009, Hills-Nieminen 2009),
which frequently require dose modifications. Analogous to other OIs, secondary pro-
phylaxis can be discontinued if immune reconstitution is permanent (Goldman
2004). Immune reconstitution syndromes are possible (Nacher 2006).
Literature
Albrecht H, Stellbrink HJ, Petersen J, et al. Disseminated histoplasmosis in AIDS. Dtsch Med Wschr 1994, 119:657-62.
Andrade RA, Evans RT, Hamill RJ, Zerai T, Giordano TP. Clinical evidence of interaction between itraconazole and
NNRTIs in HIV-infected patients with disseminated histoplasmosis. Ann Pharmacother 2009, 43:908-13.
Antonello VS, Zaltron VF, Vial M, Oliveira FM, Severo LC. Oropharyngeal histoplasmosis: report of eleven cases
and review of the literature. Rev Soc Bras Med Trop 2011, 44:26-9.
Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated
histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004, 38:1485-9.
Gutierrez ME, Canton A, Sosa N, et al. Disseminated histoplasmosis in patients with AIDS in Panama: a review
of 104 cases. Clin Infect Dis 2005;40:1199-202.
Hills-Nieminen C, Hughes CA, Houston S, Shafran SD. Drug-drug interaction between itraconazole and the pro-
tease inhibitor lopinavir/ritonavir. Ann Pharmacother 2009, 43:2117-20.
Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy of liposomal amphotericin B compared with con-
ventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002,
137: 105-9.
Mora DJ, dos Santos CT, Silva-Vergara ML. Disseminated histoplasmosis in AIDS patients in Uberaba, MG, Brazil.
Mycoses 2008;51:136-40.
Nacher M, Sarazin F, El Guedj M, et al. Increased incidence of disseminated histoplasmosis following HAART ini-
tiation. J AIDS 2006, 41:468-70.
Ocansey BK, Kosmidis C, Agyei M, et al. Histoplasmosis in Africa: Current perspectives, knowledge gaps, and
research priorities. PLoS Negl Trop Dis 2022, 16:e0010111.
Scheinfeld N. Diffuse ulcerations due to disseminated histoplasmosis in a patient with HIV. J Drugs Dermatol
2003, 2:189-91.
Wheat LJ, Connolly P, Haddad N, et al. Antigen clearance during treatment of disseminated histoplasmosis with
itraconazole versus fluconazole in patients with AIDS. Antimicrob Agents Chemother 2002, 46:248-50.
Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin
Inf Dis 2005, 40:844-52.
Opportunistic infections (OI) 347

Isosporiasis (Cystoisosporiasis)
Isospora belli is a ubiquitous intestinal parasite. Rare in Europe and the US, isospori-
asis is a major problem, especially in the tropics and subtropics – mainly affecting
PLWH in Africa (Lagrange-Xelot 2008). In India, Isospora belli was the second most
common diarrheal germ after cryptosporidia in PLWH (Kulkarni 2009). Like
cryptosporidiosis, the germ occasionally causes epidemic-like outbreaks, even in
immunocompetent individuals. Affected individuals suffer from (usually mild)
enteritis-like symptoms, occasionally severe watery diarrhea, abdominal cramps, and
nausea.
Chronic diarrhea and malnutrition may occur in immunodeficient patients (review:
Goodgame 1996). Fever is rare. The median CD4 T-cell count in isosporiasis is 150/µl,
slightly higher than in cryptosporidia or microsporidia.
Chronic isosporiasis with diarrhea lasting more than four weeks is considered AIDS-
defining. Detection of the relatively large oocysts is successful in regular stool exam-
inations for parasites and acid-fast stains. There is usually an eosinophilia in the
blood (Certad 2003).
Cotrimoxazole (960 mg/die, one week) is suitable as therapy. Somewhat less effective
is ciprofloxacin (Verdier 2000). Recurrences also occur despite ART and secondary
prophylaxis with cotrimoxazole (Lagrange-Xelot 2008).
Literature
Certad G, Arenas-Pinto A, Pocaterra L, et al. Isosporiasis in Venezuelan adults infected with HIV: clinical charac-
terization. Am J Trop Med Hyg 2003, 69:217-22.
Goodgame RW. Understanding intestinal spore-forming protozoa: cryptosporidia, microsporidia, isospora,
cyclospora. Ann Int Med 1996,124:429-41.
Kulkarni SV, Kairon R, Sane SS, et al. Opportunistic parasitic infections in HIV/AIDS patients presenting with diar-
rhoea by the level of immunesuppression. Indian J Med Res 2009, 130:63-6.
Lagrange-Xelot M, Porcher R, Sarfati C, et al. Isosporiasis in patients with HIV infection in the HAART era in
France. HIV Med 2008;9:126-30.
Verdier RI, Fitzgerald DW, Johnson WD Jr, Pape JW. Trimethoprim-sulfamethoxazole compared with ciprofloxacin
for treatment and prophylaxis of Isospora belli and Cyclospora cayetanensis infection in HIV-infected patients.
A randomized, controlled trial. Ann Intern Med 2000, 132:885-8.

Coccidioidomycosis
The mold infection with Coccidioides immitis occurs endemically in the southwestern
US (review: Ampel 2003, Crum 2022). The disease should be considered when visit-
ing Arizona or New Mexico. Disseminated coccidioidomycoses beyond the lungs and
hilar lymph nodes (chronic meningoencephalitides) occur almost exclusively in the
presence of marked immunodeficiency of less than 250 CD4 T-cells/µl. This disease
is AIDS-defining.
The spores are inhaled, primarily affecting the lungs (Pappagianis 1993). About 1–3
weeks after exposure, a pneumonia-like clinical picture develops with fever, cough,
chest pain, and feeling of illness. In immunocompetent individuals, the infection,
which is often asymptomatic, usually heals without sequelae. Occasionally, cavities
remain, rarely requiring surgical intervention (Jaroszewski 2009). In the “pre-HAART
era,” prognosis was poor, with a one-year mortality of 63% in 602 patients (Jones
1995). Today, the course is usually milder with ART (Masannat 2010).
Serology is usually of little help in immunodeficient patients. The diagnosis can
usually be made from cultures or histological materials (Adam 2009). Suspicion must
be reported to laboratory personnel, as there is a high risk of infection.
Both amphotericin and azoles are effective (Hernandez 1997); they should possibly
be combined (Ampel 2007). Detailed recommendations for different situations
348 AIDS

(meningeal or disseminated cases must be treated more intensively) can be found in

Galgiani 2005. Fluconazole should be given in high doses (400 mg) as maintenance
therapy. Posaconazole may also be considered (Schein 2011). In recent years, the
disease has become less common with ART. Maintenance therapy can probably be
discontinued if CD4 T-cells exceed 250/µl and initial pulmonary involvement is
present. However, lifelong therapy is still recommended for meningeal involvement
(Woods 2000, Galgiani 2005, Ampel 2007).
Literature
Adam RD, Elliott SP, Taljanovic MS. The spectrum and presentation of disseminated coccidioidomycosis. Am J
Med 2009, 122:770-7.
Ampel NM. Coccidioidomycosis in persons infected with HIV-1. Ann N Y Acad Sci 2007;1111:336-42.
Crum NF. Coccidioidomycosis: A Contemporary Review. Infect Dis Ther 2022, 11:713-742.
Hernandez JL, Echevarria S, Garcia-Valtuille A, Mazorra F, Salesa R. Atypical coccidioidomycosis in an AIDS patient
successfully treated with fluconazole. Eur J Clin Microbiol Infect Dis 1997, 16:592-4.
Jaroszewski DE, Halabi WJ, Blair JE, et al. Surgery for pulmonary coccidioidomycosis: a 10-year experience. Ann
Thorac Surg 2009, 88:1765-72.
Masannat FY, Ampel NM. Coccidioidomycosis in patients with HIV-1 infection in the era of potent antiretrovi-
ral therapy. Clin Infect Dis 2010, 50:1-7.
Pappagianis D. Coccidioidomycosis. Semin Dermatol 1993, 12:301-9.
Schein R, Homans J, Larsen RA, Neely M. Posaconazole for chronic refractory coccidioidal meningitis. Clin Infect
Dis 2011, 53:1252-4.
Woods CW, McRill C, Plikaytis BD, et al. Coccidioidomycosis in HIV-infected persons in Arizona, 1994-1997: inci-
dence, risk factors, and prevention. J Infect Dis 2000, 181:1428-34.

Leishmaniasis (visceral)
Leishmaniasis is the collective term for infections with protozoa of the genus
Leishmania; cutaneous leishmaniasis is to be distinguished from visceral leishmani-
asis (Kalar Azar); the form of manifestation depends, among other things, on the
species (L. donovani, L. infantum, L. chagasi). According to WHO, 12 million people
are infected, and 350 million live in risk areas. Leishmaniasis is thus one of the most
important parasitoses of all. In Europe, the Mediterranean region is particularly
affected (mostly L. infantum).
PLWH are more likely to develop visceral leishmaniasis than HIV-negative individ-
uals. In Spain, one-third are HIV-infected (Gil-Prieto 2011). Although much would
suggest this, leishmaniasis is not considered AIDS-defining. An evaluation of 15 cases
from Germany showed significant immunosuppression (mostly below 100 CD4
T-cells/µl). Some patients had not been in the endemic areas for several years
(Albrecht 1998).
The almost obligate pancytopenia, particularly pronounced in PLWH (Pintado 2001),
reflects bone marrow involvement. Fever, hepatosplenomegaly, and mucocutaneous
lesions are additional symptoms. Diagnosis is usually made by bone marrow aspi-
rate.
Treatment of visceral leishmaniasis is difficult (overview: Burza 2018). Previously
used antimony preparations such as stibogluconate (Pentostam®) and meglumine
antimonate (Glucantime®) are toxic. Myalgias, arthralgias, gastrointestinal symp-
toms, pancreatitis, and cardiotoxicity often force discontinuation (Laguna 1999).
Combination therapies are probably equally effective and allow a shortening of
therapy – a strategy hardly used in Germany (van Griensven 2010, Sundar 2011).
According to a meta-analysis, amphotericin works better than the antimony prepa-
rations (Cota 2013). In the 2016 guidelines of the German Tropical Medicine Society,
liposomal amphotericin B (AmBisome®) is considered the drug of choice for HIV:
Opportunistic infections (OI) 349

in the total dose of 30–40 mg/kg, divided into at least 5 single doses over 10–21 days,
followed by relapse prophylaxis 3 mg/kg every three weeks). However, the effect is
not always optimal (Rijtmeier 2011, Sinha 2011).
An alternative – because it is tolerable, effective, and the only Leishmania drug that
is orally bioavailable – is the alkylphosphocholine analog miltefosine (Impavido®),
approved in Germany in 2004. How miltefosine inhibits Leishmania metabolism is
still unclear, but it is effective in a large phase III study in India (Sundar 2002).
However, a randomized trial in Ethiopia showed a somewhat weaker effect in PLWH
than under stiboglucanate, albeit with better tolerability (Ritmeijer 2006). Higher
success rates are shown with combination therapy of liposomal amphotericin B and
miltefosine – versus liposomal amphotericin B alone (Diro 2019, Burza 2022). The
aminoglycoside paromomycin also appears to be effective when administered intra-
muscularly (Sundar 2007+2011). Paromomycin (Humatin®) has only been approved
as a local intestinal therapeutic in Europe.
Pentamidine may also work as secondary prophylaxis (Patel 2009), but fluconazole
is probably ineffective (Rybniker 2009). Leishmania recurrences can be expected in
almost half of the cases. ART seems to change this – another argument for the inclu-
sion of visceral leishmaniasis in the AIDS classification (de La Rosa 2002, Fernandez-
Cotarelo 2003).

Literature
Albrecht H, Sobottka I, Emminger C, et al. Visceral leishmaniasis is emerging as an important opportunistic infec-
tion in HIV-infected persons living in areas nonendemic for Leishmania donovani. Arch Pathol Lab Med 1996,
120:189-98.
Albrecht H. Leishmaniosis – new perspectives on an underappreciated opportunistic infection. AIDS 1998, 12:2225-6.
Burza S, Croft SL, Boelaert M. Leishmaniasis. Lancet 2018, 392:951-970.
Burza S, Mahajan R, Kazmi S, et al. AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy
for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India:
A Randomized Open-Label, Parallel-Arm, Phase 3 Trial. Clin Infect Dis 2022;75:1423-1432.
Cota GF, de Sousa MR, Fereguetti TO, Rabello A. Efficacy of anti-leishmania therapy in visceral leishmaniasis
among HIV infected patients: a systematic review with indirect comparison. PLoS Negl Trop Dis 2013, 7:e2195.
Diro E, Blesson S, Edwards T, et al. A randomized trial of AmBisome monotherapy and AmBisome and miltefos-
ine combination to treat visceral leishmaniasis in HIV co-infected patients in Ethiopia. PLoS Negl Trop Dis 2019,
13(1):e0006988.
de La Rosa R, Pineda JA, Delgado J, et al. Incidence of and risk factors for symptomatic visceral leishmaniasis
among HIV type 1-infected patients from Spain in the era of HAART. J Clin Microbiol 2002, 40:762-7.
Fernandez-Cotarelo MJ, Abellan Martinez J, Guerra Vales JM, et al. Effect of highly active antiretroviral therapy
on the incidence and clinical manifestations of visceral leishmaniasis in human immunodeficiency virus-infected
patients. Clin Infect Dis 2003, 37: 973-7.
Gil-Prieto R, Walter S, Alvar J, de Miguel AG. Epidemiology of leishmaniasis in Spain based on hospitalization
records (1997-2008). Am J Trop Med Hyg 2011, 85:820-5.
Laguna F, Lopez-Velez R, Pulido F, et al. Treatment of visceral leishmaniasis in HIV-infected patients: a random-
ized trial comparing meglumine antimoniate with amphotericin B. AIDS 1999, 13:1063-9.
Patel TA, Lockwood DN. Pentamidine as secondary prophylaxis for visceral leishmaniasis in the immunocom-
promised host: report of four cases. Trop Med Int Health 2009, 14:1064-70.
Ritmeijer K, Dejenie A, Assefa Y, et al. A comparison of miltefosine and sodium stibogluconate for treatment of
visceral leishmaniasis in an Ethiopian population with high prevalence of HIV infection. CID 2006, 43:357-64.
Ritmeijer K, ter Horst R, Chane S, et al. Limited effectiveness of high-dose liposomal amphotericin B (AmBisome)
for treatment of visceral leishmaniasis in an Ethiopian population with high HIV prevalence. CID 2011, 53:e152-8.
Rybniker J, Goede V, Mertens J, et al. Treatment of visceral leishmaniasis with intravenous pentamidine and oral
fluconazole in an HIV-positive patient with chronic renal failure – a case report and brief review of the literature.
Int J Infect Dis. 2009 Aug 31.
Sinha PK, van Griensven J, Pandey K, et al. Liposomal amphotericin B for visceral leishmaniasis in human immun-
odeficiency virus-coinfected patients: 2-year treatment outcomes in Bihar, India. Clin Infect Dis 2011, 53:e91-8.
Sundar S, Jha TK, Thakur CP, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 2002, 347:1739-46.
Sundar S, Jha TK, Thakur CP, Sinha PK, Bhattacharya SK. Injectable paromomycin for Visceral leishmaniasis in
India. N Engl J Med 2007;356:2571-81.
Sundar S, Sinha PK, Rai M, et al. Comparison of short-course multidrug treatment with standard therapy for vis-
ceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet 2011, 377:477-86.
van Griensven J, Balasegaram M, Meheus F, et al. Combination therapy for visceral leishmaniasis. Lancet Infect
Dis 2010, 10:184-194.
350 AIDS

Microsporidiosis
Microsporidiosis is an important cause of diarrhea in PLWH worldwide. At least four
human pathogenic genera of these obligate intracellular protozoa have been
described, Enterocytozoon bieneusi being the most important. Microsporidia were also
once among the common diarrheal pathogens in Germany (Sobottka 1998). ART has
resulted in a sharp decline in incidence. The microsporidia are not AIDS-defining,
although they almost exclusively affect massively immunocompromised individu-
als with fewer than 50 CD4 T-cells/µl.
Diarrhea is usually watery, without blood, accompanied by abdominal pain, nausea,
and vomiting. Fever is almost always absent. Rarely, myositis, keratoconjunctivitis,
and sinusitis have been described. Biliary tract infections are more common. The
laboratory must have experience! Microsporidia are very small, and those not
explicitly asked about them do not see them! Cultures are not established. Detection
is best done with special stains. Special transport or preparation is not necessary.
Albendazole (Eskazole® 2 x 1–2 tab. of 400 mg/day for 4 weeks) works relatively well,
but E. bieneusi is often resistant. Small case series on fumagillin (caveat: thrombo-
cytopenias!) have been published (Carr 2002, Molina 2002), as well as on niazoxanide
(Bicart-See 2000). However, ART-mediated immune reconstitution seems to be most
effective (Carr 1998+2002, Maggi 2000).
Literature
Bicart-See A, Massip P, Linas MD, Datry A. Successful treatment with nitazoxanide of Enterocytozoon bieneusi
microsporidiosis in a patient with AIDS. Antimicrob Agents Chemother 2000, 44:167-8.
Carr A, Cooper DA. Fumagillin for intestinal microsporidiosis. N Engl J Med 2002, 347:1381.
Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1 associated microsporidiosis and cryp-
tosporidiosis with combination antiretroviral therapy. Lancet 1998, 351:256-61.
Maggi P, Larocca AM, Quarto M, et al. Effect of antiretroviral therapy on cryptosporidiosis and microsporidiosis
in patients infected with HIV virus type 1. Eur J Clin Microbiol Infect Dis 2000, 19:213-7.
Molina JM, Tourneur M, Sarfati C, et al. Fumagillin treatment of intestinal microsporidiosis. N Engl J Med 2002,
346:1963-9.
Sobottka I, Schwartz DA, Schottelius J, et al. Prevalence and clinical significance of intestinal microsporidiosis in
HIV-infected patients with and without diarrhea in Germany: a prospective coprodiagnostic study. Clin Infect
Dis 1998, 26:475-80.

Nocardiosis
Nocardia are aerobic bacteria or actinomycetes that occur worldwide. They mainly
cause pneumonia but also systemic diseases. In one of the largest case collections
(from Florida), the lungs were affected in 21 cases in 30 PLWH (Uttamchandani
1994). Pulmonary nocardiosis is often confused with tuberculosis. Extrapulmonary
sites of manifestation include skin, brain, as well as kidney, muscle, and bone.
In most cases, severe immunodeficiency is present (Javaly 1992, Uttamchandani
1994). The CD4 T-cells were about 100/µl. Therapeutically, carbapenems (imipenem)
and cotrimoxazole are mainly used (Ott 2019). However, experience hardly goes
beyond case reports or small case series.
Literature
Javaly K, Horowitz HW, Wormser GP. Nocardiosis in patients with HIV infection. Report of 2 cases and review of
the literature. Medicine 1992,71:128-38.
Ott SR, Meier N, Kolditz M, et al. Pulmonary nocardiosis in Western Europe-Clinical evaluation of 43 patients
and population-based estimates of hospitalization rates. Int J Infect Dis 2019, 81:140-148.
Pintado V, Gomez-Mampaso E, Cobo J, et al. Nocardial infection in patients infected with the HIV. Clin Microbiol
Infect 2003, 9:716-20.
Uttamchandani RB, Daikos GL, Reyes RR, et al. Nocardiosis in 30 patients with advanced HIV infection: clinical
features and outcome. Clin Infect Dis 1994, 18:348-53.
Opportunistic infections (OI) 351

Rhodococcosis
Rhodococcus equi (formerly Corynebacterium equi) is a sporeless, Gram-positive, intra-
cellular pathogen that is ubiquitous and occurs primarily in dry, dusty soil. R. equi
has been found on every continent and is most significant in veterinary medicine
in horses. The first case of an AIDS patient was described as early as 1986 (Samies
1986). Predominantly, individuals with less than 50 CD4 T-cells/µl are affected
(Capdevila 1997). Clinically, there are severe granulomatous or abscessing pneumo-
nia and occasionally disseminated infections. The main symptoms are fever, dyspnea,
and nonproductive cough (Capdevila 1997). Radiographs often show caverns in the
upper lobes (Marchiori 2005).
Rhodococci are best detected in sputum and blood cultures (Torres-Tortosa 2003). In
sputum, however, the coryneform bacteria are often confused with diphtheroid
germs of the oral flora.
Erythromycin, azithromycin, ciprofloxacin, rifampicin, or vancomycin are effective.
The substances are also combined. However, therapy sometimes does not result in
a cure despite ART (Plum 1997, Sanz-Moreno 2002, Ferretti 2011), and surgical
intervention may be required for extensive cavities. However, ART improves the
prognosis overall; in any case, antiretroviral treatment should be given immediately
(Torres-Tortosa 2003, Gundelly 2016).
Literature
Capdevila JA, Bujan S, Gavalda J, Ferrer A, Pahissa A. Rhodococcus equi pneumonia in patients infected with HIV.
Report of 2 cases and review of the literature. Scand J Infect Dis 1997, 9:535-41.
Ferretti F, Boschini A, Iabichino C, et al. Disseminated Rhodococcus equi infection in HIV infection despite highly
active antiretroviral therapy. BMC Infect Dis 2011, 11:343.
Gundelly P, Suzuki Y, Ribes JA, Thornton A. Differences in Rhodococcus equi Infections Based on Immune Status
and Antibiotic Susceptibility of Clinical Isolates in a Case Series of 12 Patients and Cases in the Literature. Biomed
Res Int. 2016;2016:2737295.
Marchiori E, Muller NL, de Mendonca RG, et al. Rhodococcus equi pneumonia in AIDS: high-resolution CT find-
ings in five patients. Br J Radiol 2005, 78:783-6.
Plum G, Fätkenheuer G, Hartmann P, et al. Secondary prophylaxis of Rhodococcus equi pneumonia in HIV infec-
tion: breakthrough despite rifampicin/erythromycin suppressive therapy. Clin Microbiol Infect 1997, 3:141-143.
Samies JH, Hathaway BN, Echols RM, et al. Lung abscess due to Corynebacterium equi: report of the first case in
a patient with AIDS. Am J Med 1986, 80:685–688.
Sanz-Moreno J, Flores-Segovia J, Olmedilla-Arregui G, et al. Rhodococcus equi pneumonia: HAART helps but does
not cure lung infection. AIDS 2002, 16:509-11.
Torres-Tortosa M, Arrizabalaga J, Villanueva JL, et al. Prognosis and clinical evaluation of infection caused by
Rhodococcus equi in HIV-infected patients: a multicenter study of 67 cases. Chest 2003, 123:1970-6.

Talaromycosis (formerly penicilliosis)

Talaromycis (formerly Penicillium) marneffei is a problem relevant to Southeast Asia –
especially during the rainy season (Le 2011). Rather a rarity in Germany, the disease
is the most common fungal infection in PLWH in Thailand, Vietnam, and southern
China, along with cryptococcosis (Review: Cao 2019). The only patient we saw had
traveled through Thailand for several months (Sobottka 1996).
There is almost always a severe immunodeficiency; in the IVAP study (see below),
the median CD4 T-cell count of 440 PLWH was 10/µl. Nevertheless, according to the
CDC classification, the infection is not considered AIDS-defining. The only known
hosts for T. marneffei are humans, rats, and possibly dogs. Most infections likely occur
via spore inhalation.
Lungs and skin are most frequently affected, and disseminated courses are possible
(Ma 2005). Clinically, there are striking parallels to histoplasmosis. The clinic consists
of high, prolonged fever, lymphadenopathy, weight loss, malaise, cough, and
352 AIDS

hemoptysis. Cutaneous lesions, present in 80%, resemble molluscs. The liver and
spleen are often enlarged (see picture plates!). The culture from blood (successful in
70%), bone marrow, sputum, or biopsies is diagnostically decisive.
Amphotericin B, voriconazole, and itraconazole are effective (Cao 2019). However,
in the randomized IVAP trial in 440 (!) patients in Vietnam, conventional ampho-
tericin B was more clinically effective than itraconazole (Le 2017). Liposomal ampho-
tericin B at the dose of 3 mg/kg IV is considered the agent of choice in the current
EACS guidelines. Itraconazole is recommended only as an alternative relapse pro-
phylaxis at 200 mg once daily (Supparatpinyo 1998, EACS 2021). Secondary pro-
phylaxis can be discontinued when the viral load has been below the detection limit
for at least six months, and CD4 T-cells have reached at least 100/µl (Tun 2020). On
the other hand, primary prophylaxis is not advisable even for prolonged stays in
endemic areas (Chariyalertsak 2002) but is sometimes recommended for severe
immunodeficiency (Cao 2019).
Literature
Cao C, Xi L, Chaturvedi V. Talaromycosis (Penicilliosis) Due to Talaromyces (Penicillium) marneffei: Insights into
the Clinical Trends of a Major Fungal Disease 60 Years After the Discovery of the Pathogen. Mycopathologia 2019,
184:709-720.
Chariyalertsak S, Supparatpinyo K, Sirisanthana T, et al. A controlled trial of itraconazole as primary prophylaxis
for systemic fungal infections in patients with advanced HIV infection in Thailand. Clin Infect Dis 2002, 34:277-
84.
European AIDS Clinical Society (EACS), GUIDELINES Version October 2021; [Link]
lines/eacs-guidelines/[Link] (abgerufen 5.4.2022).
Le T, Wolbers M, Chi NH, et al. Epidemiology, Seasonality, and Predictors of Outcome of AIDS-Associated
Penicillium marneffei Infection in Ho Chi Minh City, Viet Nam. Clin Infect Dis 2011, 52:945-52.
Le T, Kinh NV, Cuc NTK, Tung NL. A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis.
NEJM 2017, 376:2329-2340.
Ma ES, Ho PL. Disseminated Penicillium marneffei infection. Br J Haematol 2005, 130:2.
Sobottka I, Albrecht H, Mack D, et al. Systemic Penicillium marneffei infection in a German AIDS patient. Eur J
Clin Mic Inf Dis 1996,15:256-9.
Supparatpinyo K, Perriens J, Nelson KE, Sirisanthana T. A controlled trial of itraconazole to prevent relapse of
Penicillium marneffei infection in patients infected with the HIV. N Engl J Med 1998, 339:1739-43.
Tun N, Mclean A, Deed X. Is stopping secondary prophylaxis safe in HIV-positive talaromycosis patients?
Experience from Myanmar. HIV Med 2020, 21:671-673.

Trypanosomiasis
Trypanosoma cruzi is a protozoan transmissible through the infected feces of predatory
bugs, found almost exclusively in the Americas. It causes Chagas disease, one of
South America’s most common causes of cardiomyopathy. PLWH have more frequent
and higher parasitemia (Sartori 2002), and the trypanosome-specific immune
response is predominantly cellular. Far more frequently than in uninfected persons,
there is also a usually severe meningoencephalitis that is radiologically indistin-
guishable from cerebral toxoplasmosis or primary cerebral lymphoma. Reactivation
is most likely (Diazgranados 2009, de Almeida 2011). In PLWH from South America,
trypanosome infection should be considered (Silva 1999, Cordova 2008, Llenas-
García 2012).
Diagnosis is based on serology (which can also be negative) and evidence from the
cerebrospinal fluid. Although therapy with, for example, benznidazole is effective,
mortality is nevertheless very high (Sartori 2007, Cordova 2008). Itraconazole or
ketoconazole may also be effective (de Almeida 2009).
Opportunistic infections (OI) 353

Literature
Cordova E, Boschi A, Ambrosioni J, Cudos C, Corti M. Reactivation of Chagas disease with central nervous system
involvement in HIV-infected patients in Argentina, 1992-2007. Int J Infect Dis 2008,12:587-92.
de Almeida EA, Ramos Júnior AN, Correia D, Shikanai-Yasuda MA. Co-infection Trypanosoma cruzi/HIV: sys-
tematic review (1980-2010). Rev Soc Bras Med Trop 2011, 44:762-70.
de Almeida EA, Silva EL, Guariento ME, et al. Aetiological treatment with itraconazole or ketoconazole in indi-
viduals with Trypanosoma cruzi/HIV co-infection. Ann Trop Med Parasitol 2009, 103:471-6.
Diazgranados CA, Saavedra-Trujillo CH, Mantilla M, et al. Chagasic encephalitis in HIV patients: common pres-
entation of an evolving epidemiological and clinical association. Lancet Infect Dis 2009, 9:324-30.
Llenas-García J, Hernando A, Fiorante S, et al. Chagas disease screening among HIV-positive Latin American immi-
grants: an emerging problem. Eur J Clin Microbiol Infect Dis. 2012 Jan 19.
Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomia-
sis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007;101:31-50.
Sartori AM, Neto JE, Nunes EV, et al. Trypanosoma cruzi parasitemia in chronic Chagas disease: comparison
between HIV-positive and HIV-negative patients. J Infect Dis 2002, 186:872-5.
Silva N, O’Bryan L, Medeiros E, et al. Trypanosoma cruzi meningoencephalitis in HIV-infected patients. J AIDS
Hum Retrovirol 1999, 20:342-9.
354

8. Kaposi’s sarcoma
C H R I ST I A N H O F F M A N N , ST E FA N E S S E R

Kaposi’s sarcoma (KS) is the most common AIDS-defining neoplasm. In 1981, the
simultaneous occurrence of Pneumocystis pneumonia in young MSM led to the first
description of AIDS. KS is named after the Hungarian dermatologist Moritz Kaposi,
who described “classic” KS more than 100 years ago – a variant not associated with
HIV that occurs predominantly in older men from the Eastern European-
Mediterranean region with a genetic disposition. In addition, there is also “endemic”
KS in some sub-Saharan countries. Classical CS is relatively benign, often affecting
only the skin of the lower extremities, and is thus clinically distinct from HIV-
associated KS, which will be discussed below.
HIV-associated KS primarily affects the skin and mucous membranes. However,
lymph nodes and internal organs such as the gastrointestinal tract, lungs, or liver
are also frequently affected. Lymphatic or visceral involvement also occurs in
isolation. The course of KS is highly variable, ranging from single lesions that remain
stationary for years to markedly aggressive courses that lead to death within a few
weeks. Until the 1990s, one of the most common AIDS diseases of all, the prevalence
has declined significantly due to ART (Francesci 2010) and is now barely one-tenth
compared to earlier years (Grabar 2006, Simard 2011). Also, the clinical course today
is usually milder; in particular, the sudden and severe, disfiguring, and often fatal
manifestations have become rare. In our retrospective cohort (2000–2014), KS was
the probable cause of death in only 5/230 cases (Meyer 2016). KS in the setting of
immune reconstitution syndrome (IRIS) is a particular case. Here, aggressive courses,
often with visceral involvement, occur a few months after ART initiation, and
mortality is considerable (Crane 2005, Achenbach 2012). High HHV-8 and HIV
viremia are risk factors for aggressive courses (Letang 2013).
The typical KS spindle cells probably originate from lymphatic endothelial cells
(Dupin 2006). Since 1994, KS has been known to be caused by an infection with the
human herpesvirus 8 (HHV-8, also “Kaposi sarcoma-associated herpesvirus” KSHV).
HHV-8 can always be detected in tumor tissue. HHV-8 viremia (median 6000
copies/mL) is present in approximately 40% but does not correlate with prognosis
and is unlikely to correlate with progression (Laney 2007, Haq 2016). Like other her-
pesviruses, HHV-8 is transmitted predominantly by saliva (Pauk 2000) but also sex-
ually, vertically, and via blood (Pica 2008). In some regions (Italy, Central Africa),
HHV-8 can be detected in up to 50% of the population. However, the exact role of
HHV-8 in the development is not clear. There may be a predisposition. Specific
endothelial cell receptor gene variants appear to play a role (Blumenthal 2019). HHV-8
likely manipulates transcriptional regulators of endothelial cells, interfering with
normal cell differentiation (Cancian 2013). Infection with HHV-8 does not neces-
sarily lead to KS. Interactions with HIV, possibly also with HHV-6 and HSV-1, altered
signal transduction chains, increased production of growth factors, and cytokine
dysregulation all play a role (McCormack 2005). HHV-8 is the driver, and HIV is the
trigger (Lidenge 2019).
Among PLWH in Western industrialized countries, almost exclusively homosexual
men are affected; KS is rare in women, children, or hemophiliacs. An immunodefi-
ciency or low CD4 T-cells promote development and growth but are not a condition.
Thus, KS is among the few AIDS conditions that occur even with good immune
status; nearly one-third have more than 300 CD4 T-cells/µl at diagnosis and a viral
load below the detection limit (Krown 2008). In the START trial of early ART initia-
tion, KS was primarily responsible for clinical differences (Borges 2016). Interestingly,
Kaposi’s sarcoma 355

cases of HIV-negative MSM with KS have been published (Rashidghamat 2014), and
KS lesions occur despite ART and suppressed viral load (Palich 2022). A low CD4/CD8
ratio appears to be a risk factor, especially with good CD4 T-cells and ART (Caby 2022).
New or recurrent KS lesions are also frequently seen during treatment with rituximab.

Clinical course
Typically, KS initially presents as bright to livid red, spindle-shaped patches or
nodules arranged in the direction of the skin cleavage lines. In the oral mucosa, the
hard palate is often affected. However, there are no predilection sites; any localization
is possible. The clinical course varies. The tumors may remain virtually unchanged
for years or grow and spread rapidly in a few weeks. Rapid growth is sometimes
accompanied by pain and yellow-green discoloration of the tumor surroundings
(hemorrhages!). Central necrosis and exulceration with bleeding tendency are
possible, as well as massive edema, especially on the extremities, genitals, and face.
Healing KS often initially fades, loses size, and leaves dirty grayish-brown to light
brown hyperpigmentation for months (sometimes for life). These are caused by
hemosiderin deposition and increased melanocyte stimulation due to inflammation.
Lymphedema can persist for years, especially on the lower legs.

Diagnostics
Although KS is usually a diagnosis by sight, histology (excision or incision) should
be generously taken in all unclear cases. Especially in African patients, clinical gaze
can be deceiving (Amerson 2016). This is the only way to avoid overlooking differ-
ential diagnoses such as cutaneous lymphoma, angiosarcoma, or bacillary
angiomatosis. Histologically, the typical spindle-shaped KS cells are found, accom-
panied by lymphohistiocytic infiltrates and slit-shaped vascular neoplasms sur-
rounded by erythrocyte extravasations. If the diagnosis is definitive, the spread
should be clarified by a complete inspection (oral and genital mucosa! Look in the
mouth!) and abdominal ultrasonography. If there is mucosal involvement, an
EGD/colonoscopy, as is a chest x-ray, is recommended to rule out pulmonary involve-
ment. HHV-8 viral load has no prognostic value (Haq 2016).

Treatment
In naïve and/or viremic individuals with HIV, initiation or optimization of ART is
the priority. In cases of low-level KS infection, additional therapy is rarely needed.
Immediate administration of etoposide had no sustained effect in a randomized trial
of 190 patients from Africa and South America (Hosseinipur 2018). With the decrease
in HIV viral load and onset of immune reconstitution, most mucocutaneous KS
stabilize or heal completely; however, post-inflammatory hyperpigmentation often
remains. In 213 cases of early-stage KS, 5-year survival with ART alone was 95%, with
77% remaining without progression (Bower 2014). ART improves the humoral
response against HHV-8 (Sullivan 2010), and HHV-8 viremia decreases rapidly
(Cattamanchi 2011). ART breaks should be avoided. In the SMART trial, KS was one
of the most common AIDS during treatment interruptions, especially with a history
of KS (Silverberg 2007).
Which ART is given does not matter: although a direct antiproliferative effect for PIs
has been shown in the laboratory and also in animal studies (Sgadari 2002, Gantt
2011), PIs remained without clinical advantage over other regimens in a large
randomized trial (Martin 2014). Recurrences are not more common under non-PI
356 AIDS

regimens (Lajaunie 2022). However, “oral shedding” of HHV-8 appears to be reduced

under PIs (Gantt 2014).
ART and any local therapies are not sufficient in the following situations:
• Rapid growth of multiple tumors, especially in the setting of an IRIS
• Tumors that occur despite sufficient antiretroviral therapy (for example, with
comedication with rituximab or immunosuppressants) or that are progressive
• Infiltrative or exulcerative growth
• Severely affected by the tumor (facial involvement, edema, etc.)
• Therapy request (patient’s wish)

Additional treatment methods required are as follows:

Chemotherapies: The pegylated, liposomal anthracycline doxorubicin (Caelyx®) at
a dose of 20 mg/m² body surface area is the agent of choice (Stewart 1998, Di Trolio
2006). It has replaced the previously widely used ABV regimen, a combination of
adriamycin, bleomycin, and vincristine. Up to 80% of remissions are achieved with
Caelyx® (Lichterfeld 2005). Infusions for 30–60 min every 2–3 weeks are feasible on
an outpatient basis and are usually well tolerated; antiemetic therapy is not required.
Treatment is continued until apparent partial remission (tumors flattened to skin
level, color change from livid to brownish and lighter), usually achieved after 6–8
cycles. Recurrences under Caelyx® rarely occur with concurrent ART, most likely in
the first year (Martin-Carbonero 2008). If recurrence occurs later, Caelyx® is often
quite successful again. If well tolerated, intensification of therapy with shortening
of cycles and/or increasing the dose is also possible. Myelotoxicity and cardiotoxic-
ity must be taken into account. Although the latter occurs only above cumulative
doses of 450 mg, transthoracic echocardiography (ejection fraction?) is recom-
mended at the beginning of therapy and after every six cycles. Another side effect
of Caelyx® is “palmoplantar erythrodysesthesia”, which manifests as painful macular
erythema on the hands and feet (Lorusso 2007). Given the immunosuppressive effect,
cotrimoxazole prophylaxis is recommended at least for the duration of therapy, even
for CD4 T-cells above 200 cells/µl. An alternative in case of supply shortages is lipo-
somal daunorubicin (DaunoXome®), which is probably somewhat less effective
(Cooley 2007).

Table 1: KS therapies when ART and local therapies are not sufficient.
Therapy Dosage Comment
Pegylated lipo- 20 mg/m intravenously
2 Therapy of choice, cave myelo- and
somal doxorubicin every 2 weeks cardiotoxicity, hand-foot syndrome
(Caelyx®)
Liposomal 40 mg/m2 intravenously Probably somewhat weaker, considered an
Daunorubicin every 2–3 weeks alternative in case of supply shortage
(DaunoXome®) for Caelyx®
Pegylated 50 μg subcutaneously Like IFN-α (2a,b) but better tolerated,
Interferon-α 2b* 1 x / week little data in AIDS KS! Off-label use!
(PegIntron®)
Paclitaxel 100 mg/m2 IV every 2 weeks Reserve, no first-line use
(Taxol®) or Beware of neutropenia, peripheral
135 mg/m2 IV every 3 weeks neuropathy, allergies, alopecia
Off-label use! Caution ART interactions
Kaposi’s sarcoma 357

The taxane paclitaxel (Taxol®) is also effective (Tulpule 2002, Cianfrocca 2010). In a
large randomized trial, it was better than ABV and oral etoposide (Krown 2022).
However, it is more myelotoxic than Caelyx® and almost always leads to alopecia,
often after the first dose (inform patients beforehand!). Paclitaxel should only be
used if KS is progressive or relapses under anthracycline therapy. In addition to pacli-
taxel, docetaxel (Taxotere®) also appears to be effective according to uncontrolled
studies (Autier 2005, Lim 2005). Interactions should be noted with taxanes; levels
increase with concurrent PI administration (Cianfrocca 2011).
As recurrence treatment (after anthracycline or paclitaxel therapy), oral etoposide
(Evans 2002), irinotecan (Vaccher 2005), and the ABV regimen are also suitable.
Gemcitabine is also probably effective (Strother 2010, Busakhala 2018).
Immunotherapies: Good remission rates are achieved with interferon (IFN),
although these are probably somewhat lower than with liposomal doxorubicin
(Kreuter 2005). The mechanism of action is not precise. However, in addition to the
immunomodulatory effect, interferons probably induce apoptosis in KS cells and
inhibit angiogenesis. Remission rates depend on the immune status; above 400 CD4
T-cells/µl, they are above 45%; below 200, they are only 7%. Standard regimens do
not exist. Interferon-α 2b (Roferon®), commonly used in the past, has been with-
drawn from the market. Interferon-α 2a (Intron A®) does not have approval for KS
(Krown 2002). This also applies to pegylated interferons (weekly administration
possible, more tolerable). The optimal dose is unknown; there are small case series
in AIDS KS (Rokx 2013) and classical KS (Di Lorenzo 2008). Following instructions,
injections can be self-administered. Administration can be reduced with the onset
of remission (stop of tumor growth, flattening, change from livid-red to brownish,
lighter shades). In addition to regular inspection of the local findings on the skin
and mucous membranes, adapted staging examinations are part of the therapy
control.
Local therapies are tolerable and usually inexpensive. Single aesthetically or func-
tionally disturbing lesions can be treated quickly and effectively with local therapy.
Many things are possible: simple camouflage, local compression therapy (Brambilla
2006), but also cryosurgery, purely intralesional treatment with vinca alkaloids
(Ramirez-Amador 2002), excisions, or even Imiquimod cream (Celestin Schartz
2008).
The KS is radiation sensitive (Donato 2013). Soft X-rays in single doses of 4–5 Gy
(total dose 20–30 Gy, fractionation 3x/week) are sufficient for superficial macular or
plaque tumors. In contrast, for extensive KS with edema, radiation should be
delivered with fast electrons (5 x 2 Gy per week) up to a total target volume dose of
40 Gy.
Since KS is a multilocular systemic disease, surgery usually makes little sense. If at
all, only small, cosmetically conspicuous tumors should be surgically removed.
However, scar recurrences are expected in this case due to the Koebner phenomenon.
These can be avoided by radiation therapy, the radiation field of which extends
0.5–1.0 cm beyond the tumor borders and also reaches the tumor cells spreading in
vascular lodges.
In KS-related lymphedema, especially in the extremities, mechanical lymphatic
drainage and, if necessary, adapted compression therapy should be performed early
on, provided there are no contraindications (severe cardiac and/or renal insuffi-
ciency). These promote recanalization of the damaged lymphatic vessels and prevent
complications such as chronic ulcers.
However, local therapies have become much less important in the ART era; they are
rarely necessary.
358 AIDS

New therapeutic approaches: Due to KS pathogenesis, new therapies are constantly

being proposed, including viral statics, but also cytokines and angiogenesis
inhibitors. Some of them will be mentioned here.
• Valganciclovir – decreased HHV-8 viral load in a randomized trial (Casper 2008).
The effect is probably greater than under valaciclovir and famciclovir, which also
have antiviral activity. However, clinical KS studies are lacking. Since HHV-8 is
involved in early tumorigenesis, it remains to be seen whether there is any effect
in already manifest KS. In classical KS, valganciclovir remained ineffective (Krown
2011).
• Imatinib (Gleevec®) – tyrosine kinase inhibitor used in leukemias, inhibiting
relevant growth factors (PDGF) in KS. Partial remissions were found in 10/30 AIDS
KS cases in a phase II study (Koon 2013). There are case reports of refractory cases
(Cao 2015). In contrast, sorafenib (Nexavar®) was only moderately effective and
poorly tolerated in Phase 1b (Uldrick 2017).
• Nivolumab is a checkpoint inhibitor. A pilot study found a response in 5/8 cases
(Galanina 2018). Pembrolizumab also showed some efficacy in HIV-negative
patients in Phase II (Delyon 2022).
• Interleukin-12 – high response rates in a phase II trial, albeit combined with lipo-
somal doxorubicin (Little 2007). Randomized studies are lacking.
• Sirolimus (and everolimus) – immunosuppressants used in transplantation medi-
cine. Inhibit angiogenesis by decreasing the production of vascular endothelial
growth factors. In uncontrolled studies, good response rates in HIV-negative kidney
transplant patients (Stallone 2005, Campistol 2007).
• Lenalidomide – this immunomodulator with anti-angiogenic properties achieved
response rates between 40 and 60% in Phase II (Pourcher 2017, Reid 2022). There
are also positive reports on pomalidomide from a Phase I/II trial; the most notable
was the effect on lymphedema (Polizzotto 2016).
• Bevacizumab – an early study of this VEGF antibody showed moderate response
rates of 31% in 17 PLWH with progression on ART (Uldrick 2012). The effects of
PTC299, a post-transcriptional inhibitor of VEGF, remained only moderate in a
small study (Bender 2016).
• Retinoids (all-trans-retinoic acid) inhibit KS proliferation. However, the response
rates were not convincing. This approach has not gained acceptance, and the same
is true for inhibitors of matrix metalloproteinases (MMPs).

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361

9. Malignant lymphomas
MARCUS H ENTR IC H, C H R ISTIAN HOFFMAN N

Malignant lymphomas are malignant diseases of the lymphatic system. A distinction

is made between Hodgkin’s lymphoma (HL) and the large group of non-Hodgkin’s
lymphomas (NHL). The latter are biologically and clinically divided into B and
T cells or indolent (low-malignant) and aggressive (highly malignant) lymphomas.
Compared with the normal population, PLWH are at significantly increased risk for
malignant lymphomas, particularly aggressive B cell NHL (see Table 1). The estimated
cumulative lifetime risk of NHL is 4.5% (Silverberg 2015). ART has significantly
reduced the incidence of NHL, but not as impressively as Kaposi’s sarcoma or most
other OIs (COHERE 2009, Franceschi 2010). Thus, the relative proportion of NHL in
all AIDS cases has increased. The decline is most evident in subtypes that often first
appear in the setting of massive immunodeficiencies, such as primary CNS lym-
phoma (Polesel 2008).
In some cohorts of PLWH, malignant lymphomas have overtaken Kaposi’s sarcoma
as the most common malignancy (Poizot-Martin 2021), and they are now by far the
most common cause of AIDS-related deaths, accounting for about 24% in France in
2010. In the Cologne-Bonn cohort, lymphomas accounted for 16% of all deaths from
2004–2010 (Ehren 2014). Lymphomas caused more deaths than PML and PCP com-
bined, the two most dangerous OIs (Morlat 2014). NHL also ranked first among
cancer-related deaths, ahead of lung cancer (Horner 2021).

Table 1: The relative risk of various non-Hodgkin’s lymphomas in the US among PLWH compared
with the general population 1996-2010, n=2,828 (adapted from Gibson 2014).
NHL, total 10.6
High-grade B cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) 17.6
Burkitt's lymphoma (BL) 33.7
Not classifiable 19.9
Primary CNS Lymphoma (PCNSL) 47.7
Low-grade B cell lymphoma
Follicular NHL 1.3
T cell lymphoma
Peripheral T-cell NHL 3.6

In PLWH malignant lymphomas are biologically very heterogeneous with differences

in the frequency and extent of oncogenic mutations or cytokine dysregulation and
the histogenetic origin of the malignant cells. The association with EBV and other
oncogenic viruses such as HHV-8 or SV40 is also highly variable. This is also true for
the extent of immunodeficiency. While Burkitt’s lymphoma and HL often occur even
with relatively good immune status, severe immunodeficiencies are the rule, espe-
cially in primary CNS lymphoma (PCNSL). Thus, there appear to be “opportunistic”
lymphoma subtypes that arise more because of immunodeficiency, whereas in others,
HIV-induced chronic B-cell stimulation seems to be more crucial. Cumulative viremia
is a risk factor for the development of Burkitt’s lymphoma (Zoufaly 2009, Hernández-
Ramírez 2019).
However, HIV-associated lymphomas – NHL and HL – share many clinical features.
They are usually diagnosed at advanced stages and often have extra-nodal manifes-
tations. Despite a markedly improved prognosis overall, mortality risk is about twice
362 AIDS

that of HIV-negative NHL, according to US registry data (Chao 2010, Coghill 2015).
Therapy can be fraught with complications and requires close collaboration between
HIV medicine and hematology-oncology.
The following will discuss systemic NHL, PCNSL, and HL separately. Castleman’s
disease will also be mentioned as a separate entity, although it is not a malignant
lymphoma. Low-grade (indolent) or T-cell lymphomas are so rare that they will not
be discussed here – their therapy should be based on the recommendations for HIV-
negative patients.

Systemic non-Hodgkin’s lymphoma (NHL)

The close association between NHL and AIDS has long been known – the first cases
were published even before the discovery of HIV (Ziegler 1982). Since 1985, high-
grade (aggressive) B-cell lymphomas have been considered AIDS-defining.
HIV-associated NHL are B cell lymphomas in more than 95% of cases. They are almost
always aggressive with two histological types dominating. According to WHO clas-
sification, one is Burkitt’s lymphoma, which accounts for 30–40% of cases, and the
other is diffuse large B cell lymphoma (DLBCL) in 40–60%. Up to 10% of all HIV-
associated lymphomas cannot be classified even by reference pathologies.
Plasmablastic lymphomas (PBL) are much less common. A very small proportion
(1–3%) is termed primary effusion lymphoma (PEL) and forms a largely distinct entity
(see below). Evidence shows that the proportion of Burkitt’s lymphoma in all NHL
is increasing (Ramaswami 2016, Olszewski 2016).

Screening
There is no well-documented recommendation for screening (for example, regular
sonographies, etc.). The best prevention is effective ART. It improves immune status
and reduces another risk factor, namely chronic B-cell activation (Grulich 2008).
The risk for NHL but not HL is favored by cumulative viremia (Shepard 2018,
Kimani 2020). Parameters of immune activation and B-cell stimulation such as
immunoglobulins, interleukin-6 or IL-10, and soluble CD30 (Breen 2012) or free light
chains (Landgren 2010) are associated with increased lymphoma risk. Although they
tell us something about the development of malignant lymphomas, they have no
therapeutic or prognostic relevance and are of no importance for clinical practice
(Tittle 2015).

Clinic
The leading symptom is swelling of the lymph nodes. The enlarged lymph nodes
are usually gross, challenging to move, and indolent. Many affected individuals have
an advanced stage of lymphoma (Ann Arbor stages III-IV) at the time of diagnosis,
and B-symptoms with fever and/or night sweats and/or weight loss (at least 10% in
the past six months) are present in the majority of cases (60–80%). General weak-
ness, marked feelings of illness, and rapid physical deterioration are common. Extra-
nodal involvement is also frequent, sometimes assuming large proportions. In our
cohort of 203 patients, 81% had at least one extra-nodal manifestation (Hoffmann
2003). Orbits, testes, heart, breast, bladder, kidney, muscles, and bones – all imagi-
nable organs and body regions can be affected. In particular, the gastrointestinal
tract, liver, bone marrow, and the ENT area are frequently affected. CNS involve-
ment occurs in 6% of DLBCL (Barta 2016). Depending on the location, additional
symptoms may occur if extra-nodal sites are affected. These are abdominal pain due
Malignant lymphomas 363

to liver and spleen enlargement, bleeding or ileus symptoms in intestinal

involvement, bone pain due to infiltration of the skeleton, or headache in brain
involvement.

Diagnostics
Prompt histological diagnosis is essential. Unless a bone marrow puncture has already
confirmed the diagnosis, a lymph node (for example axillary or cervical) should be
removed. Merely puncturing a lymph node is often not sufficient to determine the
subtype. The material must be sent to a pathology department with experience in
hematopathology. The basic pathological diagnosis should include information on
the subtype (Burkitt?), the proliferation rate, and the expression profile (minimum:
CD20, desirable: CD10, CD138, MUM-1) since this has therapeutic consequences
(see below). For practitioners, it is crucial not to accept a pathological diagnosis
uncritically but to discuss it, especially if there are doubts given the clinical picture.
Beware of misdiagnoses! A typical example is the diagnosis of an aggressive T-cell
lymphoma. This may be confidently doubted, since T cell infiltrates may hide a
variety of other (primarily infectious) diseases (lues maligna?).
All persons with NHL should be staged according to the Ann Arbor classification
(Tables 2a, 2b).
Basic diagnostics and staging include chest X-ray, abdominal ultrasonography, bone
marrow biopsy (aspiration is not sufficient!), and CTs of the neck, chest, and
abdomen. In addition to current immune status and viral load, at a minimum, blood
count, blood sedimentation rate, CRP, uric acid, LDH, liver and kidney values,
electrolytes, and hepatitis A, B, and C serology should be determined. ECG and
echocardiography are also necessary examinations in advance. This is the only way
to objectify the possible cardiotoxicity of chemotherapy (anthracyclines!). Lung
function should be examined before regimens containing bleomycin.

Table 2a: Dispersal stages according to the updated Ann Arbor classification.
I Involvement of a single lymph node region (I) or localized involvement of a single
extralymphatic organ or district (IE).
II Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or
localized involvement of a single extralymphatic organ or district and its regional lymph
node(s) with or without involvement of other lymph node regions on the same side of the
diaphragm (IIE)
III Involvement of lymph node regions on both sides of the diaphragm (III), possibly additional
localized involvement of an extralymphatic organ or district (IIIE), or simultaneous
involvement of the spleen (IIIS) or simultaneous involvement of both (IIIE+S)
IV Disseminated (multifocal) involvement of one or more extralymphatic organs with or
without concomitant lymph node involvement; or isolated involvement of an
extralymphatic organ with involvement of distant (nonregional) lymph nodes

Table 2b: Each stage is divided into A and B categories.

A Absence of defined general symptoms
B General symptoms
unexplained weight loss of more than 10% in the last six months and/or
unexplained persistent or recurrent fever above 38 °C and/or
strong night sweats
364 AIDS

After two cycles of chemotherapy, response to therapy should be assessed by restaging

based on the initial lymphoma localization. After completion of chemotherapy,
complete restaging with bone marrow biopsy (if there was initial involvement) and
all CTs are required. If there is complete remission, follow-up examinations should
be done at three-month intervals. After one year the intervals can be extended to
six months, and twelve months after two years. Recurrences after more than two
years are rare.
In Burkitt’s lymphoma, a lumbar puncture should always be performed at the start
of systemic chemotherapy to exclude meningeal involvement and to start intrathecal
prophylaxis. In DLBCL – in analogy to HIV-negative patients – this is only reason-
able if at least 4 of the following six factors are present (Schmitz 2016): Involvement
of the kidneys and/or adrenal glands, age > 60 years, LDH > normal value, ECOG PS
> 1, Ann Arbor stage III/IV, > 1 extra-nodal involvement.

Treatment
Any aggressive HIV-associated B-cell lymphoma should be treated quickly with
chemo-immunotherapy. Even with an unfavorable initial situation (advanced stage,
severe immunodeficiency), complete remission or cure remains the ultimate goal
(Hoffmann 2003, Hentrich 2014, Noy 2019). For this reason alone, dose reductions
should be avoided whenever possible. Surgery or radiation alone will not suffice.
There is no time to waste with staging.
Internationally, the R-CHOP regimen (usually 4–6 cycles; see Table 3) is used in most
cases of DLBCL. R is the abbreviation for the monoclonal antibody rituximab, which
binds highly specifically to CD20-positive B cells (CD20 is expressed on most lym-
phoma cells). CHOP is polychemotherapy with the cytostatics cyclophosphamide,
adriamycin (hydroxydaunorubicin), vincristine (Oncovin®), and prednisolone. To
date, no other chemotherapy has shown a convincing advantage over CHOP.
Complete remissions can be achieved at 60–80%. CHOP can be administered on an
outpatient basis and is quite well tolerated. As a rule, six cycles should be given. Four
cycles are sufficient only in cases of very low lymphoma risk, but no data exist on
treatment reduction in PLWH (Poeschel 2019). Outpatient administration is a major
advantage over similar regimens such as CDE (cyclophosphamide, doxorubicin,
etoposide) or EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide,
doxorubicin), which must be given continuously intravenously over several days.
The standard three-week CHOP regimen (“CHOP-21”) is shown in Table 3.
As antimicrobial adjuvant therapy, we recommend – regardless of the CD4 T-cell
count – cotrimoxazole until one month after chemotherapy (960 mg three times a
week). The oral mucosa should be protected and treated with mouth rinses and
amphotericin topicals (for example, Ampho-Moronal® lozenges). Good adherence is
crucial. During chemotherapy, twice-weekly blood count checks and liver and kidney
values are required.

Table 3: Standard CHOP regimen (4–6 cycles, each repeated on day 22).
Cyclophosphamide 750 mg/m2 IV day 1
Doxorubicin 50 mg/m2 IV day 1
Vincristine 1.4 mg/m2 (maximum 2 mg) IV day 1
Prednisolone 1 x 2 tbl. at 50 mg oral, days 1–5
Mesna 20% of cyclophosphamide dose at hours
0, 4, 8 IV (short infusion) or orally
Malignant lymphomas 365

Treatment is continued according to the schedule at the full dose, provided that
leukocytes return to above 3000/µl and platelets above 80.000/µl after passage of the
nadir. Patients should understand, take their temperature daily, and be urged to
present promptly, especially if they have a fever.
Treatment with rituximab is usually well tolerated but results in prolonged B-cell
depletion and occasionally causes neutropenia. Cases of progressive multifocal
encephalopathy (PML) have been described in HIV-negative patients (Carson 2009).
However, an increased risk for PML has never been demonstrated in PLWH receiv-
ing rituximab (Hoffmann 2012).
A randomized Phase III trial (AMC 010) tested CHOP versus R-CHOP in AIDS NHL.
It showed an increased rate of deaths due to bacterial infections in the rituximab
arm (2% versus 14%) (Kaplan 2005). This was particularly evident at low CD4 T-cell
counts (< 50/µl). These results are countered by several non-randomized studies that
found no increased infection rate with rituximab (Spina 2005, Sparano 2010).
Our prospective, multi-center cohort study also failed to confirm the AMC 010 data
(Wyen 2012). Meta-analyses significantly improved CR rate and survival by rituximab
(Castillo 2012, Barta 2013). Therefore, rituximab should be considered in principle
in PLWH with CD20-positive lymphomas. Even poor immune status (< 200 CD4
T-cells/µl) is not an absolute contraindication, but we would recommend
close monitoring and prophylactic administration of a quinolone (in addition to
cotrimoxazole).

Modifications of CHOP
In recent years, small pilot studies have been published in which PLWH were treated
with modified CHOP regimens. For example, doxorubicin was given as liposomal
Caelyx® (Levine 2013) or increased cyclophosphamide doses (Costello 2004). Using
CDE, potential chemotherapy resistance should be overcome with multi-day
infusions (Spina 2005). This is also true for the more intensive EPOCH regimen,
which is more costly to administer (Sparano 2010, Barta 2013). Complete remission
rates with these therapies have ranged from 50% to 75%. There is no evidence of
benefit from these modifications. On the contrary, in a randomized trial in HIV-
negative patients with DLBCL, there was no advantage with R-EPOCH over R-CHOP
regarding remission rates and survival (Bartlett 2019). Therefore, in our view, EPOCH
or CDE should not be used outside of trials.

Which ART when?

Every (every!) person with HIV infection and NHL needs ART. ART has improved
survival, response rates, and tolerability of chemotherapy (Weiss 2006, Bower 2008,
Barta 2013). There are even individual cases reported of complete remission with
ART alone (Birenda 2015). Given the new well-tolerated regimens, ART-naive patients
can start ART and chemotherapy simultaneously. For example, a good regimen would
be TAF+FTC plus raltegravir, as interaction risk and nephrotoxicity are low. HLA
status should be available with abacavir, as abacavir HSR (feeling sick! fever!) can
cause problems. TAF is preferable to TDF. Pre-treated patients should maintain ART
during chemotherapy, but with restrictions: boosted regimens (PI/r, PI/c, elvite-
gravir/c) should be avoided due to the risk of increased toxicities (Spano 2016, Focà
2018) because cases of severe neurotoxicity have been described for vinblastine
(Cheung 2010). Raltegravir-containing regimens would be a good option (Ezzat 2013,
Welz 2017). Before starting any chemotherapy regimen, a web-based check via
[Link] is worthwhile.
366 AIDS

Special entities
Burkitt or Burkitt-like lymphomas (BL/BLL). BL are treated with intensive proto-
cols including high-dose methotrexate and cytarabine due to their exceptionally
high proliferation kinetics, aggressiveness, and tendency to CNS involvement. In
Germany, a dose-adapted protocol of the German ALL Study Group (GMALL) is
mainly used for the treatment of Burkitt’s NHL/B-ALL (B-ALL protocol) (Hoffmann
2006). This consists of a pre-phase with cyclophosphamide and dexamethasone,
followed by administration of block A (MTX, vincristine, ifosfamide, teniposide,
Ara-C, intrathecal administration of MTX, dexamethasone and Ara-C) and block B
(MTX, vincristine, cyclophosphamide, doxorubicin) three times each. Among these,
4-year survival is 72% (Xicoy 2014), but at the cost of increased toxicity (including
mucositis and myelotoxicity). This very intensive chemotherapy cannot be
administered on an outpatient basis. Inpatient admission for several days with close
monitoring is necessary. Centers without experience with the protocol should not
use it in PLWH.
Other intensive therapy regimens such as CODOX/M-IVAC are similarly effective
but uncommon in Germany (Alwan 2015, Noy 2015, Vasseur 2020). Less intensive
therapy with dose-adjusted EPOCH-R resulted in an impressive 87% survival rate
after approximately six years in a study of 113 BL patients, 25% of whom were HIV-
positive (Roschewski 2020). However, the rate of high-risk cases with bone marrow
or CNS involvement was lower than in the studies with dose-intensive regimens. In
addition, the intensive CODOX/M-IVAC regimen showed a significant survival
advantage over EPOCH in a retrospective study of 249 HIV-BL patients (Alderuccio
2021). Overall, the prognosis of BL has improved significantly. Large cohort studies
no longer show differences in survival rates between DLBCL and BL (Gopal 2013,
Schommers 2015, Hentrich 2021).
Plasmablastic lymphomas are likely to be associated with DLBCL but have their
own immunophenotype, usually corresponding to a post-germinal center cell:
markers for the B-cell antigen CD20 are negative, whereas the plasma cell reactive
antibody VS38c and CD138 are positive (Castillo 2015). The oral cavity is the predilec-
tion site, although extraoral manifestations also occur. There is a close association
with EBV (Al Maki 2015, Castillo 2015). Plasmablastic lymphomas have a very high
proliferation rate and grow highly aggressively. The prognosis remains poor com-
pared to other lymphomas (Castillo 2012, Schommers 2013, Hentrich 2021). We
showed on 89 NHL that a post-germinal center profile, as often found in plasmablastic
lymphomas, is independently associated with a poor prognosis (Hoffmann 2005).
This has since been shown by other groups as well (Dunleavy 2010). Intensive
chemotherapies are not associated with any clear benefit (Castillo 2012). In contrast,
administration of the proteasome inhibitor bortezomib, approved in multiple
myeloma, in combination with chemotherapy appears useful (Bibas 2010, Fernandez-
Alvarez 2016, Castillo 2019).
Primary effusion lymphoma (PEL), relatively rare, accounts for 1–3% of all HIV
NHL (Narkhede 2018, Hentrich 2021). A distinction is made between a solid and a
classic variant (Guillet 2016). The latter is often difficult to diagnose histologically
due to the absence of a visible tumor mass and the malignant cells found only in
body cavities (ascites, pleural or pericardial effusion). Histologically, there are simi-
larities to immunoblastic and anaplastic cells with a non-B non-T phenotype. Any
pleural or pericardial effusion from an HIV+ individual in which malignant cells are
found is suspicious. Pathology should be notified of the suspicion. There is a 100%
association with human herpesvirus-8 (HHV-8), which is detectable in the cells.
Malignant lymphomas 367

Response to CHOP is usually poor, and the prognosis is unfavorable (Guillet 2016,
Aguilar 2020). Complete remissions with ART alone have been described (Boulanger
2001, Hocqueloux 2001), but do not serve as a basis for therapy. In the German
Lymphoma Cohort, only 2 of 13 cases (15%) achieved sustained remission (Hentrich
2021). A standard therapy has not been defined. The combination of bortezomib
and chemotherapy led to sometimes long-lasting remissions in a small series (Gupta
2016), but according to other case reports, bortezomib was without benefit
(Boulanger 2018). Relatively good results have been reported with modifications of
the EPOCH regimen (i.e., with/without rituximab, bevacizumab, or HD methotrex-
ate) (cancer-specific survival at three years 47%), without drawing clear conclusions
for practice (Lurain 2019).

Recurrence therapy, stem cell transplantation

In our cohort, the recurrence rate was recently just above 10% (Schommers 2018).
Consideration should always be given to high-dose chemotherapy (HDCT) with
autologous stem cell transplantation (ASCT). In SCT, the intensity of chemotherapy
can be significantly increased by prior collection of pluripotent hematopoietic stem
cells (own cells: autologous; foreign: allogeneic). Following myeloablative
chemotherapy, the stem cells are reinfused. Previous studies show that immune
reconstitution and long-term success do not differ from those in HIV-negative
patients (Krishnan 2010, Zanet 2015, Alvarnas 2016). However, transplant-associ-
ated mortality is slightly higher (Hübel 2019).
Allogeneic SCT is reserved for rare exceptional cases (Gupta 2009, Ambinder 2019,
Arslan 2019). Besides the so-called graft-vs-lymphoma effect, another effect could be
used: for example, a case of an HIV-positive patient with acute myeloid leukemia
who received stem cells from an HIV-negative donor homozygous for the Δ32 muta-
tion was published – probably the first cure (see Cure) in HIV (Hütter 2009). However,
a few more cases exist, including one woman (see Cure).
There are now several case reports on therapy with CAR-T-cells in PLWH who should
not be principally excluded from this innovative therapy (Hattenhauer 2023). Cases
with relapsed or refractory DLBCL should be presented at appropriate centers, and
health insurance coverage will be considered on a case-by-case basis (Abbasi 2020,
Allred 2021).

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370 AIDS

Shepherd L, Ryom L, Law M, et al. Differences in virological and immunological risk factors for Non-Hodgkin
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Malignant lymphomas 371

Primary CNS lymphoma

Primary CNS lymphomas (PCNSL) are a late complication of HIV infection. They
used to occur in up to 10% of AIDS patients, but have become rare (Polesel 2008).
In nearly 100% of cases, they are EBV-associated and histologically are usually diffuse
large cell non-Hodgkin lymphomas. Previously, PCNSL had the worst prognosis
among AIDS-defining diseases, with a median survival of less than three months.
ART has made survival times of several years and even cures possible (Hoffmann
2001, Gupta 2017, Moulignier 2017, Lurain 2020).

Clinic
Depending on the localization and size, neurological disorders occur. Epileptic
seizures may be the initial manifestation. Personality changes, attention disorders,
headaches, and focal deficits such as paresis are common. Fever, on the other hand,
is usually absent. Because severe immunodeficiency is usually present, constitutional
symptoms may obscure the problem.

Diagnostics
Cerebral CT or (better) MRI should be done expeditiously. The usually singular
foci take up contrast agents, show mild to moderate edema, and often have little
space-occupying activity. The most important differential diagnosis is cerebral
toxoplasmosis (TE). A solitary focus with minor edema is more suggestive of PCNSL.
However, 2–4 lesions are often present and are usually relatively large (over 2 cm in
diameter). More than four lesions are rare.
In addition to a current toxoplasmosis serology, which, if negative, makes TE unlikely,
a current CD4 T-cell count should also be available. The better the immune status,
the less likely a PCNSL. In our cohort, less than 20% had more than 50 CD4 T-cells/µl
at diagnosis. Above 100/µl, however, TE also becomes unlikely. In addition to physical
examination, CTs of the neck, thorax, and abdomen should be used to determine
whether there is secondary CNS involvement of systemic lymphoma. This should
always include fundoscopy to exclude ocular involvement (up to 20%).
Besides TE, differential diagnoses include abscesses, glioblastomas, and cerebral
metastases of solid tumors. In the absence of increased intracranial pressure, CSF
puncture is useful to detect malignant cells. A positive EBV PCR in the CSF confirms
the suspicion; however, EBV is inconclusive and often detectable even without PCNSL
(Corcoran 2008). In such a case, cerebral lymphomatoid granulomatosis should also
be considered, which presents a complex picture on MRI (Wyen 2006, Patsalides 2006).
Empirical toxoplasmosis therapy is usually warranted initially, preferably without
steroids. If this fails, this is indicative of PCNSL. In such cases, a stereotactic brain
biopsy to confirm the diagnosis cannot be omitted. However, this is only useful if
steroids have not been given previously – even low doses of steroids usually make a
histopathological diagnosis impossible.

Treatment
The advances in HIV-negative individuals with high-dose methotrexate-based (HD-
MTX) chemotherapies and rituximab have also transformed the treatment of PLWH
with PCNSL (Gupta 2017, Moulignier 2017, Lurain 2020). Cranial irradiation alone
should no longer be used to avoid late neurological damage. Regardless of the spe-
cific therapy, the key is maximizing immune reconstitution with ART. Under ART
372 AIDS

in combination with chemotherapy, durable remissions, and cures have become

realistic, and there are even case reports on ART alone (McGowan 1998, Aboufila
2007, Travi 2012).
In our cohort (n=29), three out of four individuals with a CD4 T-cell increase achieved
complete remission (Hoffmann 2001). Several affected persons lived relapse-free for
more than ten years. This positive trend has been confirmed in numerous studies.
In two recent papers, the median survival was either not yet reached (Gupta 2017)
or the 5-year survival rate was 48% (Moulignier 2017). As with established approaches
for HIV-negative patients, HD-MTX-based combination chemotherapies should be
combined with rituximab (Ferreri 2016, Schmitt 2019, Lurain 2020). In individual
cases, consolidative high-dose chemotherapy with autologous stem cell transplan-
tation may also be considered (O’Neill 2015).
If there are clear signs of increased intracranial pressure, the rapid administration of
steroids (dexamethasone 3 x 8 mg/day, then rapidly tapering off) cannot be avoided.
However, it should be not been initiated before histological confirmation of the
diagnosis.
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42:433-6.
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rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the
International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol 2016, 3:e217-27.
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phoma. Neuro Oncol 2017, 19:99-108.
Hoffmann C, Tabrizian S, Wolf E et al. Survival of AIDS patients with primary central nervous system lymphoma
is dramatically improved by HAART-induced immune recovery. AIDS 2001, 15:2119-2127.
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retroviral therapy, rituximab, and high-dose methotrexate. Blood 2020, 136:2229-32.
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Moulignier A, Lamirel C, Picard H, et al. Long-term AIDS-related PCNSL outcomes with HD-MTX and combined
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review and meta-analysis. Hematol Oncol 2019, 37:548-57.
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Malignant lymphomas 373

Hodgkin’s lymphoma (HL)

The incidence of HL, unlike NHL, has not decreased with ART and has increased by
approximately 5–15-fold in PLWH (Hernanedz-Ramires 2019, Kimani 2020, Poizot-
Martin 2021). The main risk factor is a moderately decreased CD4 T-cell count (Sheperd
2018, Kimani 2020). In the [Link] study, the hazard ratio was 6.36 with CD4 T-cells
of 100–199/µl compared to >500/µl (Sheperd 2018). Viral load does not matter. There
is evidence that the incidence decreases again with increasing ART duration
(Kowalkowski 2014). This is also supported by recent declines in incidence in some
cohort studies (Robbins 2014, Silverberg 2015, Shepard 2018). The vast majority of
people with HIV-HL are on antiretroviral treatment. With viral suppression and good
CD4 T-cells, HL is as common as NHL in PLWH (Hoffmann 2015). EBV can be detected
in > 90%. Since HL consists mainly of reactive inflammatory cells (including many
T lymphocytes – the proportion of malignant cells is only about 1%), it has been
postulated that only ART-induced immune reconstitution creates a “Hodgkin-
friendly” microenvironment (Gloghini 2007). Before the diagnosis of HL, there is a
decrease in CD4 T-cells measured in the blood (Bohlius 2011, Hoffmann 2016).
An advanced stage at diagnosis and extra-nodal involvement is typical, whereas
mediastinal involvement is much less common than in HIV-uninfected patients with
HL. As in NHL, the prognosis has improved dramatically with ART. With sufficient
viral suppression, there is no longer a survival difference compared with HIV-nega-
tive individuals (Montoto 2013, Besson 2015, Olszewski 2016, Sorigué 2017).

Clinic/Diagnostics
B symptoms are present in the majority of cases. Advanced stages are almost the
rule. The lymphomas are usually coarse, poorly displaced, and indolent. Staging is
the same as for non-Hodgkin’s lymphoma (see above) but includes an 18F-FDG
PET-CT (PET), which may obviate the need for a bone marrow biopsy in HL. High
metabolic tumor volume on initial PET is associated with an unfavorable prognosis
(Louarn 2022). A lymph node should be removed whenever possible – puncture
alone is less reliable. It is better to have a proper diagnosis once than to lose time
unnecessarily with half-hearted examinations! Extirpation is usually possible on an
outpatient basis. As with NHL, the material should be sent to reference pathologies
if possible. Because of the use of bleomycin, lung function should always be examined
before chemotherapy.

Treatment
As in HIV-negative HL, therapy should be based on the Ann Arbor stage and possible
risk factors (extranodal involvement, more than three lymph node areas, large
mediastinal tumor, or high ESR). Therapy is always curative, and the achievement
of complete remission is crucial. A distinction is made between limited (I-II without
risk factors), intermediate (I-II with risk factors), and advanced stages (III-IV). In
limited and intermediate stages, the ABVD regimen (four double cycles) followed by
radiotherapy is recommended, see Table 4. The response is excellent, with complete
remission rates of 96–100% (Hentrich 2012). Administration is possible on an out-
patient basis.
In HIV-negative patients with advanced-stage HL, the escalated BEACOPP regimen
of the German Hodgkin Study Group is more effective than ABVD regarding response
rates and long-term survival. However, it is more toxic than ABVD, and there is no
experience in PLWH. In a prospective HL study, there were high response and survival
374 AIDS

Table 4: ABVD scheme (4 double cycles, repeat on day 29).*

Adriamycin (doxorubicin) 25 mg/m2 IV day 1 + 15
Bleomycin 10 mg/m2 IV day 1 + 15
Vinblastine 6 mg/m2 IV day 1 + 15
Dacarbazine (DTIC) 375 mg/m2 IV day 1 + 15
* Because of the potent emetogenicity of dacarbazine, antiemitic combinations, including 5HT3 recep-
tor blockers (e.g., granisetron or ondansetron), NK1 inhibitors, and dexamethasone should always be
used.

rates with the lower-dose BEACOPP baseline regimen and therapy-associated deaths
(Hentrich 2012+2021). Closely monitoring patients is essential, and there should be
experience with BEACOPP. Unfortunately, PLWH are still excluded from most clinical
therapy trials, a circumstance that is no longer justifiable (Hentrich 2012, Kaplan
2012, Montoto 2013). For the CD30 antibody-drug conjugate brentuximab vedotin
in combination with AVD, there are initial results of a small Phase I trial (Rubinstein
2018); Phase 2 is still ongoing. There are no consequences for clinical practice yet.
The same applies to a PET-adapted approach (Danilov 2017). Similar to NHL, the
standard therapy for HL relapse is high-dose chemotherapy with autologous stem
cell transplantation. Later relapses should be treated with checkpoint inhibitors such
as nivolumab, which have led to impressive remissions in case reports (Sandoval-
Hus 2017, Chang 2018, Serrao 2019).
In the choice of ART, the same applies as in NHL (see NHL) – especially the combi-
nation of booster and vinblastine should be avoided due to toxicity.

Literature
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lymphoma in the modern cART era, ANRS CO16 LYMPHOVIR Cohort. Clin Infect Dis 2015, 61:1469-75.
Bohlius J, Schmidlin K, Boué F, et al. HIV-1-related Hodgkin lymphoma in the era of combination antiretroviral
therapy: incidence and evolution of CD4+ T-cell lymphocytes. Blood 2011 117:6100-8.
Chang E, Sabichi AL, Kramer JR, et al. Nivolumab Treatment for Cancers in the HIV-infected population.
J Immunother 2018, 41:379-83.
Chang E, Rivero G, Patel NR, et al. HIV-related refractory Hodgkin lymphoma: a case report of complete response
to nivolumab. Clin Lymphoma Myeloma Leuk 2018, 18:e143-6.
Danilov AV, Li H, Press OW, et al. Feasibility of interim positron emission tomography (PET)-adapted therapy in
HIV-positive patients with advanced Hodgkin lymphoma (HL): a sub-analysis of SWOG S0816 Phase 2 trial. Leuk
Lymphoma 2017, 58:461-5.
Gloghini A, Carbone A. Why would the incidence of HIV-associated Hodgkin lymphoma increase in the setting
of improved immunity? Int J Cancer 2007, 120:2753-4.
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a prospective multicenter study. J Clin Oncol 2012, 30:4117-23.
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results of a prospective multi-institutional study. Oncol Res Treat 2021, 44(Suppl. 2): V634.
Hoffmann C, Chow KU, Wolf E, et al. Strong impact of highly active antiretroviral therapy on survival in patients
with human immunodeficiency virus-associated Hodgkin’s disease. Br J Haematol 2004, 125:455-62.
Hoffmann C, Hentrich M, Gillor D, et al. Hodgkin lymphoma is as common as non-Hodgkin lymphoma in HIV-
positive patients with sustained viral suppression and limited immune deficiency: a prospective cohort study.
HIV Med 2015, 16:261-4.
Hoffmann C, Schommers P, Wolf E, et al. CD4+ and CD8+ T-cell kinetics in aviremic HIV-infected patients devel-
oping Hodgkin or non-Hodgkin lymphoma. AIDS 2016, 30:753-60.
Kaplan LD. Management of HIV-associated Hodgkin Lymphoma: How Far We Have Come. JCO 2012, 30:4056-8.
Kowalkowski MA, Mims MA, Day RS, et al. Longer duration of combination antiretroviral therapy reduces the
risk of Hodgkin lymphoma: A cohort study of HIV-infected male veterans. Cancer Epidemiol 2014, 38:386-92.
Louarn N, Galicier L, Bertinchamp R, et al. First extensive analysis of 18F-labeled fluorodeoxyglucose positron
emission tomography-computed tomography in a large cohort of patients with HIV-associated Hodgkin lym-
phoma: baseline total metabolic tumor volume affects prognosis. J Clin Oncol 2022, 40:1346-55.
Montoto S, Shaw K, Okosun J, Gandhi S, et al. HIV status does not influence outcome in patients with classical
Hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in
the highly active antiretroviral therapy era. J Clin Oncol 2012, 30:4111-6.
Malignant lymphomas 375

Olszewski AJ, Castillo JJ. Outcomes of HIV-associated Hodgkin lymphoma in the era of antiretroviral therapy.
AIDS 2016, 30:787-96.
Robbins HA, Shiels MS, Pfeiffer RM, Engels EA. Epidemiologic contributions to recent cancer trends among HIV-
infected people in the United States. AIDS 2014, 28:881-90.
Rubinstein PG, Moore PC, Rudek MA, et al. Brentuximab vedotin with AVD shows safety, in the absence of strong
CYP3A4 inhibitors, in newly diagnosed HIV-associated Hodgkin lymphoma. AIDS 2018, 32:605-611.
Sandoval-Sus JD, Mogollon-Duffo F, Patel A, et al. Nivolumab as salvage treatment in a patient with HIV-related
relapsed/refractory Hodgkin lymphoma and liver failure with encephalopathy. J Immunother Cancer 2017, 5:49.
Serrao A, Canichella M, De Luca ML, et al. Nivolumab as a safe and effective treatment in an HIV patient with
refractory Hodgkin lymphoma. Ann Hematol 2019, 98:1505-6.
Shepherd L, Ryom L, Law M, et al. Differences in virological and immunological risk factors for Non-Hodgkin
and Hodgkin lymphoma. J Natl Cancer Inst 2018, 110:598-607.
Silverberg MJ, Lau B, Achenbach CJ, et al. Cumulative incidence of cancer among persons with HIV in North
America: a cohort study. Ann Intern Med 2015, 163:507-18.
Sorigué M, Garcia O, Tapia G, et al. HIV-infection has no prognostic impact on advanced stage Hodgkin lym-
phoma. AIDS 2017, 31:1445-9.

Multicentric Castleman disease (MCD)

Multicentric Castleman’s disease (MCD) is a rare but highly problematic disease for
those affected – not only because of the somewhat unfavorable prognosis (in HIV
infection) but also because, often, neither clinicians nor pathologists really know
this entity. Most of the patients suffer from severe episodes of the disease and often
go through long diagnostic delays.
Compared to benign, localized hyperplasia of lymphoid tissue first described by US
pathologist Benjamin Castleman in 1956, HIV-associated MCD, although neither
lymphoma nor AIDS-defining, is a lymphoproliferative disorder of malignant
character. It should, therefore, be distinguished from the classic, more benign,
unicentric Castleman disease (UCD) seen in HIV-negative individuals (Talat 2011).
In contrast to UCD, HIV-MCD is life-threatening. In the “pre-HAART era”, median
survival with HIV-MCD was only 14 months (Oksenhendler 1996); in the early
“HAART era”, mortality was still 29% (Mylona 2008). In the meantime, the prognosis
has improved, especially with rituximab (Bower 2011, Hoffmann 2011, Gérard 2012,
Oksenhendler 2018).
The pathogenesis of MCD is only partially understood. Crucial is an active co-infec-
tion with human herpesvirus 8 (HHV-8). Almost all are infected with HHV-8 – it is
not surprising that about half of those affected also suffer from Kaposi’s sarcoma,
which is often present in affected lymph nodes simultaneously (Naresh 2008). In
this context, the HHV-8 viral load is probably even higher in MCD than in KS (Sayer
2011, Haq 2015). HHV-8 can induce the production of a viral interleukin that is very
similar or induces similar effects to human interleukin-6 (“vIL-6”). IL-6 and IL-10
are elevated in close association with HHV-8 viral load (Oksenhendler 2000). Viral
IL-6 differs from human IL-6 in that it only needs to bind to one of the two IL-6
receptor subunits to exert its effect (Moore 1996, Li 2001, Suthaus 2010). Therefore,
it has a much broader spectrum of target cells and thus can likely cause the clini-
cally impressive “cytokine storms” typical of HIV MCD. However, there are very dis-
tinct cytokine profiles, sometimes with elevated viral, sometimes with elevated
human IL-6 (Polizzotto 2013). Plasmablasts localized in the mantle zone of lymphoid
follicles are mainly infected. HHV-8 is presented by follicular dendritic cells (FDC)
(El-Daly 2010). Interestingly, however, there appear to be cases of MCD without HHV-8
(and without HIV) (Seo 2009), as well as cases of IL-6-associated inflammatory
syndrome that lack the pathological features of MCD (Uldrick 2010). In these cases,
it remains unclear what ultimately leads to manifestation.
376 AIDS

It is also unclear why only very few people with HIV/HHV-8 co-infection manifest
MCD. An immune defect cannot explain this. The extent of CD4 T-cell depletion
seems to play a minor role; HIV MCD can occur even with normal immune status
and low HIV viral load (Powles 2009). In a separate cohort of 52 cases, the majority
were on antiretroviral treatment at the time of HIV-MCD diagnosis, and most had
viral loads below the limit of detection (Hoffmann 2011). Poor HHV-8-specific CD8
response is also absent in MCD, in contrast to Kaposi’s sarcoma (Guihot 2008). There
is also evidence that the incidence of HIV MCD tends to increase (Powles 2009).
“Degenerating” into malignant lymphoma is common. Of 60 patients with HIV-
MCD, 14 developed malignant lymphoma after a median observation period of 20
months (Oksenhendler 2002). The risk appears significantly lower after rituximab-
containing therapies (Hoffmann 2011, Gérard 2012, Pria 2018). Typically, HHV-8-
associated lymphoma subtypes that are otherwise rare can be observed, including,
for example, plasmablastic lymphomas or primary effusion lymphomas.

Clinic
First are the often-impressive lymph node swellings, which can be soft on palpation
(as in TB) or rock-hard (as in lymphoma). In addition, there are almost always
significant B symptoms with fever, night sweats, and weight loss. Almost all affected
individuals report weakness and a significant feeling of illness. The spleen is always
massively enlarged. Hepatomegaly (70%), respiratory symptoms (65%), and a ten-
dency to edema with hypoalbuminemia (55%) are also often found.
The extent of the symptoms is highly variable and sometimes fluctuates astonish-
ingly. Typically, in relapsed cases, the disease progression and activity lasts a few days
up to weeks, during which the patients often have high fevers and are severely ill.
The relapses are interrupted by more extended periods, sometimes lasting several
months, during which the patient is relatively well again. Lymph node regression
may temporarily occur without any intervention. With the increasing duration of
the disease, the frequency of relapses is increasing. Recurrences after rituximab are
common, and the clinic does not differ from initial manifestations (Pria 2018).

Diagnostics
The diagnosis is made histologically from an extirpated lymph node, assuming the
pathologist knows what HIV-associated multicentric Castleman’s disease looks like.
The germinal centers of the lymph nodes appear layered like onion skins and are
interspersed with vessels. A distinction is made between a hyaline vascular and a
plasma cell-rich type of Castleman’s disease. Clinicians should be explicit about the
suspicion of MCD. Often, KS is present in the lymph nodes at the same time (Naresh
2008). Some cases may never be correctly diagnosed.
Sonography almost always shows hepatosplenomegaly. Laboratory findings include
elevated CRP, hypergammaglobulinemia, and hypalbuminemia. There is often
marked anemia, often in the setting of pancytopenia or hemophagocytic syndrome
(Stebbing 2009). In a relapsing course with B symptoms, splenomegaly, high CRP,
and fluctuating lymph node swelling, one should never be satisfied with a patho-
logic diagnosis of HIV-associated lymphadenopathy. HIV alone never makes you as
sick as an MCD! PET-CT can be helpful (Polizzotto 2015), but it is not routine.
In our experience, the acute phase protein CRP is particularly suitable as a diagnostic
follow-up parameter to monitor success in addition to the clinic. During a relapse,
CRP blood values are often far above 100 mg/l, but even normal values may be found
between relapses. Sometimes, the CRP elevation slightly precedes the clinical
Malignant lymphomas 377

symptoms. The CRP should, therefore, be determined with every blood sample taken
in MCD. HHV-8 viral load is also a parameter of disease progression (Marcelin 2007,
Stebbing 2011, Sayer 2011) but is reliably performed by only a few laboratories.

Treatment
In HIV-MCD, something must be done quickly: the course can be fulminant.
However, randomized studies, sufficient diagnostic criteria, and treatment recom-
mendations are still lacking, as they are now available for HIV-negative idiopathic
MCD (Fajgenbaum 2017, van Rhee 2018). Inclusion in an international registry such
as ACCELERATE is desirable (contact via author).
Given our experience and the current data, we believe the monoclonal antibody
rituximab is the drug of choice (see below). Some experts also favor the combina-
tion of rituximab and chemotherapy in aggressive courses (Bower 2010). ART should
also be given if possible, although it does not always help (Aaron 2002, Sprinz 2004,
Alzahrani 2014). Cases have been described in which ART exacerbated the inflam-
matory component of MCD (Zietz 1999).
Rituximab: This antibody against CD20-expressing cells, which is also used in
B-cell lymphomas (see above), probably eliminates a large proportion of the B-cells
infected by HHV-8, predominantly in the mantle zone of the lymph node. Several
studies have produced very encouraging results. In a French study, 16/24 patients
achieved complete remission after one year with four courses of rituximab (Gérard
2006). Overall survival at one year was 92%, and disease-free survival was 74%. In a
British study, 20/21 achieved clinical remission, and 14/21 achieved radiological
response (Bower 2007). Overall survival in this study was as high as 95% after two
years, and disease-free survival was 79%. CRP, immunoglobulins, and HHV-8 viral
load each decreased with rituximab. This was also true for cytokines such as IL-5,
IL-6, and IL-10 (Bower 2009). Survival was also significantly improved with ritux-
imab compared to conventional therapies in our retrospective cohort of 52 patients
(Hoffmann 2011). Moreover, lymphomas in MCD are significantly less frequent with
rituximab (Bower 2011, Gérard 2012, Pria 2017).
A dose of 375 mg per m² of body surface area is given once a week for four weeks.
Care should be taken to ensure good hydration. Health insurance should be contacted
in advance, as rituximab is not approved for MCD. Rituximab is well tolerated, and
tumor lysis syndrome has not been observed. The main complication appears to be
the reactivation of Kaposi’s sarcoma, which probably occurs in up to one-third of
cases (Bower 2007) and is challenging to treat. Combining rituximab with liposomal
doxorubicin may be possible in cases with KS/MCD coincidence (Uldrick 2014).
Attention should also be paid to infectious complications, especially in immunod-
eficiency. Even in relapses, which are not uncommon, re-administration is readily
available and very effective (Powles 2007, Pria 2018).
However, in some, rituximab seems ineffective (Neuville 2005, Buchler 2008).
Therefore, other approaches for which at least case reports or small case series exist
will be briefly addressed in the following.
Valganciclovir: In a double-blind, randomized study, valganciclovir significantly
reduced HHV-8 replication and is a potential choice for MCD treatment (Casper
2008). In a case series on HIV-MCD, 12/14 patients achieved “clinical improvement,”
and CRP, IL-6, and HHV-8 viral load also decreased (Uldrick 2011). However, our
own experience has only partially confirmed this (Hoffmann 2011). There is a
possible role for valganciclovir as maintenance therapy (Bower 2010). In contrast to
valganciclovir, foscarnet or cidofovir do not appear to have any benefit (Coty 2003,
Senanayake 2003, Berezne 2004).
378 AIDS

Chemotherapy: Well-tolerated agents such as vincristine (2 mg IV as a bolus at

14-day intervals), vinblastine, or oral etoposide (50 mg daily) are effective according
to some reports and also in our experience (Scott 2001, Kotb 2006). CHOP chemother-
apy may also be helpful but does not significantly prolong survival.
Splenectomy: may be useful in severe cases. Speculation is that IL-6 production is
curbed by removing a large HHV-8 reservoir. In 40 patients, the median survival with
splenectomy was 28 versus 12 months (Oksenhendler 2002). One US study group
reported that symptoms improved in 10/10 cases (Coty 2003).
IL-6 receptor blockers: There is data from Japan on several dozen HIV-negative indi-
viduals successfully treated with anti-IL-6 receptor monoclonal antibodies such as
tocilizumab (Nishimoto 2005, Matsuyama 2007). Tocilizumab was approved for treat-
ing rheumatoid arthritis in 2009 under the trade name RoActemra®. Two cases of
HIV-MCD showed rapid, albeit short-term, clinical improvements (Nagao 2014). For
siltuximab, an anti-IL-6 monoclonal antibody, there is a randomized trial in as many
as 53 negative individuals, showing durable remissions in 34% of patients (van Rhee
2014). In HHV-8 MCD, siltuximab has not yet been systematically tested because it
probably does not bind to viral IL-6. However, there is evidence that it may still be
effective (Polizzotto 2013).
Thalidomide: is supposed to suppress the cytokine dysregulation or the inflamma-
tory component. There are case reports (Lee 2003, Jung 2004), some combined with
rituximab (Stary 2008). We did not have a good experience with two patients;
complications occurred, including pulmonary embolism.
Other immunotherapies: There are positive and negative alpha-interferon case
reports (Coty 2003, Nord 2003). Steroids have no effect.

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381

10. Non-AIDS-defining malignancies

C H R ISTIAN HOFFMAN N

People living with HIV have an increased risk of cancer. This applies not only to the
three AIDS-defining malignancies (ADM), Kaposi’s sarcoma, non-Hodgkin’s
lymphoma, and cervical carcinoma. There is also an overall two- to three-fold
increased incidence for most non-AIDS-defining malignancies (NADM) (Franceschi
2010). For some diseases like Hodgkin’s disease (see Malignant Lymphomas) and anal
carcinoma (see below), the risk is so evident that calls have been made to classify
them as AIDS-defining diseases. Breast carcinomas, on the other hand, do not appear
to be more common (Latif 2011).
In recent years, some authors have suggested that instead of ADM and NADM, it is
better to distinguish infection-related malignancies (IRMs) and infection-unrelated
malignancies (IURMs) (Borges 2016, Shepherd 2016). However, this classification has
drawbacks: infection as a cause is not always confirmed or ruled out; consider gastric
carcinomas, hepatocellular carcinoma (it does not always have to be hepatitis), and
some lymphomas.
NADM account for about two-thirds of all new malignancies in HIV-infected indi-
viduals (Shepherd 2016). They are thus more common than lymphoma and Kaposi’s
sarcoma. In developed countries, NADM result in more deaths than ADM, hepatitis
C, or cardiovascular disease (Smith 2014). Among patients with virologic control,
NADM are by far the most common cause of death at 19% – in contrast, hardly
anyone dies of AIDS (Goehringer 2017). Figure 1 shows the percentage of malig-
nancies among causes of death in France between 2000 and 2010 (Vandenhende
2015). In a newer French analysis restricted to the Paris area, 31% of all deaths were
due to non-AIDS non-viral hepatitis-related NADM in 2020/21 (Sellier 2023).
In the [Link] study, the major risk factors for fatal NADM were increasing age, current
nicotine use, and the level of CD4 T-cells: the lower, the higher the risk for NADM.
Individuals below 50 CD4 T-cells/µl had a 15-fold higher risk than those with more
than 500/µl (Monforte 2008). The risk persisted once CD4 T-cells were low (Worm
2013). The correlation between NADM and immunodeficiency was also confirmed
in the EuroSIDA study (Reekie 2010). However, immunodeficiency does not explain

Figure 1: Malignant diseases as a proportion of causes of death. Deaths among PLWH in France in 2000
(light, n=964), 2005 (gray, n=1042), and 2010 (black, n=728). Figures according to Vandenhende 2015.
382 AIDS

everything. Smoking contributes to the increased incidence of many tumors

(Helleberg 2014), and the proportion of active smokers is still significantly higher
than in the general population. Alcohol, lifestyle (UV exposure), and co-infections
(HPV, HBV, HCV) also play a role. The thesis that the incidence of all malignancies
will increase given the increasing age of PLWH is only partly true. The increase will
mainly affect IURMs and fewer IRMs due to the aging of the HIV-infected popula-
tion and high smoking prevalence (Shepherd 2016). Incidence of UIRMs appears not
to be positively influenced by an earlier start of therapy (Borges 2016).

Screening and prevention

Whether PLWH need more frequent screening or earlier detection examinations is
still being determined. With regard to anal carcinoma, there seems to be evidence
for a benefit, but screening is controversial (see below). The situation is unclear for
colon cancer, although there is evidence that neoplastic changes are found more
frequently in PLWH on the occasion of screening colonoscopies (Bini 2009). There
are no specific recommendations for prostate-specific antigen screening beyond
discussing its utility in the general population (Tyerman 2012). For gynecologic
screening, see the Gynecology chapter. In HCV co-infection, regular (biannual)
sonography could be beneficial, as shown in a study of 70 patients: hepatocellular
carcinomas were less advanced when detected, even resulting in slightly better
survival (Nunez 2010).
Finally, support for smoking cessation has become an essential part of medical care
– smoking is also a major contributor to mortality in HIV. While superfluous
“preventive” examinations are often demanded (“Shouldn’t we have another
X-ray?”), it is usually forgotten: nicotine abstinence is and remains the most important
preventive measure, even for malignant diseases. PLWH today lose more years of life
to smoking than HIV (Helleberg 2013); non-smokers are not at increased risk for
many tumors (Helleberg 2014, Shepherd 2016). US projections found cumulative
lung cancer mortality risks of 29, 23, and 19% for a 40-year-old HIV-positive man
with continued heavy, moderate, or light nicotine use. If this patient quits at age 40,
the risk drops to 8%, 6%, and 4%, respectively. By comparison, someone who has
never smoked has a cumulative lung cancer risk of 1.6% (Reddy 2017). Avoiding
excessive obesity and healthy lifestyles also do more than costly screenings.

Treatment
A problem of therapy for many NADM is that little is often known about chemother-
apeutic agents and ART interactions, and the new targeted agents are primarily
unexplored in PLWH. Prospective studies are virtually nonexistent, and data on
critical new agents are limited. Data are also still limited for checkpoint inhibitors
(which interfere with the T cell response and were therefore initially used cautiously
in PLWH) (Cook 2019, Luo 2022).
For many malignancies, there are only uncontrolled cohorts with HIV. In most cases,
those affected are younger than those from the general population, although this
could also be due to better surveillance (Shiels 2010). However, experience in entities
as diverse as glioblastoma (Wang 2018), carcinoma of the colon (Chapman 2009,
Alfa-Wali 2011), bladder (Gaughan 2009), prostate (Pantanowitz 2008), or esophagus
(Stebbing 2010, Jensen 2017) shows that PLWH generally benefit from advances in
oncology. They should generally be treated in the same way as HIV-negative
individuals – although this often requires mediating discussions with oncologists,
whose HIV picture is sometimes still limited today. There is considerable potential
for improvement in communication (Suneja 2015).
Non-AIDS-defining malignancies 383

Anal carcinoma
Anal carcinoma is one of the most common non-AIDS tumors in PLWH. It is closely
associated with HPV co-infections and usually arises from pre-cancerous precursors.
Regarding the frequency, sometimes dramatic reports circulate, often leading to
uncertainty. It will, therefore, be discussed here in more detail than other tumors.

HPV association, epidemiology

Human papillomavirus (HPV) infections are among the most common sexually trans-
mitted viral infections ever. HPV belongs to the Papovaviridae family and infects the
basal cells of the epithelia of the skin and mucosa. PLWH have a 2–6-fold increased
risk of anal HPV infection, independent of sex, sexual practices, and preferences. The
risk of persistent HPV infections is 7-fold higher and inversely correlates with CD4
T-cell count (Piketty 2003). Nearly 100 different HPV types are now known, and
about 20 are associated with anal or cervical cancer. HPV-16 and HPV-18 have a high
oncogenic potential, with an increased risk of anal carcinomas.
HPV infections are present in most PLWH, often with multiple subtypes. In a meta-
analysis, the pooled prevalence for anal HPV infections in HIV-positive men was
89% overall and 79% for potentially vaccine-preventable high-risk types such as
HPV-16/18 (Machalek 2012). A study from Bochum (Kreuter 2005) found anal HPV
infection in 86% of 103 male patients, mostly HPV-16 (53%) and -18 (27%).
Persistent HPV infection can lead to precancerous lesions, anal intraepithelial neo-
plasms (AIN). These are classified histologically according to the degree of dysplasia
into grade I (mild), grade II (moderate), and grade III (severe). In severe AIN, the
entire epidermis is affected. AINs, including those of higher grade, are widespread;
AIN II/III are found in approximately 30% of HIV-positive men (Machalek 2012).
The enormous (and at first glance disturbing) prevalence of anal HPV infections and
pre-cancerous precursors contrast with an overall relatively low incidence of anal
carcinoma (AC). A meta-analysis of all data through the end of 2011, based on
100,000 patient-years, showed an overall incidence of 78 for the HAART era,
compared with 22 in the pre-HAART era (Machalek 2012). Significant regional
differences exist. For example, the incidence in the United States was most recently
147 (Chiao 2013); in the European-dominated [Link] cohort, it was only 45 (Worm
2013), and in the Swiss cohort, it was even lower at 25 (Franceschi 2010). Thus, anal
carcinoma remains a rare disease, even in HIV. However, the relative risk is signifi-
cantly increased compared to the general population (where it is a rarity) – about
80-fold for MSM and 27-fold for heterosexual men, probably also in women
(Silverberg 2012). The incidence may be declining in recent years (Colón-López 2018).
It follows from this discrepancy that HPV infections and higher-grade precursors do
not necessarily result in tumor disease: according to currently available data, one
invasive AC per year develops from 377 high-grade changes (Machalek 2012). Many
AINs regress spontaneously (Tong 2013, Grulich 2014). Spontaneous clearance of
HPV viruses often occurs (Goldstone 2019, Alberts 2020), but the rate is probably
somewhat lower overall in HIV infection (Wei 2022).
Thus, most PLWH with HPV and AIN will not develop cancer; the estimated
cumulative lifetime AC risk is about 1.5% (Silverberg 2015). Moreover, the risk is
different for everyone. Many studies have shown that AC incidence is much higher
for low CD4 T-cells than individuals whose CD4 T-cells never fell below 200/µl
(Piketty 2012, Bertisch 2013, Chiao 2013, Duncan 2015). CD4 nadir, in particular,
appears to be a significant risk factor. Cumulative viral load is also one, as is smoking
(Bertisch 2013, Chiao 2013). There does not appear to be an apparent protective
384 AIDS

effect from ART. Early ART may slow progression (Duncan 2015). However, in a sep-
arate cohort of 121 cases, most had been successfully treated with antiretroviral
therapy for many years, and CD4 T-cells were at almost 400/µl (Hoffmann 2011).

Screening and treatment of precursors

In 2013, the German AIDS Society, among others, developed a guideline for pre-
venting, diagnosing, and treating anal dysplasia and anal carcinoma in PLWH, which
provides detailed instructions for action despite the limited data available (see
Dermatology). In this guideline, routine examinations (inspection, palpation, smear,
cytology) are recommended once a year for all PLWH. However, there is controversy
about whether such comprehensive screening is beneficial. Given the discrepancy
between enormously high AIN prevalences and the low AC incidence, there is a
considerable risk of over-diagnosis, over-therapy, and the associated uncertainty for
everyone involved.
Since years usually elapse between AIN and the manifestation of anal carcinoma,
early treatment of AIN has a good chance of success, at least in theory. However, no
treatment of pre-cancerous lesions has sufficient evidence, as shown by a Cochrane
analysis (Macaya 2012). For AIN 1, topical therapy with imiquimod (or podophyl-
lotoxin) is warranted; AIN 2+3 should be removed surgically (electrocaustic ablation
using a snare) or by laser ablation. Infrared coagulation is also possible (Stier 2008).
The complete clearance rate of higher-grade lesions increased to 62% in one year
with repeated treatments, compared with 30% with observation alone (Goldstone
2019). In another randomized trial of 148 HIV-positive MSM with AIN, electrocautery
was superior to topical treatment with imiquimod or 5-FU regarding tolerability
(Richel 2012). However, recurrences were very common.
Off-label use of imiquimod (multiple manufacturers) is an option for high-grade AIN
in PLWH on ART. The dosage is ½ sachet of imiquimod cream 5% topical three times
per week; for severe local irritation, discontinuation for several days until irritation
subsides. Duration of treatment is at least 16 weeks; if there is no response, contin-
uation for another 16 weeks. Treatment should be discontinued after 32 weeks if no
therapeutic response is observed.
Condylomas should also be eliminated (electrocoagulation, cryotherapy). Topical
therapy with the immunomodulator imiquimod (i.e., Aldara® cream) is also possible
here, but the effects are less impressive in PLWH. Imiquimod seems better suited as
post-treatment, where it probably significantly reduces the recurrence rate.
Imiquimod does not have a direct antiviral effect but probably a cytolytic-destruc-
tive effect via cytokine induction. The most important side effect is local erythema
(erythema means effect!); less frequent are burning and pruritus. Severe skin reactions
occur only rarely.
2022, the ANCHOR data were presented, a large randomized Phase III trial (Palefsky
2022). In this, nearly 4,500 people over 35 years of age and with HIV and biopsy-
proven HSIL (high-grade squamous intraepithelial lesions, equivalent to AIN II/III)
had been randomized to receive either treatment of these lesions (in 84% ablation
with electrocautery, but also other methods) or only “active monitoring” (high-
resolution anoscopy every six months). After an observation period of 26 months,
9 cases had occurred in the treatment arm compared with 21 cases in the treatment
arm, corresponding to 173 rather than 402 cases per 100,000 person-years. Despite
these results, controversy remains over the treatment of pre-cancerous lesions.
Despite the immense effort, the overall clinical effect in ANCHOR was small, and
overall mortality was not affected. Moreover, seven serious adverse events were
observed in the treatment arm and only one in the observation arm.
Non-AIDS-defining malignancies 385

Many believe that better risk stratification is needed, especially in light of these data
and the limited capacity for high-resolution anoscopy. There is a need to identify
those at the highest risk for developing cancer (HPV-16? DNA methylation?) and,
from this, to develop viable screening and treatment strategies. Hopefully, further
sub-analyses from ANCHOR will provide answers to this.

Diagnosis
The most common symptom is rectal bleeding. A person reporting blood in the stool
must see a proctologist! One should not be satisfied with the “suspected diagnosis”
of hemorrhoids often voiced by the patient. Other symptoms are burning, pain
during defecation, or pruritus. Histologically, squamous cell carcinomas are usually
present and, more rarely, transitional epithelial carcinomas. Early on, the anal canal
and sphincter may be infiltrated. Regional lymph nodes are affected depending on
the location of the anal carcinoma. Deep-seated anal carcinomas infiltrate inguinally,
intermediate pelvic, and high-seated mesenteric. Distant metastases are rare. Never-
theless, in addition to proctoscopy and endosonography if possible, CT abdomen
and pelvis should always be done.

Treatment
In manifest AC, small lesions of < 2 cm are operated on with continence preserva-
tion if possible, and adjuvant chemotherapy or radiotherapy is unnecessary. Larger
lesions are treated with combined radiochemotherapy (mitomycin 10 mg/m2 on
days 1 and 29 and 5-FU 1000 mg/m2 on days 1–5 and 29–33, followed by radio-
therapy fractionated up to 50 Gy). More intensive therapies are also possible (Blazy
2005). The complications that can occur under such a regimen should be noted.
What can go wrong, does go wrong: We have experienced a patient who first
developed severe extravasation under mitomycin, then myocardial infarction under
5-FU, and finally perforating fecal radiation colitis. Invariably, affected patients
should receive concomitant oncologic care. After completion of radiochemotherapy,
proctoscopy is performed every six months. ART-naive patients should always be
started on ART. Overall, the prognosis of AC does not appear to be significantly worse
than in HIV-negative individuals (Chiao 2008, Hoffmann 2011, Alfa-Wali 2012). In
a large study of 605 cases from 2004–2018, HIV was only a risk factor for disease-
free survival in T1-2/N0 cases but not in later stages (Martin 2022).

Vaccination
An HPV vaccine that protects intraepithelial neoplasia and persistent HPV infection
in cervical carcinoma (Harper 2006) also appears protective against anal carcinoma
(Palefsky 2011). Approved vaccines induce an adequate immune response in PLWH
(Toft 2014, Staadegard 2022). However, PLWH are usually already HPV-co-infected,
so the purely protective effect of such vaccination will likely come too late. However,
vaccination may also have a therapeutic effect (Anderson 2009). However, a recent
large randomized trial in patients over 26 years of age yielded disappointing results.
Neither persistent HPV infection nor precursors were favorably affected by the
vaccine (Wilkin 2018).
386 AIDS

Testicular tumors
Testicular tumors are the most common cancer in men between 20 and 35, and HIV
infection increases the relative risk by a factor of 2–5, especially for seminomas
(Goedert 2007). Two early case collections reported 34 and 35 patients, including 26
and 16 seminomas and 18 and 9 non-seminomatous germ cell tumors, respectively
(Powles 2003, Fizazi 2001). Median CD4 T-cells at diagnosis ranged from 300 to
350/µl, although with a wide range. The prognosis was generally good and no worse
in a matched-pair study than in HIV-negative individuals (Powles 2004). Other
studies also report quite favorable courses (Fizazi 2001).
In a recent international cohort study with 92 cases, progression-free survival at
5 and 10 years was 81% and 73%, respectively, and overall survival rates were 91%
and 85% (Hentrich 2022). Most were diagnosed at early stages (stage 1 at 56%).
Overall, only five deaths from refractory disease were observed.
HIV-positive men with testicular cancer should be treated with the standard regimens
recommended for HIV-negative patients. Depending on histology and stage, these
consist of orchiectomy, lymph node extirpation or radiation, and/or platinum-based
chemotherapy. High-dose therapies are also possible (Hentrich 2009). Treatment
should be performed by an oncologically knowledgeable urologist (or urologist) in
collaboration with an HIV center.

Lung cancer
In the general male population, lung cancer (LC) is the most frequent type of cancer
leading to death; in women, it is in third place, and the trend is upward. In PLWH,
the relative risk is at least doubled (Haas 2022) and increases with increasing immun-
odeficiency (Reekie 2011). In the United States, since about 2011, the risk of disease
for lung cancer has been higher than for KS and lymphoma for people over age 60
living with HIV (Haas 2022). In France, LC is now more likely to cause death
than non-Hodgkin lymphoma, accounting for about 8% of all causes of death
(Vandenhende 2015). It is estimated that about 9% of all PLWH will eventually die
from LC if smoking habits do not change.
Rising incidences are likely to have many reasons: first, PLWH live longer and thus
have more time to develop LC, and second, PLWH smoke too much. Smoking is the
most critical risk factor (Clifford 2012) for LC: time to quit – opportunities to quit
are plentiful. However, there are also increasing voices calling for strategies that go
beyond just smoking cessation, as many people are not ready to do so (Shuter 2021).
In addition, other factors contribute to the increased risk besides age and nicotine
(Review: Frega 2020). This is also supported by the fact that, with adenocarcinomas,
the subtype that is most elevated is the subtype that is least associated with increased
nicotine use of all LC subtypes. Because severe immunodeficiency is often not
present, other factors have been postulated, including specific infections in the lung
and scarring, but also increased levels of pro-inflammatory cytokines in the lung or
decreased levels of glutathione, as found in HIV infection. These factors could exac-
erbate the damage caused by smoking. PLWH appear to be more sensitive to car-
cinogens (Frega 2020). In a US cohort, increased risk persisted even after adjusting for
smoking, age, ethnicity, and COPD (Sigel 2012). Predisposition also plays a role. The
risk is exceptionally high if the parents already have the disease (Engsing 2011).
As with HIV-negative patients, only those whose LC is detected early have a chance.
Symptoms are non-specific, and diagnosis is rarely made in time. In our cohort of
72 cases from 2000–2010, only 34% were in stages I-IIIa (Hoffmann 2013). In early
tumor stages, surgery should be performed with curative intention if possible;
Non-AIDS-defining malignancies 387

chemotherapies only grant a delay. The median survival times in our evaluation were
one year – the level of CD4 T-cells and limited stages were significant influencing
factors. Long-term survival is possible in the early stages.
PLWH with LC do not have a worse overall outcome than HIV-negative LC patients
(Rengan 2012). Carboplatin/gemcitabine are tolerated quite well, as are taxanes
(Bridges 2008). HIV is not a contraindication for any drug. Especially with regard to
potential interactions, the choice of antiretroviral options has grown significantly
in recent years, and switching ART is rarely a problem. The recommendations for
HIV-negative individuals should, therefore, guide treatment. Differentiation is made
not only by stage but also by histologic and genetic markers. In recent years, immune
checkpoint and kinase inhibitors associated with predictive biomarkers have
improved prognosis. New cytostatics, angiogenesis inhibitors, and local and
supportive therapies are available. Although data are limited on HIV infection, all
new approaches should be considered in principle, including immune checkpoint
inhibitors (ICIs), with growing experience (Cook 2019, Lavole 2022, Luo 2022). For
example, in a recent analysis of 390 PWH, ICIs demonstrated differential activity
across cancer types with no excess toxicity. The safety and activity of ICIs were similar
between matched subgroup cohorts of PLWH and negative controls with metastatic
lung cancer (El Zharif 2023).

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SECTION 4

Other Infections
392

11. HIV and HBV/HCV co-infections

K AT H R I N V A N B R E M E N , C H R I S T O P H B O E S E C K E , J Ü R G E N K U R T R O C K S T R O H

HIV and HCV co-infection

Epidemiology and transmission routes
Due to the same transmission routes, HIV/HCV co-infections occur frequently. In
the US, 240,000 people (30% of all PLWH) are infected with both viruses. In Eastern
Europe, rates are often higher (Peters 2014). For example, in Russia, because of the
high number of intravenous drug users, about 70% of the 860,000 people with HIV
are also HCV-positive. In Western Europe, syringe exchange programs and rehabili-
tation efforts significantly decreased the rate of new HCV infections due to IV drug
use. In Barcelona, for example, HCV prevalence among newly diagnosed PLWH fell
from 24% in 2000–02 to 10% in 2006–08 (Trevino 2009).
Since HCV is about ten times more infectious than HIV in blood-to-blood contacts,
intravenous drug users and recipients of blood products are particularly affected by
dual infections. Needlestick injuries have a transmission probability of less than 2%
after exposure to HCV-contaminated blood, possibly even lower, i.e., by 0.3% as for
HIV (Kubitschke 2007). Sexual transmission of HCV, on the other hand, is much less
common compared to HBV or HIV; it is less than 1% for heterosexual intercourse.
Approximately 4–8% of HIV-infected men who have sex with men (MSM) also have
hepatitis C. The first cases of recently acquired HCV infection in HIV-positive MSM
were observed in the early 2000s in metropolitan areas such as London, Paris,
Amsterdam, and Berlin, as well as in the United States, Australia, and Taiwan. In the
following decade, this developed into a global epidemic (Boesecke 2015). Risk factors
for sexual transmission are co-existing infections such as syphilis or lymphogranuloma
venereum, sexual practices with increased risk of injury to the mucous membranes
such as fisting or group sex, but also the use of drugs such as cocaine or ampheta-
mines (See Chemsex), which is sometimes also used intravenously (GMFA 2013).
The perinatal transmission rate of hepatitis C is low in immunocompetent women
(< 1%) but increases up to 20% in untreated HIV-infected pregnant women with
immunodeficiency. On ART, the risk is probably not increased and is less than 3%
with cesarean section (Pembrey 2005). However, in HCV-mono-infected women,
HCV transmission risk is unlikely to be reduced by cesarean section (Indolfi 2009).

Clinical course & interactions between HIV and HCV

The clinical course of HCV co-infection is determined by HIV-associated immuno-
suppression. As immunosuppression progresses, the course of hepatitis C is acceler-
ated. Conversely, there is no particular influence of hepatitis C on the course of HIV
infection (Rockstroh 2005). The latency period to liver failure or hepatocellular car-
cinoma is 10–20 years in co-infected individuals, compared to 30–40 years in HCV
mono-infection (Benhamou 1999). ART improves immune function and thus the
unfavorable course of hepatitis C. In cases of good immune reconstitution, liver
failure is delayed (Pineda 2007). Therefore, early initiation of antiretroviral therapy
has always been recommended in HCV co-infection, which was further emphasized
in 2015 following the results of the START trial (EACS 2017). Possible hepatotoxic-
ity of antiretroviral drugs no longer plays a relevant role today and should not be a
reason to delay initiation. Hepatotoxic agents such as nevirapine and tipranavir are
barely used anymore. Elevated transaminases, often temporarily elevated after ART
initiation, are probably due to increased inflammatory activity of hepatitis C with
HIV and HBV/HCV co-infections 393

improved immune status. However, as mentioned above, long-term observations

suggest that ART favors the course of hepatitis C and that the benefits clearly out-
weigh the possible side effects (Rockstroh 2009).

Diagnostics
Diagnosis in co-infection is the same as in HCV mono-infection (Table 1). Positive
HCV antibodies (HCV Ab) prove exposure to HCV but do not distinguish between
cured or chronic hepatitis C. The latter is only confirmed by detecting HCV viremia
(HCV RNA). It should be noted that in the course of HIV infection, loss of HCV anti-
bodies may occur due to immunodeficiency. Although this phenomenon has become
rare with today’s testing methods, it may be helpful to determine HCV RNA in cases
of clinical suspicion or advanced immunodeficiency, even though the HCV Ab test
is negative. This also applies to suspected recently acquired HCV infection since HCV
Ab can only be detected after 1–6 months. Especially with HIV, seroconversion is
often delayed: three months after HCV RNA was first detected, 37% of cases were
still without HCV Ab (Thomson 2009).
In HIV/HCV co-infection, HCV viremia is, on average, one log higher than in HCV
mono-infection. The level of viremia has no predictive value, and follow-up is
unnecessary. We consider once-yearly determinations appropriate in the (rare) cases
where HCV initially remains untreated. In rare cases, affected individuals lose their
HCV RNA with increasing immunodeficiency and develop “HCV flares” with clinical
symptoms when on ART (Kim 2006).
Maviret® (glecaprevir/pibrentasvir) and Epclusa® (sofosbuvir/velpatasvir), two pan-
genotypically active preparations, are available. Thus, HCV genotype determination
for therapy selection is only indicated when non-pan-genotypic agents are used or
in the case of retreatment (EACS 2022). Six genotypes with numerous subtypes are
known. Genotypes 1 and 3 dominate in Europe, 4 and 5 in Africa, and genotype 6
in Asia. Double infections with multiple genotypes are rare.
In addition, determining the degree of fibrosis is essential to estimate the extent of
liver damage. The most important non-invasive procedure is the fibroscan system,
which uses transelastography to assess liver stiffness, which correlates directly with
the degree of fibrosis of the liver. A liver biopsy is not necessary but may provide
valuable differential diagnostic information in individual cases (e.g., autoimmune
hepatitis). An alternative to the fibroscan can be indices formed from serum markers
correlating with the degree of fibrosis, e.g., APRI score, FIB-4, or scores such as
Fibrometer or Hepascore.
In most cases, the fibrosis stage is classified on a 5-point scale analogous to the
METAVIR score (0 = no fibrosis, 1 = portal fibrosis without septa, 2 = few septa, 3 =
numerous septa without cirrhosis, 4 = cirrhosis). Because progression can be con-
siderably more rapid in HIV infection, annual determinations are reasonable with a
wait-and-see procedure. In a US study (Sulkowski 2007), 25% deteriorated by two or
more fibrosis stages (Ishak score, stages 0–6) within only three years. In case of clin-
ical suspicion, further investigations (skin biopsy, urine diagnostics, possibly kidney
biopsy, cryoglobulins in serum) may be necessary to detect or exclude extrahepatic
manifestations (vasculitis, glomerulonephritis, systemic cryoglobulinemia).
In people with liver cirrhosis, an ultrasound examination of the liver should be per-
formed every 6–12 months to detect hepatocellular carcinoma (HCC) in time. The
risk of carcinoma remains elevated in cirrhosis even after HCV eradication. Since
fibrosis progression can be significantly accelerated in HIV co-infection and HCC
develops in 10–30% even in the absence of cirrhosis, regular follow-up examinations
should be considered for all individuals with higher-grade fibrosis (> F3) (EACS 2022).
394 Other Infections

Table 1: Diagnosis of hepatitis C coinfection in PLWH (modified after EACS 2021).

For diagnosis
HCV Ab (positive 1–6 months after infection, delayed seroconversion in HIV, and loss in advanced
immunodeficiency possible).
HCV RNA
Clarification of other liver diseases or extrahepatic HCV manifestations
Alcohol consumption, heart disease, renal insufficiency, autoimmune disease, genetic or metabolic
liver disease (e.g., hemochromatosis, diabetes mellitus, obesity), and drug-induced hepatotoxicity.
To assess the liver status
Degree of fibrosis (e.g., by fibroscan, liver biopsy, serum fibrosis marker).
Blood count, GOT, GPT, GGT, ALP, liver synthesis parameters (e.g., coagulation, protein, albumin,
cholinesterase).
Semiannual liver ultrasound in cirrhosis.
When cirrhosis is first diagnosed, gastroscopy (after that, every 2–3 years if no varices are present;
more frequently if varices are present).
Before starting treatment
HCV RNA, renal, and liver function test. HCV genotype only necessary when using non-pan-geno-
typic agents.
During treatment
Blood count, transaminases, creatinine, bilirubin, and albumin for fibrosis ≥ F3 to week 2–4.
HCV RNA at the end of therapy and 12 weeks after that (SVR).

Recently acquired hepatitis C

Recently acquired cases of HCV continue to be observed mainly among MSM. They
are often preceded by sexual contact with a very high risk of infection (unprotected
anal intercourse, especially with sex toys, fisting, and chemsex practices). Due to the
long latency of antibody formation, the diagnosis can often only be made based on
medical history, elevated transaminases (usually at least five times the upper normal
limit), and HCV RNA detection. Many cases are overlooked because the infection is
asymptomatic in up to two-thirds of people. Spontaneous recovery (up to 40% HCV
mono-infected) is much rarer in HIV co-infection with 10–15% (Monin 2023).
Favorable factors include IL28B CC genotype, female gender, sexual transmission
(compared to intravenous drug use), or a clinically symptomatic course. However,
there are no practical consequences. Directly Acting Agents (DAAs) have also replaced
interferon-containing therapies for recently acquired hepatitis C. Guidelines
recommend immediate treatment after diagnosis of HCV infection if risk behaviors
persist to reduce transmission (e.g., attending sex parties, engaging in injury-prone
sexual practices, active chemsex) (EACS 2022). If therapy is not immediately indi-
cated, it should be started if there has not been a drop in HCV RNA of at least 2 logs
4 weeks after diagnosis (EACS 2022), at which time chronicity is very likely. DAA
combinations with a short duration of therapy (8 weeks) should be used, analogous
to treating chronically HCV-infected individuals without cirrhosis or prior treatment.

Treatment of chronic hepatitis C

The goal of treatment is a permanently negative HCV RNA, i.e., a cure. This sustained
virological response (SVR) is defined as a negative HCV RNA either 12 or 24 weeks
after the end of treatment (SVR12, SVR24). Since 2014/2015, various DAAs have been
approved. The decisive success parameter is now SVR12; all others no longer play a
relevant role.
HIV and HBV/HCV co-infections 395

Eradication of HCV improves prognosis in all stages of liver disease and prevents
further transmission. Initiation of therapy should be considered in any HIV/HCV
coinfection, even in low fibrosis stages (F0/F1), because of the increased risk of pro-
gression. Antiretroviral treatment should be given, regardless of CD4 T-cell count.

Medication
The decisive factors are the genotype and the possible presence of liver cirrhosis
(Table 2). Within individual genotypes, response rates differ only minimally,
consistently exceeding 95%. Ribavirin may be added to shorten the duration of
therapy and/or reduce relapse rates, especially in cirrhosis. First-generation HCV
protease inhibitors (PIs) such as telaprevir and boceprevir are no longer recom-
mended. Simeprevir has since been withdrawn from the market. The tolerability of
all DAAs (except ribavirin) is good. Common side effects include fatigue, headache,
and nausea. Severe side effects are infrequent, as are discontinuations. However, cases
of decompensation have been described in cirrhosis, so hepatically metabolized
agents such as HCV PIs are contraindicated.

Table 2: Recommended DAA combinations, according to genotype (GT) in HCV-infected individuals

without PI or NS5A pretreatment.
GT DAA combination Duration of therapy and ribavirin use (RBV)
Non-cirrhotic Compensated Decompensated
cirrhosis cirrhosis CTP Class B/C
1+4 SOF/LDV ± RBV 8–12 W without RBV1 12 W with RBV2
12 W with RBV2
SOF/VEL 12 W 12 W 12 W with RBV
EBR/GZR 12 W3 Not recommended
GLE/PIB 8W 8–123b W Not recommended
2 SOF/VEL 12 W 12 W with RBV
GLE/PIB 8W 8–123b W Not recommended
3 SOF/VEL ± RBV 12 W4 12 W with RBV5 12 W with RBV
GLE/PIB 8 W6 8–12 W6 Not recommended
SOF/VEL/VOX – 12 W Not recommended
5+6 SOF/LDV ± RBV 12 Wo ± RBV7 12 W with RBV2 12 W with RBV
SOF/VEL 12 W 12 W with RBV
GLE/PIB 8W 8–12 W
3b Not recommended

EBR elbasvir, GLE glecaprevir, GZR grazoprevir, LDV ledipasvir, PIB pibrentasvir, RBV ribavirin,
SOF sofosbuvir, VEL velpatasvir, VOX voxilaprevir.
1 8 weeks without RBV only in therapy-naive individuals with F< 3 and HCV RNA < 6 million IU/mL.
2 In case of RBV intolerance, extend therapy to 24 weeks. RBV may be omitted in therapy-naïve or –

experienced individuals with compensated cirrhosis and without NS5A resistance.

3 Prolongation to 16 weeks and addition of RBV in GT1a and HCV RNA > 800,000 IU/mL and/or NS5A

resistance and in GT4, prior therapy and HCV RNA > 800,000 IU/mL. 8 weeks may be considered in
GT1b without prior therapy and with F0-F2 fibrosis.
3b 8 weeks in therapy-naive patients.
4 RBV only in treatment-experienced individuals with NS5A resistance; if RBV intolerant, extend to

24 weeks without RBV.

5 In the absence of a Y93H NS5A mutation, RBV can be omitted in therapy-naïve patients with

compensated cirrhosis
6 Duration of therapy to 16 weeks in GT3 patients with prior treatment failure on IFN and RBV ± SOF

or SOF and RBV.

7 In therapy-experienced (IFN/RBV/SOF) with RBV for 12 weeks or 24 weeks without RBV.
396 Other Infections

There are numerous interactions to consider when treating with DAAs and concur-
rent ART (Table 3), especially with boosted ART regimens. If the resistance situation
allows, ART can be modified at least for the duration of HCV therapy: INSTI-based
regimens with raltegravir, dolutegravir, or bictegravir may be used. It is reasonable
to switch ART at least one month before DAA initiation. In addition, interaction
modules are available (e.g., [Link]), which can also be used
to check interactions with concomitant drugs.

Re-treatment and resistance testing

Patients treated with inadequate therapy from today’s point of view (e.g., use of a
too-low ribavirin dosage; standard interferon instead of PEG-interferon, interferon
monotherapy) can be treated with DAAs without restrictions. Interestingly, however,
even after previously unsuccessful DAA therapy, re-therapy is often successful –
possibly with doubled therapy duration or with the addition of ribavirin.
Resistance testing is not recommended before initial DAA use. In case of (rare)
treatment failure, resistance testing is recommended before renewed therapy to
assemble the new DAA combination based on the existing resistance-associated
substitutions.

Table 3: Important interactions between common HCV and HIV drugs.

SOF SOF/LDV SOF/VEL SOF/VEL/VOX EBR/GZR GLE/PIB
ABC ↔ ↔ ↔ ↔ ↔ ↔
FTC ↔ ↔ ↔ ↔ ↔ ↔
3TC ↔ ↔ ↔ ↔ ↔ ↔
TAF ↔ E32% ↔ E ↔ ↔
TDF ↓6% E Ea E ↓7%/14% E29%
BIC ↔ ↑7%/↓13% ↔ ↑9%/↓4% ↔ E
DTG ↔ ↔ ↓8% ↔ ↔ ↔
EVG/c ↔ ↑36%/78%a ↑a ↑–/–/171% ↑ ↑205%/57% E47%
RAL ↓5% D27% ↓5% ↓6% D≈20% ↔ ↔ ↓19%/11% E47%
DOR ↔ ↑4%/↓8% ↔ ↔ ↓4%/↑7% ↔
EFV ↓6% ↓–/34% a ↓3%/53% ↓ ↓54%/83% ↓
ETV ↔ ↔ ↓ ↓ ↓ ↓
NVP ↔ ↔ ↓ ↔ ↓ ↓
RPV ↑9% ↑10% ↑8% a ↑16% ↔ ↑7% ↓2% E84%
ATV/c ↔ ↑a ↔ a ↑ ↑ ↑
ATV/r ↔ ↑8%/113% a ↑–22%/142 % ↑40%/93%/331%
a 376%/958% ↑553%/64%
DRV/c ↑ ↑a ↔a ↑ ↑ ↑
DRV/r ↑34% ↑34%/39% ↓28%/16%a ↓28%/5%/143% 66%/650% ↑397%/–
LPV/r ↔ ↔ a ↓29%/12% ↑ ↑271%/1,186% ↑338%/146%

Black: These substances should not be combined. Gray: Combination possible under close observation
or dose adjustment. Arrows: possible change in DAA; E = increased or D = decreased level of HIV drug
a = monitoring of renal function recommended by increased TDF concentration if regimen contains TDF
HIV and HBV/HCV co-infections 397

Treatment in people with cirrhosis

For these patients, in particular, treatment options have improved dramatically.
However, there is still a risk that liver function may deteriorate. This is particularly
true in decompensated cirrhosis, where the indication must be carefully considered.
An exceptionally high risk exists with a decreased serum albumin < 35 mg/dl and a
platelet count < 90,000/µl. In this case, liver transplantation should be considered
(see Organ Transplantation). Regular examinations are also necessary after successful
treatment – these include, in particular, ultrasound controls regarding HCC detec-
tion and endoscopic controls regarding esophageal varices.

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and patient groups are affected? Liver Int 2015; Apr 15. Doi: 10.1111/liv.12848.
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titis C virus in HIV coinfection. PLoS Med 2006; 3:e492.
Kubitschke A, Bader C, Tillmann HL, et al. Injuries from needles contaminated with hepatitis C virus: how high
is the seroconversion risk for medical personnel? Internist (Berl) 2007; 48:1165-72.
Monin MB, Ingiliz P, Lutz T, et al. Low Spontaneous Clearance Rates of Recently Acquired Hepatitis C Virus in
Human Immunodeficiency Virus-Positive Men Who Have Sex With Men (PROBE-C Study). Clin Infect Dis. 2023
Feb 8;76(3):e607-e612.
Nattermann J, Vogel M, Nischalke HD, et al. Genetic variation in IL28B and treatment-induced clearance of hep-
atitis C virus in HIV-positive patients with acute and chronic hepatitis C. J Infect Dis 2011, 203:595-601.
Pembrey L, Newell ML, Tovo PA, EPHN Collaborators. The management of HCV infected pregnant women and
their children European paediatric HCV network. J Hepatol 2005; 43:515-25.
Peters l, Mocroft A, Lundgren J, Grint D, Kirk O, Rockstroh J. HIV and hepatitis C co-infection in Europe, Israel,
and Argentina: a EuroSIDA perspective. BMC Infect Dis 2014;14 Suppl 6:S13.
Pineda JA, García-García JA, Aguilar-Guisado M, et al. Clinical progression of hepatitis C-related chronic liver
disease in human immunodeficiency virus-infected patients undergoing highly active antiretroviral therapy.
Hepatology 2007, 46:622-30.
Rockstroh JK, Mocroft A, Soriano V, et al. Influence of hepatitis C virus infection on HIV-1 disease progression
and response to highly active antiretroviral therapy. J Infect Dis 2005; 192:992-1002.
Rosenthal E, Pialoux G, Bernard N, Pradier C, et al. Liver-related mortality in human-immunodeficiency-virus-
infected patients between 1995 and 2003 in the French GERMIVIC Joint Study Group Network (MORTAVIC 2003
Study). J Viral Hepat 2007, 14:183-8.
Sulkowski MS, Mehta SH, Torbenson MS, et al. Rapid fibrosis progression among HIV/hepatitis C virus-co-infected
adults. AIDS 2007, 21:2209-16.
Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated
chronic HCV infection. N Engl J Med 2014, 370:211-21.
Thomson EC, Nastouli E, Main J, et al. Delayed anti-HCV antibody response in HIV-positive men acutely infected
with HCV. AIDS 2009; 23:89-93.
Trevino A, Rivas P, Herrero-Mendoza M, et al. Newly Diagnosed HIV-1 Individuals in Spain since Year 2000. Non-
B Subtypes, and Hepatitis C and B Virus Co-infections. Abstract 300, 16th CROI 2009, Montreal.
398 Other Infections

HIV and HBV co-infection

Introduction
The hepatitis B virus is one of the most common human pathogens worldwide.
Up to 95% of all people with HIV have undergone a hepatitis B infection, and about
10–15% have chronic hepatitis B. About 100,000 PLWH (6%) in the US with chronic
hepatitis B. Prevalence diverges regionally and among at-risk groups (Konopnicki
2005, Alter 2006). In countries with vaccination programs, there is a decrease in HBV
transmission, especially in younger populations.
HBV is mainly transmitted sexually. Transmission is also possible via blood and is
even significantly more likely than HIV or HCV. In the case of a percutaneous needle-
stick injury, the risk is 30% (HCV < 2%, HIV approx. 0.3%). In immunocompetent
adults, acute HBV infection progresses to chronic hepatitis in 2–5%; in HIV co-infec-
tion, it is five times more likely. This is probably due to immunosuppression, whereas
viral factors such as the level of HBV viremia or genotype are unlikely to play a role
(Bodsworth 1991).
The hepatitis B virus shares some characteristics with HIV, although it is not inte-
grated and exists as circular DNA in hepatocytes (“closed circular supercoiled” DNA,
cccDNA). Because HBV is one of the few non-retroviral viruses with reverse tran-
scription in the replication cycle, replication can be inhibited by NRTIs. Although
elimination is, in principle, possible by virus-specific cytotoxic T lymphocytes (CTL),
HBV DNA can usually be assumed to persist for life (cccDNA). Reactivation is possible
after many years, e.g., through immunosuppression in advanced HIV infection or
chemotherapy – regardless of the antibody constellation present.
The diagnosis is made in the same way as in HIV-negative persons – possible sero-
logical test constellations are shown in Table 1. Screening includes HBs antigen, anti-HBs,
and anti-HBc. If HBsAg is positive, HBeAg, anti-HBe, and HBV DNA are needed for
further differentiation.
A relatively frequent finding in PLWHis the detection of isolated anti-HBc (in blood
donors, less than 2%). Three situations are conceivable: 1) an early phase of acute
hepatitis B (in this case, IgM antibodies are involved), 2) a so-called loss of anti-HBs
many years after hepatitis B, or 3) low-replicative hepatitis B, in which HBsAg is
bound by anti-HBs and is thus not detected. Most often, this is a loss of anti-HBs
without clinical consequences. “Occult” infection is the detection of HBV DNA (with
or without anti-HBc) and lack of detection of HBsAg. Individuals with chronic
hepatitis B should constantly be tested for hepatitis D superinfection as well.
Table 1: Interpretation of HBV serological test results.
Interpretation HBsAg anti-HBs anti-HBc HBeAg anti-HBe HBV-DNA
No contact with HBV – – – – – –
Acute infection + – + (IgM) + – +
Cured infection – + + (IgG) – + –
with immunity
Chronic hepatitis B + – + (IgG) + – +
Latent/occult infection1 – – +/– (IgG) – – +
Pre-core mutant + – + (IgG) – + +
"Healthy" carrier + – + (IgG) – + –
Immunity through vaccination – + – – – –
1 Controversial. See text.
HIV and HBV/HCV co-infections 399

It is recommended to perform an ultrasound examination of the liver every 6 to 12

months in chronic hepatitis B patients who have already developed cirrhosis to detect
hepatocellular carcinoma (HCC) in time. Since HCC develops in 10–30% even
without cirrhosis, this also applies to some subgroups without cirrhosis: age
> 45 years, HDV co-infection, Asian and African patients, and those with a family
history of HCC (EACS 2022).
Liver biopsy is not necessary for diagnosis or treatment decisions. Detection of the
degree of fibrosis by transelastography or non-invasive markers also plays a minor
role. However, further useful information includes differential diagnoses (e.g.,
hepatotoxicity) and inflammatory activity.

The course of hepatitis B in HIV infection

HIV negatively influences the course of chronic hepatitis B. Mortality from events
directly associated with liver disease is about 15 times greater than in HIV-negative
individuals. In addition, the progression of hepatitis B is more rapid, and the risk of
cirrhosis increases. Direct mechanisms of damage to the hepatocyte by HIV have
been described, providing a pathophysiological correlate for the altered course (e.g.,
CCR5-mediated direct cytopathic effect and indirect upregulation of proinflamma-
tory and apoptotic factors). Despite these unfavorable influences from HIV co-infec-
tion, hepatitis B often takes a milder course clinically despite increased viral
replication. The cause of this paradox is impaired cellular immunity, which increases
viral replication but simultaneously decreases hepatocyte damage. Thus, transami-
nases are often only slightly elevated in HBV/HIV coinfection, whereas HBV DNA is
higher than in immunocompetent individuals. Accordingly, fibrosis and cirrhosis
are more frequent despite lower inflammatory activity. This phenomenon is also
observed in other immunocompromised individuals, such as organ transplant
recipients.
There is a direct correlation between the extent of immunosuppression and the
control of HBV viral replication: even in cases with apparently cured hepatitis B (anti-
HBe positive, HBV DNA negative), reactivations are possible if the immune system
deteriorates (Soriano 2005). Interestingly, reactivations of hepatitis B under immune
reconstitution after ART initiation have also been described in isolated cases.
It is also possible that the course of HIV infection is worsened with concurrent
hepatitis B. An increase in all-cause mortality and AIDS-defining events have been
described (Nikolopoulos 2009, Chun 2012). In addition, the risk of hepatotoxicity
of ART is about three times higher.
Whether ART and HBV therapies change the prognosis of co-infected individuals is
an open question. According to some studies, such as the French GERMIVIC cohort,
HBV-associated mortality decreases significantly with effective HBV treatment (Puoti
2007, Rosenthal 2009). Under TDF/TAF-containing ART for at least 12 months, the
risk of HCC can be reduced by 58% (Kim 2021).

Prevention
People with HIV and with negative hepatitis B serology should be vaccinated.
However, vaccination may be less effective, and about 30% have a primary non-
response (only 2.5% in immunocompetent individuals). Vaccination response
depends on CD4 T-cell count and level of HIV viremia. Therefore, it is recommended
that patients with less than 200 CD4 T-cells/µl who are not yet receiving antiretro-
viral therapy first initiate ART and wait for immune reconstitution. Vaccination
should follow the usual schedule (20 µg each; months 0, 1, and 6). If vaccination
400 Other Infections

response is insufficient (i.e., anti-HBs < 10 IU/mL 12 weeks after a vaccination cycle),
re-vaccination may be considered. Increasing the single vaccine dose and more fre-
quent doses may improve vaccine response (40 µg each; months 0, 1, 6, and 12)
(Fonseca 2005, Launay 2011).
Since successfully vaccinated HIV patients lose about 30% of their acquired immu-
nity per year, the anti-HBs status should be checked annually, and, if necessary, the
vaccination should be refreshed (if anti-HBs titer < 100 U/l). HBV screening is
recommended about once a year without successful immunization to detect re-infec-
tion in time.
If the ART contains HBV-active substances – in particular, tenofovir disoproxil
fumarate (TDF) or alafenamide (TAF) – there is an excellent protective effect against
de novo infection with hepatitis B, which is comparable to the effectiveness of suc-
cessful vaccination (Heuft 2014). Especially for unsuccessful HBV vaccination, HBV-
active substances should be integrated into antiviral therapy.
HIV/HBV-co-infected persons with negative HAV serology should be vaccinated
against hepatitis A (months 0 and 6) since severe or fulminant courses are possible
in the case of acute hepatitis A. A combination vaccination is useful for negative
HBV serology (months 0, 1, and 6).
Education about prevention (safer sex, avoidance of needle re-use, etc.) or progres-
sion of liver disease should be self-evident. The latter is avoiding alcohol, nicotine
(controversial), or herbal medications that may be hepatotoxic. Hepatotoxic drugs
(e.g., tuberculostatic therapy) should be given with caution. Newborns of patients
with chronic hepatitis B should receive hepatitis B immunoglobulin and active
immunization within 12 hours post-partum.

Treatment
Due to impaired immune function in co-infected individuals, treatment of chronic
hepatitis B is more problematic. Loss of HBsAg with the formation of protective anti-
HBs antibodies is rarely achievable. Therefore, realistic therapeutic goals are sero-
conversion of HBeAg to anti-HBe and associated suppression of HBV DNA, normal-
ization of transaminases, and improvement of liver histology. Reduction in
transmission risk and possibly ART-associated hepatotoxicity are other potential ben-
efits. As mentioned above, HBV-associated mortality is also expected to decrease if
HBV replication is effectively inhibited.

Drugs with activity against HBV

Nucleoside analogs, nucleotide analogs, and interferon are available (Table 2).
Compared to TDF and TAF, all other drugs play a minor role. Also effective against
HIV and HBV are 3TC, FTC, and, to some extent, entecavir. Adefovir and telbivu-
dine are effective against HBV only. Interferon, occasionally used in HBV mono-
infections, plays hardly any role in HIV co-infection.
The most effective drug is tenofovir (TDF or TAF), with more than 95% of people
achieving virologic control beyond five years. To date, no apparent mutations asso-
ciated with phenotypic resistance have been described (this is questionable for the
A194T mutation). In contrast to tenofovir, resistance mutations are relevant with
other agents: For example, 3TC monotherapy selects for a mutation in the YMDD
locus of the polymerase gene, which may occur in at least 20% per year (mutations
at this site may fail to produce HBeAg, similar to the pre-core mutant). Potential
cross-resistance exists between 3TC, FTC, entecavir, and telbivudine, which can only
be partially compensated by a dose increase (e.g., entecavir is dosed higher after
3TC pre-treatment). Although adefovir has different resistance mechanisms as a
HIV and HBV/HCV co-infections 401

Table 2: Drugs for chronic hepatitis B in HIV co-infection (numerous generics exist for FTC, 3TC, TDF,
and some combinations; see chapter on ART).
Drug Trade name Dosage
Adefovir Hepsera® 10 mg daily
Emtricitabine Emtriva®, also in: Atripla®, Biktarvy®, 200 mg daily
(FTC) Descovy®, Eviplera®, Genvoya®,
Odefsey®, Stribild®, Symtuza®, Truvada®
Entecavir Baraclude® 0.5 mg (3TC-naive) 1 mg (3TC-pretreated)
Lamivudine Epivir®, also in: Combivir®, Delstrigo®, 300 mg daily. Do never use Zeffix® (dose
(3TC) Dovato®, Trizivir®, Kivexa®, Triumeq® too low for HIV!)
Telbivudine Sebivo® 600 mg daily
Tenofovir- Viread®, also in: Truvada®, Atripla®, 300 mg daily
disoproxil (TDF) Eviplera®, Delstrigo®, Stribild®
Tenofovir- Vemlidy®, also in: Biktarvy®, Descovy®, 10–25 mg daily (depending on conco-
alafenamide (TAF) Odefsey®, Genvoya®, Symtuza® mitant ART or concomitant medication)
Interferon-α Intron A® 5 MU per day
Pegylated Pegasys® Pegasys® 180 μg 1 x / week
interferon PEG-Intron® PEG-Intron® 1.5 μg/kg 1 x / week

nucleotide analog, an A181T mutation with persistent viral replication has been
described in the presence of pre-existing 3TC resistance. Combining two HBV-active
drugs may delay or even prevent the development of resistance. In small cohorts,
no resistance has been described when a nucleoside analog was combined with a
nucleotide analog. However, there is no evidence that combination is more effec-
tive. Nevertheless, because of the potential benefits and the experience gained from
HIV therapy, it is recommended. As an alternative to drug therapy, organ trans-
plantation should also be considered in people with liver cirrhosis.

Treatment recommendations
HIV-infected individuals with hepatitis B (and also C) co-infection benefit from HIV
therapy by reducing the progression of liver fibrosis. ART should include HBV-active
substances – neither liver biopsy nor fibroscan is necessary for indication.
• Therapy should include TDF or TAF. Without FTC or 3TC pre-therapy, the combi-
nation of TDF/TAF with FTC or 3TC is reasonable.
• In cases of renal insufficiency, TDF can be dosed lower since the IC50 is lower for
HBV than for HIV, or switch to TAF. However, tenofovir may not be considered an
active component of ART.
• If tenofovir is contraindicated, entecavir is an alternative for 3TC-naive patients
on fully active ART.
• Caution when switching from TDF or TAF to a compound with a low genetic barrier
(i.e., FTC or 3TC; entecavir after 3TC pre-treatment): rebound due to pre-existing
mutations is possible.
• In cases of persistent low HBV viremia on tenofovir, there are currently no clear
options. Therapy should be continued since no resistance has been described in
these cases. Adding, e.g., entecavir is not recommended in this situation.
After the start of treatment, a transient and usually moderate increase in transami-
nases is often observed. It is a sign of immune reconstitution and increased inflam-
matory activity. In case of pronounced or prolonged increase, other reasons should
402 Other Infections

be considered (increased HBV replication, resistance of HBV, lactic acidosis, hepato-

toxicity of antiretroviral drugs, superinfection with other hepatitis viruses, especially
HCV/HDV).
Normal transaminases (AST, ALT) and a significant reduction in HBV DNA are almost
always achieved initially. However, ALT levels do not correlate well with inflamma-
tory activity and are influenced by numerous other factors, such as hepatotoxicity
of ART or other drugs, alcohol consumption, and immune reconstitution. Therefore,
their importance in monitoring the success of therapy is low. Since seroconversion
cannot be achieved in all cases, continuous suppression is required, similar to HIV.
HBeAg seroconversion can be achieved with tenofovir at about 40% HBsAg loss in
about 18% after 3.5 years of therapy (van Bremen 2020).
Caution: If HBV-active drugs are discontinued, the clinical picture of acute hepatitis,
including fatal liver failure, is possible. Any interruption in therapy in HBV/HIV
co-infection must, therefore, be carefully considered and avoided, especially in
cirrhosis, to prevent decompensation. On the other hand, if an HBV drug loses its
efficacy, it can be discontinued; then, no rapid clinical deterioration of hepatitis is
to be expected. It should also be noted that the dose of all nucleos(t)ide analogs must
be adjusted in renal insufficiency.
Treatment of acute hepatitis B is not recommended in cases with stable liver func-
tion because of the high likelihood of cure (although lower than in HIV-negative
individuals) and the lack of sufficient data on this (risk of rapid development of
resistance with early therapy and no further options?).

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Van Bremen K, Hoffmann C, Mauss S et al. Obstacles to HBV functional cure: Late presentation in HIV and its
impact on HBV seroconversion in HIV/HBV coinfection. Liver Int. 2020;40:2978–2981.
403

12. HIV and COVID-19

C H R ISTIAN HOFFMAN N

At the end of October 2022, more than 35 million SARS-CoV-2 infections were
reported in Germany. Suppose one considers the high number of unreported cases
or cases not confirmed by PCR. In that case, considering the high number of
unreported cases or cases not confirmed by PCR, it is inevitable that at least half of
everyone living with HIV has now experienced a SARS-CoV-2 infection. Here, the
most critical aspects relevant to daily practice in an HIV clinic will be discussed.
However, given the rapidity of developments, especially with regard to variants but
also with regard to therapies, this is just a snapshot.

Susceptibility to SARS-CoV-2
There are studies on PLWH with higher, as well as with comparable or even lower
incidence. Where the incidence was lower, protection by antiviral therapies (see
below) or immune activation has been discussed. However, other factors are probably
far more critical, including primarily testing behavior and testing strategies, but also
sociodemographic factors and behavioral differences. It seems almost impossible to
adjust for these factors, especially in large populations. In a meta-analysis of over 30
studies, the risk of SARS-CoV-2 infection was comparable for PLWH (Wang 2022).
Thus, it does not appear that HIV infection per se substantially increases or decreases
susceptibility to SARS-CoV-2.

Morbidity and mortality

Are COVID-19 morbidity and mortality increased in HIV infection, or is HIV infec-
tion an independent risk factor? Upon closer examination, what seems straightfor-
ward at first glance becomes increasingly challenging to answer. There are several
extensive studies with often several thousand patients, in which the morbidity (rate
of severe illness), as well as the mortality (mainly evaluated as “in house”, i.e.,
in-hospital), was increased compared to uninfected people (Tesoriero 2021,
Bertagnolio 2022, Yang 2022). In a meta-analysis of 32 studies involving nearly
800.000 PLWH, the relative risk of serious illness was 1.25, and the relative risk of
mortality was about 1.3 (Wang 2022).
However, this does not mean that HIV is an independent risk factor. PLWH differ
from healthy controls concerning numerous factors that significantly affect COVID-19-
related morbidity and mortality. Not all can be “matched” or adjusted for. If PLWH
are hospitalized sooner than others out of concern or caution, morbidity increases
(if hospitalization is considered “severe”). At the same time, overcautious hospital-
izations may reduce overall in-hospital mortality. Mortality can increase if PLWH
(because they have less health insurance like in the US) go to the hospital a little
later. Do they smoke more, are they less overweight? This may have a significant
impact on the results. Also, many studies were done in unvaccinated people and the
pre-omicron era – the results could be quite different today.
In a large study out of Canada, PLWH had about two times the risk of COVID-19
hospitalization than HIV-negative individuals in crude analyses, which attenuated
in propensity score-weighted models. This suggests that the risk differential can be
explained by sociodemographic factors and a history of co-morbidity, underscoring
the need to address these issues (Puyat 2023). In another large matched-pair study
comparing COVID-19 cases of the same age and sex but at the same time of diag-
nosis, HIV was not an apparent risk factor (Rosenthal 2022). However, once again,
404 Other Infections

it became clear that people living with and without HIV differed markedly regard-
ing co-morbidities and other risk factors (more smoking, more obesity in PLWH).
Nevertheless, older age is by far the most critical risk factor for HIV (Tesoriero 2021,
Bertagnolio 2022, Yang 2022). Fortunately, the age structure of the HIV population
in most countries is relatively “favorable” – only a few PLWH are 70 years and older.

Immunosuppression as a risk factor

It is now considered certain that severe immunodeficiency is unfavorable in SARS-
CoV-2 infection. It can impair both antibody and T-cell responses. Given the impor-
tance of T cell immunity in SARS-CoV-2, this finding is hardly surprising – it is one
more argument in favor of early antiretroviral therapy, which should not be inter-
rupted whenever possible.
In a combined analysis of three cohorts from Madrid, Milan, and Germany with 175
cases, PLWH with severe or fatal courses had significantly lower current CD4 T-cells
and a lower CD4 nadir (Hoffmann 2020). In a multivariate analysis, a current CD4
T-cell count below 350 remained the only risk factor for a severe course. A nadir
below 200 was associated with increased mortality. Many other papers have identi-
fied low CD4 T-cells and viremia as significant risk factors. One US study also found
severe courses below 350 CD4 T-cells in vaccinated or breakthrough infections (Lang
2022). However, in one of the most extensive studies from Catalonia, low CD4
T-cells in 749 cases remained a risk factor only in viremic individuals (Nomah 2021).
Low CD4 T-cells are a risk factor for prolonged shedding. In a larger study, this phase
was a median of 27 days in individuals with less than 200 CD4 T-cells, compared
with only seven days in immune healthy individuals (Meiring 2022). Thus, it may
be that these individuals are infectious for extended periods. Several long courses in
severe immunodeficiency have been described in which SARS-CoV-2 remained
detectable, sometimes for many months (Yousaf 2021, Cele 2022, Maan 2022,
Spinicci 2022). These cases fuel speculation that such cases are responsible, among
other things, for the selection of new variants of SARS-CoV-2 during the months-
long battle with the immune system. This has not been proven. A possible drop in
CD4 T-cells during COVID-19 seems limited (Casado 2022).

Effect of ART
The initial hopes for a possible protective effect of antiretroviral therapies such as
lopinavir or darunavir have been dashed. Several randomized trials, such as RECOVERY,
have shown that lopinavir is ineffective – the plasma levels achieved with
conventional doses are probably many times too low. The PI darunavir was already
ineffective in vitro. Still under debate is the nucleotide analog tenofovir, which has
chemical similarities to remdesivir and binds with high binding energy to the RNA-
dependent polymerase of SARS-CoV-2. Several randomized trials of tenofovir as
therapy or prophylaxis did not yield a congruent response, in part because of low
event counts (Parienti 2021, Gaitán-Duarte 2022, Montejano 2022, Nomah 2022,
Polo 2022). Overall, however, the beneficial effect of tenofovir is likely to be small
(if any). In two Dutch observational cohorts of PLWH, the use of TDF, etravirine, or
INSTIs was not independently associated with either the risk of incident SARS-CoV-2
infection or severe COVID-19 outcomes (Verburgh 2023). The current data do not
support modifying antiretroviral therapy to include these agents to protect against
SARS-CoV-2 infection and severe COVID-19 outcomes.
HIV and COVID-19 405

SARS-CoV-2 vaccination
People living with HIV should be vaccinated in any case. Like vaccinations, infec-
tions count as immunological “episodes”, so they are also counted. In the German
recommendations, HIV infection is considered an underlying disease “with an
increased risk of severe COVID-19 courses.” Furthermore, in the context of fewer
than 200 CD4 T-cells and/or detectable viral load, it is considered one of the diseases
“associated with a relevant limitation of vaccination response, either directly or as
a result of the necessary therapy.” In this case, serological checks of the vaccination
success and further boosters are recommended, even beyond four vaccinations, if
necessary, and mainly with mRNA vaccines. However, whether this makes sense in
young PLWH and an excellent immune status is considered somewhat cautiously by
many. Ultimately, a very low risk of severe disease is offset by an (albeit only slightly
increased) risk of vaccine side effects (myocarditis, zoster, appendicitis).
It is noteworthy that PLWH were underrepresented in many vaccination studies. In
particular, those with severe immunodeficiency were completely excluded in almost
all studies. Much of the vaccination data comes from uncontrolled studies. Overall,
the following can be said: vaccine response is “generally comparable” to that of
uninfected individuals, especially with mRNA vaccines (Lapointe 2022). However, a
recent meta-analysis analyzing 50 studies with 7,160 PLWH demonstrated that only
75.0% of PLWH achieved a seroconversion after incomplete vaccination, which
improved to 89.3% after complete vaccination and 98.4% after booster vaccination.
The seroconversion rates were slightly lower compared to controls at all stages, while
the risk ratios for incomplete, complete, and booster vaccination were 0.87, 0.95,
and 0.97, respectively, emphasizing the need for booster vaccinations in PLWH (Zhou
2023). In any case, the immune response of PLWH is better than in other immun-
odeficient patients, such as organ transplant recipients (Speich 2022). However,
unsurprisingly, the immune response is probably also reduced in those with low
CD4 T-cells (Antinori 2022, Corma-Gómez 2022) and in people over 60 years of age
(Chammartin 2022).
In a study of 113,994 fully vaccinated people (33,029 PLWH), breakthrough infec-
tion rates were low, but the risk with HIV was 28% higher (Coburn 2022). Among
PLWH, younger age (< 45 years), a history of COVID-19, and not receiving an addi-
tional dose of vaccine were associated with increased risk. A high CD4 T-cell count
of more than 500 CD4 T-cells was protective, but suppressed viral load was not. It
appears that PLWH with moderate or severe immune suppression should be included
in groups prioritized for additional vaccine doses and risk-reduction strategies.

PrEP, PEP, and treatment in times of omicron

Many people believe that omicron causes “only” mild courses. However, the high
case fatality rates in Hong Kong in February 2022 (higher than in Italy 2020 or
in Portugal 2021!) have shown that significant mortality is to be expected when
vulnerable populations are not vaccinated. Mild courses cannot be relied upon.
For example, unvaccinated cancer patients have a mortality risk with omicron
comparable to the alpha or delta waves (Pinato 2022).
In the meantime, there are some antibodies and drugs, such as molnupiravir
(Lagevrio®) and nirmatrelvir/r (Paxlovid®), that many governments have purchased.
It must be emphasized that most studies published to date have been in unvacci-
nated subjects and from the pre-omicron era. In addition, the effect of the antibod-
ies, in particular, is highly dependent on the circulating variants. It seems evident
that their impact may be lost entirely due to new mutations. For this reason, no clear
406 Other Infections

recommendations can currently be made as to when PLWH should receive specific

therapy or prophylaxis.
We recommend specific COVID-19 therapy in cases of severe immunodeficiency with
less than 200 CD4 T-cells, people older than 60, and those with co-morbidities, regard-
less of previous vaccinations. However, it remains a case-by-case decision. Where
therapies such as nirmatrelvir/r or molnupiravir are used, interactions should be
considered and are common (Lakatos 2022). If a detectable viral load is present,
caution is needed with nirmatrelvir/r because the low-dose ritonavir may lead to
resistance.

Avoid collateral damage

From the beginning, one concern was the collateral damage caused by the COVID-
19 pandemic. In many countries, it was feared that the disruption in general health
care would have significant negative consequences beyond the direct damage caused
by COVID-19. Lockdown measures and fears of SARS-CoV-2 infection would signif-
icantly decline ART and TB drug supplies in several African countries (Jewell 2020).
Although some initial reports also indicated that the rate of late HIV diagnoses
increased significantly during lockdown (Bell 2021), it can now be assumed that,
overall, the damage was not as great as feared. To mitigate the negative consequences
of the pandemic, service providers and communities adapted and accelerated an
array of HIV interventions to meet the needs of PLWH and those at risk of acquir-
ing HIV in diverse geographical and epidemiological settings. As a result of these
adaptations, services such as HIV treatment showed programmatic resilience and
remained relatively stable (Murphy 2022).

COVID-19 and HIV – Practical consequences

• There is no evidence of increased (or reduced) susceptibility to SARS-CoV-2.
• Mortality and morbidity seem to slightly increase overall, especially in severe
immunodeficiency and possibly in active viremia – another argument for ART
for all!
• Overall, however, the risk is only moderately increased – even with HIV, older age
is the most critical factor.
• The ART, if successful, does not need to be switched – so far, there is no (direct)
evidence of efficacy against SARS-CoV-2.
• All patients should be vaccinated with mRNA vaccines (4 x, as of early 2023),
more often if CD4 T-cells are less than 200 (control of antibody titer/success rec-
ommended).
• Specific therapies such as nirmatrelvir/r (beware of drug-drug interactions) should
be considered in immunodeficient patients, at least in the presence of other risk
factors.
• In high-incidence phases, controls and visits in the HIV center are dispensable
but breaks in ARV therapy are to be avoided.

Even in Western countries, however, the care of PLWH is not always easy. Lockdowns,
but also the understandable fears of those affected, influence treatment. Every effort
should be made to avoid ART interruptions. Medications should not be hoarded, nor
should blood tests generally be suspended. However, a sense of proportion is required,
especially for older PLWH. Especially for those over 70, unnecessary risk contacts
should be avoided. This applies to time-consuming journeys by public transport and
long waiting times in cramped waiting rooms. What can be done by telephone or
HIV and COVID-19 407

telemedicine? While these means may not always replace the confidential direct con-
versation with the doctor, they still offer good options for getting through these dif-
ficult times.

Literature
Antinori A, Cicalini S, Meschi S, et al. Humoral and cellular immune response elicited by mRNA vaccination
against SARS-CoV-2 in people living with HIV (PLWH) receiving antiretroviral therapy (ART) according with
current CD4 T-lymphocyte count. Clin Infect Dis 2022, 75:e552-e563.
Bell N, Bracchi M, Dalla Pria A, Nelson M, Boffito M. Indirect HIV morbidity and mortality due to COVID-19.
Clin Infect Dis. 2021 Feb 13:ciab128.
Bertagnolio S, Thwin SS, Silva R, et al. Clinical features of, and risk factors for, severe or fatal COVID-19 among
people living with HIV admitted to hospital: analysis of data from the WHO Global Clinical Platform of COVID-
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Casado JL, Vizcarra P, Vivancos MJ, et al. Low risk of bacterial co-infection, opportunistic diseases, and persistent
immunosuppression in people living with HIV and COVID-19. Infection 2022 Mar 31:1-5.
Cele S, Karim F, Lustig G, et al. SARS-CoV-2 prolonged infection during advanced HIV disease evolves extensive
immune escape. Cell Host Microbe 2022, 30:154-162.e5.
Chammartin F, Kusejko K, Pasin C, et al. Determinants of antibody response to severe acute respiratory syndrome
coronavirus 2 mRNA vaccines in people with HIV. AIDS 2022, 36:1465-1468.
Coburn SB, Humes E, Lang R, et al. Analysis of Postvaccination Breakthrough COVID-19 Infections Among Adults
With HIV in the United States. JAMA Netw Open 2022, 5:e2215934.
Corma-Gómez A, Fernández-Fuertes M, García E, et al. Severe immunosuppression is related to poorer immuno-
genicity to SARS-CoV-2 vaccines among people living with HIV. Clin Microbiol Infect 2022, S1198-743X(22)00276-2.
Gaitán-Duarte HG, Álvarez-Moreno C, Rincón-Rodríguez CJ, et al. Effectiveness of rosuvastatin plus colchicine,
emtricitabine/tenofovir and combinations thereof in hospitalized patients with COVID-19: a pragmatic, open-
label randomized trial. EClinicalMedicine 2022 Jan;43:101242.
Hoffmann C, Casado JL, Härter G, et al. Immune deficiency is a risk factor for severe COVID-19 in people living
with HIV. HIV Med 2020 Dec 27.
Hoffmann C, Wolf E. Older age groups and country-specific case fatality rates of COVID-19 in Europe, USA and
Canada. Infection 2021, 49:111-116.
Jewell BL, Mudimu E, Stover J, et al. Potential effects of disruption to HIV programmes in sub-Saharan Africa
caused by COVID-19: results from multiple mathematical models. Lancet HIV 2020, 7:e629-e640.
Lakatos B, Kowalska J, Antoniak S, et al. Retrospective evaluation of an observational cohort by the Central and
Eastern Europe Network Group shows a high frequency of potential drug-drug interactions among HIV-positive
patients receiving treatment for coronavirus disease 2019 (COVID-19). HIV Med 2022, 23:693-700.
Lang R, Humes E, Coburn SB, et al. Analysis of Severe Illness After Postvaccination COVID-19 Breakthrough
Among Adults With and Without HIV in the US. JAMA Netw Open 2022; 5:e2236397.
Lapointe HR, Mwimanzi F, Cheung PK, et al. People with HIV receiving suppressive antiretroviral therapy show
typical antibody durability after dual COVID-19 vaccination, and strong third dose responses. J Infect Dis 2022
Jun 7:jiac229.
Maan I, Paraskevopoulou SM, Cwynarski K, et al. Prolonged SARS-CoV-2 shedding in a person living with advanced
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Meiring S, Tempia S, Bhiman JN, et al. Prolonged shedding of SARS-CoV-2 at high viral loads amongst hospi-
talised immunocompromised persons living with HIV, South Africa. Clin Infect Dis. 2022 Feb 2:ciac077.
Montejano R, de la Calle-Prieto F, Velasco M, et al. Tenofovir Disoproxil Fumarate/Emtricitabine and Baricitinib
for Patients at High Risk of Severe COVID-19: The PANCOVID Randomized Clinical Trial. Clin Infect Dis. 2022
Jul 30:ciac628.
Murphy E, Doherty M, El Sadr W, et al. Innovations, adaptations, and accelerations in the delivery of HIV serv-
ices during COVID-19. Lancet HIV. 2022 Dec;9(12):e884-e886.
Nomah DK, Reyes-Urueña J, Díaz Y, et al. Impact of tenofovir on SARS-CoV-2 infection and severe outcomes
among people living with HIV: a propensity score-matched study. J Antimicrob Chemother 2022 Jun 9:dkac177.
Nomah DK, Reyes-Urueña J, Díaz Y, et al. Sociodemographic, clinical, and immunological factors associated with
SARS-CoV-2 diagnosis and severe COVID-19 outcomes in people living with HIV: a retrospective cohort study.
Lancet HIV 2021, 8:e701-e710.
Parienti JJ, Prazuck T, Peyro-Saint-Paul L, et al. Effect of Tenofovir Disoproxil Fumarate and Emtricitabine on
nasopharyngeal SARS-CoV-2 viral load burden amongst outpatients with COVID-19: A pilot, randomized, open-
label phase 2 trial. EClinicalMedicine 2021, 38:100993.
Pinato DJ, Aguilar-Company J, Ferrante D, et al. Outcomes of the SARS-CoV-2 omicron (B.1.1.529) variant out-
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408 Other Infections

RKI. Epidemiologisches Bulletin 2022, 40, 6. Oktober 2022 [Link]

Archiv/2022/Ausgaben/40_22.pdf?__blob=publicationFile
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among and between persons living with and without diagnosed HIV infection in New York State. PLoS One 2022,
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409

13. HIV and sexually transmitted diseases

ST E FA N E S S E R

Epidemiology
A sexually transmitted infection (STI) rarely comes alone. All STIs are more common
in PLWH, and each favors transmission of HIV or other venereal infections. Early
diagnosis and timely, consistent therapy reduce onward transmission. STI screening
should also be offered to asymptomatic sexually active people who frequently have
sex with many people, always including all orifices (oral, genital, anal). In the case
of STIs, sexual partners should also be educated, examined and, if necessary, treated.
Until healing is complete, sex should be abstained from or at least adequate protec-
tion of sex partners should be observed. An examination should be carried out after
an appropriate time after treatment to ensure healing.
WHO estimates the incidence of bacterial STIs and trichomoniasis (excluding
mycoplasma) to be 376 million new infections annually worldwide (WHO 2021,
Rowley 2019). STIs have been increasing significantly in the last decades, particularly
among men who have sex with men (MSM). New ways to prevent HIV transmission
(PrEP, TasP) and the treatability of HIV infection have reduced the fear of HIV and
led to a significant decrease in condom use.
Since the introduction of PrEP and concomitant STI screening (EACS 2019), the
number of diagnosed STIs continues to rise. International studies observe a further
decline in condom use and higher STI rates among PrEP users (Molina 2017, Serpa
2019). In Germany, both the Robert Koch Institute MSM Screening Study (chlamy-
dia 9%, gonococcus 10%, mycoplasma 17%) and the BRAHMS Study (chlamydia
13%, gonococcus 10%, mycoplasma 19%, syphilis 4%) found high bacterial STI
prevalences among MSM, regardless of HIV status. STIs were most commonly
detected rectally and most STIs were asymptomatic (Jansen 2018, Streeck 2019). In
the case of proven STIs, national guidelines recommend treatment of sexual partners
of the last 6 months – in case of doubt, even without prior testing.
The opportunities and risks of PrEP with regard to STIs are debated. For example,
PrEP reaches people at high risk of HIV and STI who have often not been medically
connected; moreover, early STI detection and treatment could reduce incidence,
prevalence, and resistance development in the long term (Scott 2016, Werner 2018).
However, other experts doubt this and instead fear an increase in resistant pathogens
due to the increased use of antibiotics (Tsoumanis 2018). How often, where and for
which pathogens screening should take place remains controversial (Kenyon 2019).
In IPERGAY trial, 232 MSM were randomized to take occasion-related post-exposure
prophylaxis (PEP) with doxycycline 200 mg once, within 24 hours of “risky” sex
(Molina 2018). After 9 months, 28 new bacterial STIs had occurred, compared with
49 in the control arm. While the time to first occurrence of new syphilis or fresh
chlamydial infection was delayed by PEP, gonorrhea was unaffected. Studies of
mycoplasma, resistance development, and microbiome changes are pending. Overall,
the median monthly doxycycline dose in the PEP arm was 680 mg.
Many people are still not vaccinated against sexually transmitted pathogens such as
human papillomaviruses (Wojcinski 2021) or hepatitis A and B viruses. Due to uncon-
trolled antibiotic use, the development of resistance continues to progress, especially
in Neisseria gonorrhoeae and Mycoplasma genitalium (Unemo 2017). Often, STI and
HIV infections are detected late. A sexual history is not part of routine medical care
and is not infrequently perceived as embarrassing by all involved. Out of shame and
fear of discrimination, some people with an STI present late or not at all. Many STIs
410 Other Infections

run (for a long time) without symptoms or with few symptoms (Heiligenberg 2012)
and sometimes only cause symptoms after years that are not associated with a
sexually transmitted disease (STD). An STI diagnosed (too) late can cause permanent
damage, ranging from infertility to rheumatoid and neurological diseases, sepsis, and
even death. As long as an STI has not been diagnosed and treated, it will continue
to be transmitted to sexual partners.
The incidence of syphilis has also multiplied in many countries in recent years,
especially among MSM, reaching a peak in Germany in 2019 (Jansen 2020) and
declining slightly in 2020. Outbreaks of lymphogranuloma venereum (LGV), long
an STI epidemic predominantly in the tropics and subtropics, are repeatedly observed
in major European cities. Infections that have not previously been categorized as
classic STIs, such as hepatitis A and C (Larson 2011) or even shigella (Aragón 2007,
Daskalakis 2007, Braam 2022), are also diagnosed regionally in more significant
numbers among MSM in large cities.
In both women and men, infections with human papillomaviruses (HPV) are among
the most frequently sexually transmitted pathogens. While these usually heal
without symptoms in the general population, they often persist in PLWH and cause
condylomata acuminata or precancerous lesions, so-called intraepithelial neoplasms,
from which invasive carcinomas can develop. In addition to cervical carcinomas, anal
carcinomas and their precursors are increasingly diagnosed in PLWH (Esser 2015).
Even asymptomatic PLWH should be actively offered STI screening and further rec-
ommended condom use, which is most effective in protecting against all STIs
(Heiligenberg 2012). Previously HIV-negative patients with STIs should be offered
HIV testing and PrEP counseling. The most important STIs are discussed in more
detail below. Monkeypox was also included on short notice. STIs such as hepatitis B
and C, but also herpes simplex, vulvovaginal candidiasis or bacterial vaginosis, and
HPV-associated neoplasms are described elsewhere.
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have sex with men visiting a sexual health clinic in Amsterdam. Sex Transm Infect 2022 Feb 11.
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individuals: prevention, diagnosis, and treatment. J Dtsch Dermatol Ges 2015, 13:1302-19.
Heiligenberg M, Rijnders B, Schim van der Loeff MF, et al. High prevalence of sexually transmitted infections in
HIV-infected men during routine outpatient visits in the Netherlands. Sex Transm Dis 2012, 39:8-15.
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Kenyon C. Toward a Set of Criteria to Decide Which STIs to Screen for in PrEP Cohorts. Front Public Health 2019,
7:154.
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Men: The HEPAIG Study. PLoS One 2011, 6:e29322.
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demand pre-exposure prophylaxis for HIV in men who have sex with men: an observational cohort study. Lancet
HIV 2017, 4:e402-e410.
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Syphilis (Lues)
Syphilis is caused by Treponema pallidum (T. p.), a bacterium of the Spirochaetaceae
family. Treponemata are most commonly transmitted through direct sexual contact,
penetrating through microlesions of the mucosa or skin. Even kissing can be
contagious. With a single unprotected sexual contact, the risk of transmission is
between 30% and 60%. Hematogenous or congenital transmission is rare in Western
countries.

Clinic
The incubation period is usually 14–24 days. About 40–50% of infections are asymp-
tomatic or heal spontaneously. In persistent infections, a chronic progressive
systemic disease develops in stages, affecting various organ systems. However, these
stages may be skipped or repeated. During the symptomatic stages of early syphilis
(lues I and II), the risk of transmission of infection is highest. During the asympto-
matic early (< 1–2 years postinfection) and late (> 1–2 years postinfection) latent
stages, the infectiousness of syphilis is controversial or low. The symptomatic late
stages (lues III and IV: 2–50 years post-infection) are no longer infectious (Ghanem
2020, Schöfer 2020).
Syphilis I (primary syphilis): 2 to 3 weeks after infection, the primary ulcer with
ulcus durum (hard chancre, erosive chancre) appears at the inoculation site. This
painless, gross ulcer with infiltrated margins, from which a clear treponema-rich
irritant secretion can be obtained, is accompanied in the drainage area by a usually
unilateral, gross lymphadenitis, the bubo. Untreated, the primary complex heals
spontaneously after 4–6 weeks.
Syphilis II (secondary syphilis): After four weeks to 6 months, variable general
symptoms appear at intervals, including lymph node swelling and symptoms in
various organs. The clinical variety of common syphilides on the skin and mucous
membranes ranges from exanthema typically with palmoplantar involvement, rose-
olae, to alopecia syphilitica, plaques muqueuses, angina specifica, condylomata lata
genital and perianal, and pigmentary changes (leucoderma specificum) to lues
maligna. Rising liver enzymes and ocular involvement, such as episcleritis or iritis,
are uncommon. Visual field loss, dizziness, and hearing loss indicate cranial nerve
involvement. Headache may be suggestive of early syphilitic meningitis cerebro-
spinalis. Syphilitic meningitis presents with cranial nerve palsies, intracranial
pressure elevation, and other neurologic symptoms. PLWH with advanced immun-
odeficiency develop early neurosyphilis more often and more rapidly, which is why
CSF sampling is recommended when symptoms are present.
412 Other Infections

Syphilis latens seropositiva: In the clinically asymptomatic latent stages, syphilis

remains serologically detectable, and recurrence or progression is possible.
Syphilis III (tertiary syphilis): Years after the initial infection, gummatous lesions
may occur that can affect any organ as tuberous or granulomatous changes with a
tendency to ulceration and scarring healing. Granulomatous vascular changes can
lead to mesaortitis lucia with aneurysms and, if cerebral vessels are involved, to lues
cerebrospinalis. The increased incidence of cerebral insults has also been observed
with syphilis.
Syphilis IV (quaternary syphilis): Without treatment, late neurosyphilis can occur
after years (RKI 2022). Several forms occur. Tabes dorsalis is characterized by shoot-
ing pain, sensory ataxia, reflex pupillary rigidity (Argyll-Robertson sign), and optic
atrophy. Progressive paralysis is dominated by symptoms such as headache, per-
sonality changes, speech disorders, convulsions, dementia, and apoplectic insults.
Untreated progressive paralysis leads to death within 4 to 5 years.
Connatal syphilis: Diaplacental transmission usually occurs in the 4th/5th month
of pregnancy. Depending on the stage of lues in the pregnant woman, either mis-
carriage or stillbirth occurs. In the infant, the main symptoms of lues connata praecox
are rhinitis syphilitica (Coryza syphilitica), interstitial hepatitis, encephalomeningi-
tis with hydrocephalus communicans hypersecretorius, and Parrot pseudoparalysis
(ulnar epiphyseal solution due to osteochondritis syphilitica). The typical stigmata
of lues connata tarda (from 3 years of age) are: Saddle nose, Parrot furrows, and
Hutchinson’s triad: barrel teeth, keratitis parenchymatosa, and sensorineural hearing
loss.
In PLWH, syphilis more frequently shows unusual manifestations and foudroyant
courses like lues maligna (Gregory 1990, Tucker 2009). Reactivations and shorter

Figure 1: Diagnostic algorithm for Syphilis infection

HIV and sexually transmitted diseases 413

latency periods to the late stages, including neurosyphilis, occur, as do symptoms of

several stages in parallel. In 20% of co-infected persons, neurosyphilis can already
be diagnosed during early syphilis using cerebrospinal fluid puncture, irrespective
of the clinical symptoms (Esser 2011). The indication for CSF puncture is in
co-infected individuals with suspected neurosyphilis, poor response to syphilis
therapy and unexplained relapses/reactivations, low CD4 T-cells (< 350 cells/µl),
detectable HIV viral load, lack of ART, and neuropsychiatric symptoms including
cranial nerve involvement, late syphilis, syphilis connata, and markedly elevated
serum VDRL titers (> 1:64) (Marra 2004, Ghanem 2020, Schöfer 2020,).

Diagnostics
If a primary effect is suspected, serology is usually still negative. The pathogen can
be detected directly in the irritant secretion from the ulcus durum. In the elaborate
dark-field microscopy of the native preparation, silver-glowing, spiral-shaped tre-
ponemes are conspicuous by their rotational and buckling movements.
IgM antibodies appear as the first serological reaction (screening test and lipoid anti-
body detection still negative!). Syphilis diagnosis is often difficult in PLWH. The
reasons for this are not only the occasionally unspecific clinical and atypical course
but also unreliable screening tests and atypical lues serologies such as a later IgM
drop, fluctuating VDRL titers (Venereal Disease Research Laboratory test, detection
of phospholipid antibodies). Quantitative PCR may facilitate the diagnosis and
monitoring of treatment for early syphilis in the future. Because of the possible
overlap of disease stages, each case with serologic evidence should be clinically eval-
uated neurologically. The indication for CSF puncture should be generous in cases
with neurologic symptoms, as it has therapeutic consequences. Interpretation of CSF
findings in co-infected individuals should include ITpA index (Intrathecal-produced
Treponema pallidum antibodies: TPHA titer in CSF: TPHA titer in serum x IgG in
CSF: IgG in serum), parameters of a barrier disorder, evidence of lymphomonocytic
pleocytosis, and neurological symptoms should be considered and performed by
experts (Schöfer 2020).

Interpretation of syphilis serology in PLWH

Luesserology is based on treponema-specific addiction tests. These are TPHA
(Treponema pallidum hemagglutination test), TPPA (Treponema pallidum particle
agglutination test), or EIA (enzyme-linked immunosorbent assay). If positive,
treponema-specific confirmatory tests such as IgM ELISA, IgM, and IgG Western blot
or 19-S IgM FTA-abs (fluorescent Treponema antibody absorption test) follow. In the
case of a reactive 19-S-IgM-FTA-abs test in previously untreated patients or a renewed
reactivity of the difficulty in treated patients (lues non satis curata), treatment is
always needed.
False-negative test results can occur due to inadequate antibody production or sup-
pression of IgM production at very high IgG levels. Therefore, specific tests such as
FTA-ABS should be ordered in case of doubt, although false negative results can also
occur. In the case of positive treponeme-specific tests, an additional (quantitative)
baseline determination of the non-treponeme-specific activity parameters (lipoid
antibodies, e.g., VDRL test or CFT) is required before therapy is initiated (Schöfer
2020). These correlate with the disease activity of syphilis. Extremely high VDRL
antibody titers can lead to false negative test results via disrupting the antigen-anti-
body lattice network as a prozone phenomenon (Smith 2004). Conversely, false
positive VDRL tests are possible due to the often non-specific B cell activation in HIV
infection and other co-infections and co-morbidities (Paul 2021).
414 Other Infections

Diagnostic algorithm for suspected syphilis infection

The longer untreated syphilis has existed, the slower serological findings normalize
after therapy. In PLWH, the IgM test can remain reactive for years, even after suc-
cessful syphilis therapy. The success of treatment is then only indicated by a clear
drop in the titer of the non-treponeme-specific activity parameters (reduction of the
VDRL by at least two titer levels within three months). If decreased activity param-
eters rise again, a re-infection or reactivation is suspected: a serological differentia-
tion is impossible! Since the activity parameters are non-specific, they often change
in PLWH or run an atypical course, especially in the case of additional infections,
intravenous drug use, and pregnancy (Geusau 2005, Paul 2021). Misinterpretation
of increased activity parameters can lead to unnecessary therapies. In repeated
reactivations, neurosyphilis should be ruled out using cerebrospinal fluid puncture.

Treatment
The generation time of Treponema pallidum is 30–33 hours; a therapy duration with
treponemicidal levels should not fall below 10–11 days. Parenteral administration
of penicillin is the therapy of choice in all stages, with the dosage and time depend-
ing on the stage. Penicillin resistance is not known to date. In the case of early
syphilis, a single administration of benzathine penicillin 2.4 million IU IM is suffi-
cient, even in PLWH (Tardocillin® or Pendysin®: 1 ampoule of 1.2 million IU IM in
each buttock). Late syphilis is treated with injections at weekly intervals for at least
three weeks (Schöfer 2020). Even if the time of infection is unclear, treatment should
be given over three weeks.
In case of penicillin intolerance, doxycycline 2 x 100 mg per os or ceftriaxone (IM,
IV) are recommended. Due to increasing resistance, macrolides should no longer be
used (Lukehart 2004, Stamm 2016, Ndeikoundam Ngangro 2019). In cases where
benzathine penicillin G is not available or appropriate, the following alternative
therapies are recommended: for early syphilis, daily ceftriaxone 2 g IV (as a short
infusion, 30 min) for ten days; for late syphilis, for 14 days. In exceptional cases,
doxycycline 2 x 100 mg (not in pregnant women and children < 8 years of age) can
be considered as a third choice, which should be given for 14 days in early syphilis
and 28 days in late syphilis (Schöfer 2020). Good adherence is urgently required here
– only briefly ineffective drug levels mean that therapy must be started again from
the beginning. Simultaneous intake of dairy products and intensive light exposure
should be avoided.
Neurosyphilis is treated like syphilis with cranial nerve involvement with 3 x 10
million IU or 6 x 5 million IU penicillin G IV for 21 days. In the case of penicillin
intolerance, neurosyphilis can also be treated with ceftriaxone 2 g once daily intra-
venously for about 10–21 days after a single initial dose of 4 g ceftriaxone (Schöfer
2020).
Cross-allergies (< 10%) between penicillins and cephalosporins are possible. The alter-
native is then doxycycline 2 x 100 mg/daily. Controlled penicillin hardening (habit-
uation) in specialized centers can be performed under inpatient conditions (readi-
ness for resuscitation) up to the full therapeutic dose despite suspected penicillin
allergy.
At the beginning of syphilis treatment, the Jarisch-Herxheimer reaction should be
distinguished from a penicillin allergy, regardless of the stage. Depending on the
stage of syphilis, the Jarisch-Herxheimer reaction is observed in almost 20% within
the first 48 hours after the first antibiotic administration. Due to the release of pyro-
genic, vasoactive endotoxins due to the rapid decay of bacteria, exanthema and flu-
like symptoms such as chills, fever, and joint or muscle pain may occur. The Jarisch-
HIV and sexually transmitted diseases 415

Herxheimer reaction can be prevented or significantly reduced in its clinical mani-

festation by a single administration of 0.5–1 mg/kg prednisolone per os or intra-
venously before the first antibiotic administration (Schöfer 2020).
The success of therapy is monitored clinically and serologically 3, 6, 12, 18, and 24
months after the end of treatment. It is indicated by the healing of clinical symp-
toms and a significant drop in the titer of the non-treponemal activity parameters
(reduction of the VDRL at least two titer levels within three months). A rebound
may signify re-infection or reactivation requiring treatment. This is assumed if sero-
logical titers increase by more than two titer levels from baseline after the end of
therapy. Even in PLWH, the IgM test should no longer be reactive after two years at
the latest following sufficient treatment. If the IgM test was no longer reactive, a
renewed reactivity means a re-infection or reactivation requiring treatment – see
above (Schöfer 2020).
Despite the detection of treponemal antibodies, there is no immunity either after
healing or after successful treatment. A new infection is possible immediately after
the antibiotic levels have dropped.
Literature
Czelusta A, Yen-Moore A, Van der Staten M et al. An overview of sexually transmitted diseases. Part III. Sexually
transmitted diseases in HIV-infected patients. J Am Acad Dermatol 2000, 43: 409-32.
Esser S, Riehemann A, Jablonka R, et al. Diagnosis of Early Neurosyphilis (NSI) by Cerebrospinal Fluid (CSF) in
HIV-infected Patients with Primary (LI) or Secondary (LII) Syphilis-Infection (SI). Abstract H1-1396, 51st ICAAC
2011, Chicago.
Geusau A, Kittler H, Hein U, Dangl-Erlach E, Stingl G, Tschachler E. Biological false-positive tests comprise a high
proportion of Venereal Disease Research Laboratory reactions in an analysis of 300,000 sera. Int J STD AIDS 2005,
16:722-6.
Ghanem KG, Ram S, Rice PA. N Engl J Med 2020, 382:845-854.
Gregory N, Sanchez M, Buchness MR. The spectrum of syphilis in patients with HIV infection. J Am Acad Derm
1990, 6:1061-67.
Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and
Ireland. N Engl J Med 2004, 351:154-8.
Marra CM, Boutin P, McArthur JC, et al. A pilot study evaluating ceftriaxone and penicillin G as treatment agents
for neurosyphilis in human immunodeficiency virus-infected individuals. Clin Infect Dis 2000; 30:540-4.
Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid abnormalities after neurosyphilis
therapy: does HIV status matter? CID 2004 38:1001-6.
Medical Society for the Study of Venereal Diseases (MSSVD). Clinical standards for the screening and manage-
ment of acquired syphilis in HIV-positive adults. London, 2008. [Link]
Medical Society for the Study of Venereal Diseases (MSSVD). UK National guidelines on the management of
syphilis 2008. [Link]/[Link]?id=14277.
Ndeikoundam NN, Viriot D, Fournet N, et al. Bacterial sexually transmitted infections in France: recent trends
and patients’ characteristics in 2016. Euro Surveill 2019 Jan;24.
Paul G, Wesselmann J, Adzic D, et al. Predictors of serofast state after treatment for early syphilis in HIV-infected
patients. HIV Med 2021, 22:165-171.
Peterman TA, Heffelfinger JD, Swint EB, Groseclose SL. The changing epidemiology of syphilis. Sex Transm Dis
2005, 32: S4-S10.
Schöfer H, Endres M, Esser S, et al. Diagnosis and treatment of syphilis: Update of the S2k guidelines 2020 of the
German STI Society (DSTIG) in cooperation with the following specialist societies: DAIG, dagnä, DDG, DGA,
DGGG, DGHM, DGI, DGN, DGPI, DGU, RKI. Hautarzt 2020, 71:969-999.
Sellati TJ, Wilkinson DA, Sheffield JS, et al. Virulent Treponema pallidum, lipoprotein, and synthetic lipopeptides
induce CCR5 on human monocytes and enhance their susceptibility to infection by HIV type1. J Inf Dis 2000,
181: 283-93.
Smith G, Holman RP. The prozone phenomenon with syphilis and HIV-1 co-infection. South Med J 2004, 97:379-382.
Stamm LV. Syphilis: Re-emergence of an old foe. Microb Cell 2016, 27:363-370.
Taiwan HIV and Syphilis Study Group, Comparison of effectiveness of 1 dose versus 3 doses of Benzathine Penicillin
in treatment of early syphilis in HIV-infected Patients: Multicenter, prospective observational study in Taiwan.
Abstract 872, 20th CROI 2013, Atlanta.
Tucker JD, Shah S, Jarell AD, et al. Lues maligna in early HIV infection case report and review of the literature.
Sex Transm Dis 2009, 36:512-4.
416 Other Infections

Gonorrhea (gonorrhea)
Gonorrhea is caused by gram-negative diplococci Neisseria gonorrhoeae. These bacte-
ria, which are widespread worldwide, develop regionally varying resistances. They
typically affect the mucous membranes of the genitourinary tract, rectum, pharynx,
and eyes and are almost exclusively sexually transmitted (with the exception of
neonatal conjunctivitis). The incubation period is 2–10 days.

Clinic
In men, the primary symptoms of urethritis are frequent urination, burning during
urination, and pain in the urethra. Characteristic is the “bonjour drop”, purulent
fluorine from the urethra after several hours of micturition abstinence, which can
be easily stroked out. Concomitant balanitis often exists. If left untreated, gonorrhea
can lead to prostatitis. Symptoms may include burning at the end of micturition,
pain in the perineal area, and prostate enlargement. Epididymitis is another com-
plication. In women, gonorrhea is usually asymptomatic. Vaginal colonization is
possible only in girls before puberty. Involvement of the cervix and adnexa can lead
to peritonitis and “pelvic inflammatory disease”.
Extragenitally, gonorrhea manifests as pharyngitis or proctitis. Conjunctivitis is
rarely transmitted perinatally, so the previously standard credé prophylaxis for new-
borns is no longer used in most Western countries. Systemic infections with fever,
arthritides, and endocarditides up to gonococcal sepsis are rare (Rompalo 1987).
Often, other STIs exist, especially co-infections with chlamydia (Abraham 2013).

Diagnostics
PCR or nucleic acid amplification tests show high sensitivity and specificity but say
nothing about possible resistance. In the case of urogenital manifestation, detection
is usually successful from the initial urine stream. Swabs are taken urethral, anally,
pharyngeal, and endocervical in women. If pus is not spontaneously discharged,
affected individuals should not have urinated for four hours before the urethral swab.
Diagnosis from the smear can already be established by microscopic detection of
intracellular gram-negative diplococci in the methylene blue or Gram preparation.
Cultural cultivation of smear material is mainly used for the detection of resistance.
Molecular biological methods for monitoring and identifying resistance are currently
being developed and are expected to complement or even replace culture in the
future.
Worldwide, Neisseria gonorrhoeae is increasingly developing regionally varying resist-
ance: since the 1970s to penicillin, since the 1980s to spectinomycin and tetracycline,
and since 2000 to ciprofloxacin (50–70% of all isolates worldwide). Meanwhile, resist-
ance to azithromycin has been increasingly described (Crisholm 2009, Buder
2018+2019), as well as to 3rd generation cephalosporins (Bala 2010, Ison 2010,
Chisholm 2011, Unemo 2011, Buder 2019). Rarely resistance to ceftriaxone has been
published (Chisholm 2009, Ison 2010, Unemo 2017). Isolated cases of clinical resist-
ance occurred primarily with treatments below 1 g (IM or IV) (Fifer 2016). Globally,
the incidence of multidrug-resistant pathogens is increasing (Buder 2019). Neisseria
gonorrhoeae has been classified as a “superbug” by the CDC since 2012 (CDC 2012)
and as “priority 2” by the WHO in the global priority list for antibiotic-resistant
bacteria (WHO 2017).
Surveillance data from 2016–2020 from the German gonococcal resistance network
GORENET observed persistently high rates of resistance to ciprofloxacin (around
60%) and penicillin (15%) in Germany. The rate of azithromycin-resistant isolates
fluctuated during the observation period and most recently rose to 12%. Against
HIV and sexually transmitted diseases 417

cefixime, it was 0.9%. The resistance rate to ceftriaxone remains low (0.2%). No resist-
ant isolates to ceftriaxone or spectinomycin were recorded in GORONET in 2019
and 2020. Older studies from the network found resistance to tetracyclines in about
40% (Buder 2019).

Treatment
The regional resistance situation should be taken into account when selecting
therapy. In many countries, there is a lack of systematic studies, and many practi-
tioners treat suspected cases without cultural evidence of the pathogen. So far, resist-
ance to fluoroquinolones, tetracyclines, and penicillin G has been detected. National
guidelines recommend a single IM or IV administration of 1,000–2,000 mg ceftriaxone
with or without additional concurrent administration of 1,500 mg azithromycin for
uncomplicated gonococcal infection of the cervix, urethra, and rectum. Because of
the resistance situation and frequent chlamydial co-infections, combinations of
cephalosporins and azithromycin or doxycycline are given. Single-stage antibiotic
therapy is preferred in high-risk groups. Even in asymptomatic individuals, success
should be monitored no earlier than two weeks after completion of treatment.
In cases of treatment failure, intolerance to cephalosporins, and in persons infected
with Neisseria gonorrhoeae in regions with high resistance rates (e.g., Southeast Asia)
(travel returnees), treatment should always be based on resistance tests.

Literature
Abraham S, Poehlmann C, Spornraft-Ragaller P. Gonorrhea: Data on antibiotic resistance and accompanying infec-
tions at the University Hospital Dresden over 10 years. J Dtsch Dermatol Ges 2013, 11:241-9.
Bala M, Sood S. Cephalosporin Resistance in Neisseria gonorrhoeae.J Glob Infect Dis 2010, 2:284-90.
Buder S, Dudareva S, Jansen K et al. GORENET study group. Antimicrobial resistance of Neisseria gonorrhoeae in
Germany: low levels of cephalosporin resistance, but high azithromycin resistance. BMC Infect Dis 2018; 18: 44.
Buder S, Schöfer H, Meyer T, et al. Bacterial sexually transmitted infections. J Dtsch Dermatol Ges. 2019, 17:287-315.
CDC: Increases in Fluoroquinolone-Resistant Neisseria gonorrhoeae Among Men Who Have Sex with Men -United
States, 2003, and Revised Recommendations for Gonorrhea Treatment, 2004. MMWR 2004 ; 53: 335-8.
Chisholm SA, Alexander S, et al. Collaborative Group Emergence of a Neisseria gonorrhoeae clone showing
decreased susceptibility to cefixime in England and Wales. J Antimicrob Chemother. 2011 Aug 16.
Chisholm SA, Neal TJ, Alawattegama AB, et al. Emergence of high-level azithromycin resistance in Neisseria gon-
orrhoeae in England and Wales. J Antimicrob Chemother 2009, 64:353-8.
CDC. Cephalosporin-Resistant Neisseria gonorrhoeae Public Health Response Plan; CDC: Atlanta, GA, USA, 2012;
pp. 1–43.
Cole MJ, Chisholm SA, Hoffmann S, Stary A, Lowndes CM, Ison CA. European Surveillance of Sexually Transmitted
Infections Network. European surveillance of antimicrobial resistance in Neisseria gonorrhoeae. Sex Transm Infect
2010, 86:427-32.
Enders M, Turnwald-Maschler A, Regnath T. Antimicrobial resistance of Neisseria gonorrhoeae isolates from the
Stuttgart and Heidelberg areas of southern Germany. Eur J Clin Microbiol Infect Dis 2006, 25:318-22.
Fifer H, Natarajan U, Jones L, et al. Failure of Dual Antimicrobial Therapy in Treatment of Gonorrhea. N Engl J
Med 2016, 374:2504-6.
Handsfield HH, Dalu ZA, Martin DH, et al. Multicenter trial of single-dose azithromycin vs. ceftriaxone in the
treatment of uncomplicated gonorrhea. Azithromycin Gonorrhea Study Group. Sex Transm Dis 1994, 21:107-11.
Ison CA, Hussey J, Sankar KN, et al. Gonorrhoea treatment failures to cefixime and azithromycin in England,
2010. Euro Surveill 2011, 16(:p11.
Moodley P, Sturm AW. Ciprofloxacin-resistant gonorrhoea in South Africa. Lancet 2005, 366: 1159.
Rompalo AM, Hook EW 3rd, Roberts PL, et al. The acute arthritis-dermatitis syndrome. The changing importance
of Neisseria gonorrhoeae and Neisseria meningitidis. Arch Intern Med 1987, 147: 281-3.
Roy K, Wang SA, Meltzer MI. Optimizing treatment of antimicrobial-resistant Neisseria gonorrhoeae. Emerg Infect
Dis 2005, 11: 1265-73.
Selb R, Bremer V, Jansen K, et al. Einführung einer Meldepflicht für N. gonorrhoeae mit verminderter
Empfindlichkeit gegenüber Azithromycin, Cefixim oder Ceftriaxon Epid Bull 2020;10:6 –12.
Unemo M, Golparian D, Stary A, Eigentler A. First Neisseria gonorrhoeae strain with resistance to cefixime causing
gonorrhoea treatment failure in Austria, 2011. Euro Surveill 2011, 16. pii: 19998.
Unemo M, Bradshaw CS, Hocking JS, et al. Sexually transmitted infections: challenges ahead. Lancet Infect Dis
2017, 17:e235-79.
WHO. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new
antibiotics; 2017. [Link]
418 Other Infections

Chlamydia, lymphogranuloma venereum (LGV)

Chlamydiae undergo a complex replication cycle, live obligately intracellularly, and
can persistently infect host cells over time. Genitoanal infections caused by
Chlamydia trachomatis are the most common bacterial STI worldwide. Women are
particularly affected (Rowley 2019). Chlamydia strains are classified into different
serotypes by membrane proteins: serotypes D-K are widely distributed in Europe and
cause sexually transmitted urogenital and anal infections and conjunctivitis and
pneumonia following perinatal transmission. Serotypes L1-3 are the cause of
lymphogranuloma venereum (LGV). Whereas LGV used to be considered a disease
of the tropics, local outbreaks have been occurring in Europe and the US for several
years, especially in large cities (Gotz 2004, Krosigk 2004).

Clinic
In men, genital chlamydiosis caused by serotypes D-K – if symptomatic- usually
presents as urethritides with mostly glassy-turbid fluorine. However, similar to
gonorrhea, MAGI (Male Accessory Gland Infection), epididymitis, prostatitis, or
proctitis also occur. Reactive arthritis in the context of Reiter’s syndrome (see below)
is also possible.
In women, the infection causes symptoms in about 20% and may then manifest as
urethritis, cervicitis, bartholinitis, salpingitis, endometritis, pelvic inflammatory
disease (PID), perihepatitis (Fitz-Hugh-Curtis syndrome), proctitis, and arthritis. In
cervicitis, there is usually purulent fluorine. Possible consequences of salpingitis
include sterility due to tubal occlusion or extrauterine pregnancy. Chlamydia screen-
ing is covered by payers for pregnant women and women up to the age of 25.
In LGV, a primary lesion initially develops at the site of infection. After a few weeks,
very painful swellings of the regional lymph nodes (bubo) form, which may exude.
After healing, scars develop that can cause drainage problems and fistulas by block-
ing the lymphatic vessels. Highly painful and often therapy-refractory proctitis and
peri- and intra-anal ulcerations are also typical (Peerenboom 2006). More than 90%
of L1-3 infections detected in Germany occurred in HIV-infected MSM and mainly
cause painful proctitis (Martin-Iguacel 2010). Urethritides without proctitis, on the
other hand, are relatively rare.
Reiter’s disease refers to the symptom triad of urethritis (sterile yellowish discharge),
conjunctivitis (serous or purulent), and arthritis (especially knee, foot, and sacroiliac
joints; pain until immobility). There is usually a genetic predisposition (HLA-B27)
and chlamydial infection. The incidence in male PLWH is tenfold higher than in
the general population. The course is chronic-recurrent. Skin symptoms: erythema
with sterile pustules on the palms and soles, later psoriasiform skin changes, hyper-
keratotic, scaly, weeping foci (= keratoderma blenorrhagicum), balanitis circinata
(disc-shaped, polycyclic, erosive foci).

Diagnostics
Because of their high sensitivity and specificity, nucleic acid amplification tests (men:
initial stream urine; women: swabs) are the method of choice (Morre 2005).
Resistance has been rare in Chlamydia trachomatis (Buder 2019). Procedure: When
swabbing with a dry cotton swab, obtain epithelial cells with some pressure for a
few seconds and then send the cotton swab in the dry tube to the laboratory (now
mostly routine test). Regular testing is usually only for Chlamydia trachomatis. PCR
detection of serovars L1-3 (therapeutic consequence, see below!) has usually only
been performed on specific requests in specialized laboratories. Regardless of the
HIV and sexually transmitted diseases 419

serovar, detection is always an indication for treatment. The serological determina-

tion of antibodies against Chlamydia is used to diagnose chronic invasive infections
and plays no role in venereology.

Treatment
Treatment is with doxycycline 2 x 100 mg over 7–14 days. The single dose of 1,000–
1,500 mg azithromycin or 1 x 500 mg over three days, still considered an alternative
until 2016, is no longer recommended everywhere without restriction. However, it
can be regarded as when nonadherence to the doxycycline regimen is a substantial
concern. It might require posttreatment evaluation and testing because it has demon-
strated lower treatment efficacy among persons with rectal infection (CDC 2021).
Alternatives are moxifloxacin 1 x 400 mg or erythromycin 4 x 500 mg over seven
days. For anorectal chlamydial infection, doxycycline is more effective than
azithromycin (Lau 2021).
LGV requires a significantly longer duration of therapy: doxycycline 2 x 100 mg
should be given for at least three weeks. Some experts recommend this if the serotype
remains unclear in PLWH with proctitis and chlamydia detection (Mohrmann 2011).
So far, resistance has not been a problem with Chlamydia trachomatis (Buder 2019).
At the earliest, success should be monitored eight weeks after the end of treatment.
In Reiter’s disease, additional treatment with anti-rheumatic drugs can be given, if
necessary, short-term high doses of steroids. Alternatively, sulfasalazine, methotrex-
ate, and anti-TNF-alpha antibodies (etanercept, adalimumab, infliximab) and other
biologics have been used (Adizie 2016).
Literature
Adizie T, Moots RJ, Hodkinson B, et al. Inflammatory arthritis in HIV-positive patients: A practical guide. BMC
Infect Dis 2016 Mar 1;16:100.
Buder S, Schöfer H, Meyer T, et al. Bacterial sexually transmitted infections. J Dtsch Dermatol Ges 2019, 17:287-315.
CDC: Sexually Transmitted Infections Treatment Guidelines, 2021. [Link]
lines/[Link]
European Guideline for the management of chlamydial infection. Int J STD AIDS 2001; 12: S30-3.
[Link]
Gotz HM, Ossewaarde JM, Nieuwenhuis RF, et al. A cluster of lymphogranuloma venereum among homosexual
men in Rotterdam with implications for other countries in Western Europe. Ned Tijdschr Geneeskd 2004, 148:
441-2.
Jebbari H, Alexander S, Ward H, et al. Update on lymphogranuloma venereum in the United Kingdom. Sex Transm
Infect 2007, 83:324-6.
Krosigk A, Meyer T, Jordan S, et al. Auffällige Zunahme des Lymphogranuloma venereum unter homosexuellen
Männern in HH. JDDG 2004, 8: 676-80.
Lau A, Kong FYS, Fairley CK, et al. Azithromycin or Doxycycline for Asymptomatic Rectal Chlamydia trachoma-
tis. N Engl J Med 2021, 384:2418-2427.
Martin DH, Mroczkowski TF, Dalu ZA, et al. A controlled trial of a single dose of azithromycin for the treatment
of chlamydial urethritis and cervicitis. N Engl J Med 1992, 327: 921-5.
Martin-Iguacel R, Llibre JM, Nielsen H, et al. Lymphogranuloma venereum proctocolitis: a silent endemic disease
in men who have sex with men in industrialised countries. Eur J Clin Microbiol Infect Dis 2010, 29:917-25.
Morre SA, Spaargaren J, Fennema JS, et al. Real-time polymerase chain reaction to diagnose lymphogranuloma
venereum. Em Inf Dis 2005, 11:1311-2.
Nieuwenhuis RF, Ossewaarde JM, van der Meijden WI, Neumann HA. Unusual presentation of early lym-
phogranuloma venereum in an HIV-1 infected patient: effective treatment with 1 g azithromycin. Sex Transm
Infect 2003, 79: 453-5.
Paavonen J. Pelvic inflammatory disease. From diagnosis to prevention. Dermatol Clin 1998, 16: 747-56.
Perenboom RM. Lymphogranuloma venereum proctitis: An emerging sexually transmitted disease in HIV-posi-
tive men in the Netherlands. Drugs Today (Barc) 2006; 42: Suppl: 43-5.
Rowley J, Vander Hoorn S, Korenromp E, et al. Chlamydia, gonorrhoea, trichomoniasis and syphilis: global preva-
lence and incidence estimates, 2016. Bull World Health Organ. 2019;97(8):548-562P.
Schachter J, Grossman M, Sweet RL, et al. Prospective study of perinatal transmission of Chlamydia trachomatis.
JAMA 1986, 255: 3374-7.
420 Other Infections

Genitoanal mycoplasma infections

The pathogens Mycoplasma hominis, Ureaplasma urealyticum and other Mycoplasma
species frequently colonize the genital tract of healthy women and men. However,
the pathogenic significance of these pathogens is controversially discussed.
Mycoplasma (M.) genitalium remains asymptomatic in 40–75% (Jansen 2020) but is
responsible for 10–35% of non-chlamydial or non-gonococcal urethritides in men.
In women, it is reported to be associated with cervicitis, acute endometritis, and
pelvic inflammatory disease (PID) (Buder 2019). Proctitis can also be caused by
M. genitalium (Chow 2021). Often, M. genitalium is not screened for when an STI is
suspected, although detection influences the choice of antibiotic therapy, and resist-
ance has increased significantly in recent years (Dumke 2019, Spornraft-Ragaller 2020).
During STI screening of MSM in various specialized centers independent of clinical
symptoms, Mycoplasma genitalium was most frequently detected rectally (Jansen 2020).

Clinic, diagnostics
In addition to genitoanal dysfunction, urethritis, proctitis, and SARA (sexually
acquired reactive arthritis), additional menstrual cramps, cervicitis, PID, and tubular
infertility occur in women and balanoposthitis and epididymitis in men. NAAT or
multiplex PCR studies from swabs and/or urine are used to detect this small cell wall-
less microorganism. In addition, the use of appropriate assays to detect antibiotic
resistance is recommended.

Treatment
Due to the increasing development of resistance in M. genitalium, resistance testing
is recommended even for uncomplicated infections (Jensen 2022). The calculated
use of azithromycin should be avoided (de Salazar 2020). European guidelines
recommend azithromycin per os over five days to treat macrolide-susceptible
M. genitalium (Jensen 2022): once each 500 mg on the first treatment day and 250 mg
on the following treatment days 2–5. Macrolide-resistant or persistent infections
should be treated with moxifloxacin 400 mg per os over 7–10 days and in case of
complications (PID, epididymitis) over 14 days. The resistance rate to moxifloxacin
is also increasing alarmingly in Germany (Dumke 2019, Spornraft-Ragaller 2020).
Despite low eradication rates (just under 30%), the alternative is oral doxycycline
2 x 100 mg for 14 days. Pristinamycin can be obtained from international pharma-
cies and taken per os at 4 x 1 g over ten days as a reserve antibiotic. Increasingly
complex therapeutic algorithms are being used to treat resistant M. genitalium infec-
tions, as cases have now been described that failed to respond even to pristinamycin
(Durukan 2020). To avoid false positive test results, a success control should not be
performed until six weeks after the start of therapy.
Multiplex PCR for sexually transmitted pathogens usually includes testing for
mycoplasma. While this is useful in symptomatic STI patients, screening of asymp-
tomatic individuals is controversial. A proven infection with M. genitalium should
be treated regardless of symptoms to avoid potential long-term complications (e.g.,
infertility).
Literature
Buder S, Schöfer H, Meyer T, et al. Bacterial sexually transmitted infections. J Dtsch Dermatol Ges. 2019
Mar;17(3):287-315.
Chow EPF, Lee D, Bond S, et al. Nonclassical pathogens are causative agents of proctitis in men who have sex
with men. Open Forum Infect Dis 2021, 8:ofab137.
HIV and sexually transmitted diseases 421

Dumke R, Ziegler T, Abbasi-Boroudjeni N, Rust M, Glaunsinger T. Prevalence of macrolide- and fluoroquinolone-

resistant Mycoplasma genitalium strains in clinical specimens from men who have sex with men of two sexually
transmitted infection practices in Berlin, Germany. J Glob Antimicrob Resist. 2019 Sep;18:118-121.
Durukan D, Doyle M, Murray G, et al. Doxycycline and Sitafloxacin Combination Therapy for Treating Highly
Resistant Mycoplasma genitalium. Emerg Infect Dis 2020, 26:1870-1874.
Jansen K, Steffen G, Potthoff A, et al.; MSM Screening Study group. STI in times of PrEP: high prevalence of
chlamydia, gonorrhea, and mycoplasma at different anatomic sites in men who have sex with men in Germany.
BMC Infect Dis 2020, 20:110.
Jensen JS, Cusini M, Gomberg M, et al. 2021 European guideline on managing Mycoplasma genitalium infec-
tions. J Eur Acad Dermatol Venereol. 2022 Feb 19. doi: 10.1111/jdv.17972. Epub ahead of print.
de Salazar A, Barrientos-Durán A, Espadafor B, et al. Macrolide and fluoroquinolone resistance of Mycoplasma
genitalium in southern Spain, 2018-2019. Sex Transm Infect 2021, 97:8-10.
Spornraft-Ragaller P, Dumke R. Prevalence and antibiotic resistance of rectal Mollicutes in HIV-infected men who
have sex with men at the University Hospital of Dresden, Germany. Infection 2020, 48:259-265.
Unemo M, Salado-Rasmussen K, Hansen M, et al. Clinical and analytical evaluation of the new Aptima Mycoplasma
genitalium assay, with data on M. genitalium prevalence and antimicrobial resistance in M. genitalium in
Denmark, Norway and Sweden in 2016. Clin Microbiol Infect. 2017 Sep 18.

Chancroid
The genital ulcer disease chancroid is caused by Haemophilus ducreyi. It is endemic
in tropical and subtropical areas. In the last two decades, the incidence of chancroid
has declined sharply in many countries.

Clinic, diagnostics
Usually, after 2–7 days, one or more ulcers that look like frayed ulcers develop at the
site of entry, which is generally genital or perianal. These are not indurated (“soft”
chancre) but typically cause severe pain. In about half of cases, regional lymph nodes
are swollen, as in LGV, usually unilaterally and very painful. Balanitis or phimosis,
or paraphimosis are less common. Clinical diagnosis is difficult because of the wide
variety of symptoms, which can mimic ulcerative genital infections such as syphilis
or even herpes simplex. Smears sometimes show “fish-train-like” gram-negative rods.
A more reliable clue is provided by purulent punctate from inguinal lymph nodes
(Lewis 2003, King 1996). Biopsies are taken from the ulcer margin to exclude malig-
nancy.

Treatment
Azithromycin, as a single dose of 1 g to 1.5 g, is considered the treatment of choice
(Martin 1995, Romero 2017). Alternatively, ceftriaxone 250 mg (IM or IV) or erythro-
mycin 4 x 500 mg for 4–7 days are used. Ciprofloxacin 2 x 500 mg, given for three
days, is also effective. Lymph nodes severely swollen and at risk of rupture should
not be cleft but punctured to relieve them (Lewis 2003, Romero 2017). If abscesses
(“bubones”) occur, antibiotic treatment should be given for at least two weeks. There
are few publications on Haemophilus ducreyi in PLWH (King 1998, Romero 2017).
Literature
King R, Choudhri SH, Nasio J, et al. Clinical and in situ cellular responses to Haemophilus ducreyi in the pres-
ence or absence of HIV infection. Int J STD AIDS 1998, 9: 531-6.
King R, Gough J, Ronald A, et al. An immunohistochemical analysis of naturally occurring chancroid. JID 1996,
174: 427-30.
Lewis DA. Chancroid: Clinical manifestations, diagnosis, and management. Sex Transm Infect 2003, 79: 68-71.
Martin DH, Sargent SJ, Wendel GD Jr, et al. Comparison of azithromycin and ceftriaxone for the treatment of
chancroid. Clin Inf Dis 1995, 21: 409-14.
Romero L, Huerfano C, Grillo-Ardila CF. Macrolides for treatment of Haemophilus ducreyi infection in sexually
active adults. Cochrane Database Syst Rev. 2017 Dec 11;12(12): CD012492.
422 Other Infections

Granuloma inguinale (donovanosis, granuloma venereum)

Low-contagious granuloma inguinale is caused by Klebsiella granulomatis and was
endemic in tropical and subtropical areas. It is now considered nearly extinct
(O’Farrell 2018, Muller 2020). Sporadic infections are introduced in Europe (RKI
2022).

Clinic, diagnostics
After an incubation period of 1–2 weeks (days – 3 months), the primary effect appears
at the entry site as a painless, rapidly disintegrating papule. In the further course,
subcutaneous nodules, multiple easily bleeding ulcerations, and sometimes mon-
strous granulations develop in the surrounding area and slowly spread peripherally.
Extensive tissue destruction is accompanied by lymphedema. Diagnosis is made by
PCR, culturing, or microscopic detection of the pathogen from a tissue curettage
stained according to Giemsa (intracellular bipolarly stained, coccoid rods, so-called
Donovan’s corpuscles.

Treatment
Macrolides, doxycycline, fluoroquinolones, or trimethoprim-sulfamethoxazole
should be used for at least 21 days or until lesions completely heal. Azithromycin 1
g weekly is recommended as the treatment of choice (O’Farrell 2018). Additionally,
wound debridement or excision of lesions may be necessary.
Literature
Muller EE, Kularatne R. The changing epidemiology of genital ulcer disease in South Africa: has donovanosis been
eliminated? Sex Transm Infect 2020, 96:596-600.
O’Farrell N, Hoosen A, Kingston M. 2018 UK national guideline for managing donovanosis. Int J STD AIDS 2018,
29:946-948.

Condylomata acuminata (genital warts)

Human papillomaviruses (HPV) exclusively infect epithelial cells and are among the
most common sexually transmitted viral infections. The incubation period is at least
three weeks. Transmission through smear infection or contaminated objects is also
possible. In addition to promiscuity and smoking, immunodeficiency and other
genital diseases are important risk factors. Most HPV infections can be eradicated.
The onset of clinical symptoms of HPV infection may take months to years. Among
PLWH, persistent HPV infection is high (up to 90%). Of the HPV subtypes, more
than 20 can lead to genitoanal infections. “Low-risk” (LR) are distinguished from
“high-risk” (HR) HPV types. LR-HPV infections cause condylomata acuminata, while
persistent HR-HPV-infected epithelial cells may transform malignantly, from which
carcinomas and their precursors may develop. Co-infection with multiple HPV
subtypes, including oncogenic ones, is common in PLWH. The risk of persistent and
symptomatic HPV infection is 7-fold higher and correlates inversely with CD4 T-cell
count (Piketty 2003). PLWH more often show clinical symptoms, a chronic course,
recurrences, and malignant degeneration. In recent years, an increase in HPV-asso-
ciated intraepithelial neoplasia (IN) and carcinoma has been observed despite ART.
In the US, 6 of the 10 most common malignancies in PLWH are caused by persistent
HR-HPV infections: anal carcinoma, cervical carcinoma, oropharyngeal carcinoma,
HIV and sexually transmitted diseases 423

and vulvar and penile carcinoma. The risk of anal carcinoma is over 80 times higher
for male PLWH than in the general population, with a frequency of 35–70/100,000
(Chiao 2006, Silverberg 2012, Yarchoan 2018). PLWH with anal carcinoma often
have a history of condylomata acuminata (Hoffmann 2011). Adequate follow-up and
regular screening following treatment of HPV-associated lesions may prevent the
development of cervical, anal, and other HPV-associated carcinomas (Revollo 2019,
Palefsky 2022).

Clinic
Most HPV infections are asymptomatic, are eradicated during the course, and there-
fore not diagnosed. The most common clinical manifestation of sexually transmit-
ted HPV infections is genital warts. Spontaneous remissions are also possible with
symptomatic infections. However, giant condylomas and carcinomas may also
develop with persistent HPV infection.
Condylomata acuminata are usually caused by the “LR” HPV subtypes HPV 6 or HPV
11. Genital warts are not an obligate precursor of genitoanal intraepithelial neoplasia
and carcinoma but are often difficult to differentiate clinically and are associated
with an increased frequency of additional, persistent associated HR-HPV infections.
In addition to the predilection sites, genital, peri- and intra-anal condylomas may
occur enorally and in the urethra. Condylomas affect the sexual life of affected indi-
viduals and can lead to hygienic and psychological problems. Rare symptoms include
itching, burning, or bleeding, usually due to mechanical forces. Condylomata acumi-
nata are clustered with other HPV-associated intraepithelial lesions and carcinomas.
Early detection of HPV-associated lesions is helpful because some time may elapse
between the development of anal carcinoma and the appearance of condylomata
and anal intraepithelial neoplasia.

Diagnostics
The diagnosis of genital warts is usually made clinically. Trial biopsies to exclude
malignancy are recommended before starting therapy. They are strongly indicated
in cases of therapeutic resistance, early recurrence, and rapid or suspected infiltrative
growth. Cytologic smears are another screening method for cervical and anal
carcinomas and their precursors. Anal cytologic smear findings are usually classified
according to the Bethesda system. This distinguishes between normal, inflammation
and various atypia: atypical squamous cells (ASC: -US (undetermined significance),
-H (cannot exclude HSIL), atypical glandular cells (ACG), low-grade or high-grade
squamous intraepithelial lesion (LSIL or HSIL). The sensitivity and specificity of
cytological anal smears are unsatisfactory so far, so an additional HPV typing for
screening, as in cervical carcinoma, is discussed (Panther 2004, Esser 2020). Any
repeatedly abnormal (ASC-H, LSIL, HSIL) cytological findings should prompt a
colposcopy or proctoscopy (Duerr 2006).
High-resolution anoscopy/colposcopy (HRA) as the gold standard for early detection
of HPV-associated lesions is offered in specialized centers. It improves the accuracy
of genital, peri- and intra-anal inspection for necessary sample biopsies, especially
after application of acetic acid (3 percent mucosa, 5 percent skin) and additional
staining with Lugol’s solution (caution: containing iodine). Histologically, condylo-
mata acuminata, intraepithelial neoplasia according to severity grade I-III (IN), and
invasively growing carcinomas are differentiated. The anatomic localization is
indicated in advance. Thus, an AIN III corresponds to an anal carcinoma in situ. In
addition, the HPV subtype can also be determined to distinguish between high-
424 Other Infections

Algorithm: Anal cancer screening diagnosis and therapy of Condylomata acuminata,

anal intraepithelial Dys-/Neoplasia and anal cancer in HIV-infected persons
HIV and sexually transmitted diseases 425
426 Other Infections

risk/low-risk types. If persistent HR-HPV subtypes are detected for over one year, HRA
is indicated (Ledger 2000).
Men living with HIV, especially MSM, should be screened proctologically just as with
HIV-infected women (Jamieson 2006, Scott 2008, Wexler 2008, Esser 2015, Revollo
2019, Palefsky 2022). All PLWH with a history of genitoanal or oral-genital warts,
IN, or carcinoma are at increased risk for developing anal carcinoma. HRA with smears
and timely targeted sampling, as well as timely treatment of HPV-associated lesions,
can prevent fatal tumor growth and avoid mutilating surgeries such as rectal ampu-
tation, anus praeter, etc. (Kreuter 2003, Pindea 2008, Esser 2015, Revollo 2019,
Palefsky 2022). Rectal palpation and external inspections of the anogenital region
are insufficient for PLWH screening. By the time anal carcinoma becomes palpable,
it is usually well advanced. Why PLWH cytological, virological, colposcopic, and
proctoscopic examinations are necessary in addition to the routinely performed
genitoanal palpations and inspections, and how is clarified in a German-Austrian
guideline developed by various professional societies (Esser 2015).
Patients at high risk for developing anal carcinoma should undergo anoscopy with
appropriate tissue staining (acetic acid, Lugol’s solution) and targeted specimen
biopsy if necessary.
All conspicuous HPV-associated, clinically relevant findings should be treated imme-
diately. Therapy does not differ from that in HIV-negative patients. Since the tran-
sition from persistent HPV infection to intraepithelial neoplasia and anal carcinoma
can occur more rapidly, the necessary measures should be initiated promptly.

Treatment
To date, there is no satisfactory treatment for condylomas. Recurrences are common,
even after adequate treatment and even in immunocompetent individuals (40–60%
after tissue-destructive therapy procedures). Nevertheless, all clinically conspicuous
findings should be removed early, even at the risk of repeated interventions.
Treatment requires surgical removal as completely as possible with histologic control
of dignity and depth of invasion. In addition to surgical excision, scissor cutting,
and electrocaustic ablation, condylomas can be removed by laser surgery, infrared
coagulation, caustics such as trichloroacetic acid (Bilbilis 2021) or podophyllotoxin,
local chemotherapy or cryotherapy with liquid nitrogen. Many practitioners subse-
quently attempt to reduce the high recurrence rate by adjuvant local immunother-
apy with imiquimod (Aldara® cream). Imiquimod is approved for topical treatment
of HPV-related lesions and can also be used successfully as a sole therapy primarily
for flat, low hyperkeratotic condylomas (Kreuter 2008). For intra-anal treatments,
formulations for tampositories containing imiquimod exist (off-label, extempora-
neous formulation). Local therapy with imiquimod is usually prolonged (at least
three months). Without surgical intervention, the treatment duration is several
months. Adherence-reducing side effects such as inflammation, itching, and burning
are common. An herbal 10% ointment containing purified dry extract of green tea
leaves (Camellia sinensis) is also approved as a drug for dermal topical therapy of
external genital and perianal condylomata (Abramovits 2010). Condylomas can also
be treated locally or systemically with interferons (often not covered by health insur-
ance, the low initial cure rate of 31% – but reports of a much lower recurrence rate
than destructive therapies). In a prospective study, electrocaustic ablation of HPV-
associated genitoanal lesions was superior to local immunotherapy with imiquimod
and topical chemotherapy (Richel 2013).
Effective preventive vaccination is available against the most common genitoanal
low-risk types HPV-6/11 and the high-risk types HPV-16/18/31/33/45/45/52/58.
HIV and sexually transmitted diseases 427

Studies in children and adolescents living with HIV have shown good tolerability
and good efficacy with sufficient CD4 T-cell counts (Wilkin 2010, Weinberg 2012).
The current EACS guidelines recommend vaccination with the nanovalent HPV
vaccine in a 3-dose schedule (months 0, 2, 6–12) until 26 years of age for all PLWH
and until 40 years of age for HIV-positive MSM (EACS 2021).
Unlike protective vaccines, progress with therapeutic vaccines is still pending.
Isolated cases of lower recurrence rates after ablation of HPV-associated lesions and
therapeutic off-label use of preventive vaccines have been reported (Swedish 2012).
However, a randomized ACTG trial of the therapeutic use of quadrivalent HPV
vaccine, which enrolled more than 500 PLWH with conspicuous HPV-associated anal
findings excluding diagnosed carcinomas, was discontinued because it failed to
demonstrate efficacy on HPV infection or cytologic results (Wilkin 2016).

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HIV-infected Adults. Abstract 161, 23th CROI 2016, Boston, USA.
Wilkin T, Lee JY, Lensing SY, Stier EA, et al. Safety and immunogenicity of the quadrivalent human papillomavirus
vaccine in HIV-1-infected men. J Infect Dis 2010, 202:1246-53.
Yarchoan R, Uldrick TS. HIV-Associated Cancers and Related Diseases. N Engl J Med. 2018 Mar 15;378:1029-1041.

Shigellosis
Shigellae (S) are Gram-negative enterobacteria with a worldwide distribution, into
different pathogenic serogroups according to biochemical characteristics and anti-
gens (group A: S. dysenteriae, B: S. flexneri, C: S. boydii, D: S. sonnei). The pathogens
of shigellosis (shigella dysentery) possess an endotoxin involved in the inflamma-
tion of the intestinal mucosa. In addition, S. dysenteriae type 1 forms an exotoxin
that can lead to severe clinical pictures with circulatory insufficiency and central
nervous symptoms.
Humans are the only relevant reservoir for Shigella. Transmission is through the fecal-
oral route, predominantly through direct contact, such as smear infections in the
case of inadequate hand hygiene. Sexual transmission among MSM is common
(Aragón 2007, Daskalakis 2007, Zayet 2021, Braam 2022). Shigella is rather vulnera-
ble outside the human body. However, in warmer countries, infections can be found
through contaminated drinking water or food and contaminated bathing water.
Even less than 100 microorganisms ingested perorally are sufficient to cause
shigellosis. Shigellae multiply in the intestine and are excreted in the stool. The
incubation period is rarely longer than 12–96 hours. Following the acute phase of
illness, contagiousness persists as long as shigella is excreted in the stool – usually
no longer than four weeks. Asymptomatic shedders hinder the containment of shigel-
losis.
As with hepatitis A, regional clusters of sexual transmissions among MSM have been
observed in many countries during recent years (Keay 2014, Mohan 2018). Among
389 MSM attending the Amsterdam Centre for sexual health in 2020, shigella preva-
lence was 2.8% in asymptomatic men, 3.7% in men who recently had diarrhea, and
4.4% in men with current diarrhea (Braam 2022).
Antimicrobial resistance is increasing (Niyogi 2007, Gaudreau 2010, Hoffmann 2013,
Nüsch-Inderbinen 2016, Zayet 2021).
HIV and sexually transmitted diseases 429

Clinic
The clinical course varies considerably, ranging from asymptomatic excretory
diarrhea to profound watery diarrhea, with mucous-bloody-purulent diarrhea and
life-threatening septic-toxic events. Shigellosis usually begins as watery diarrhea and
may progress to inflammatory colitis. Abdominal cramps (colic and tenesmus) are
typical. Up to 50 defecations per day can occur, often accompanied by dehydration
and protein loss. The disease is usually self-limiting within seven days. Severe courses
are associated with fever, mucous-bloody, and purulent diarrhea. Focal ulceration
and necrosis may occur, predominantly in the distal colon, and in extreme cases,
progress to colonic dilatation and perforation with peritonitis and sepsis.
In rare cases (1–3%), shigellosis manifests outside the intestine: the cytotoxin (Shiga
toxin) produced by S. dysenteriae serotype 1 (SD1) is almost identical to Shiga toxin 1
(verotoxin 1) of enterohemorrhagic E. coli (EHEC) and also causes hemolytic uremic
syndrome (HUS). Other possible consequences are infectious arthritis (dysentery
rheumatoid) and Reiter’s syndrome.
Other infectious diseases such as typhoid, schistosomiasis, or amoebiasis may have
been transmitted at the same time as the shigella or an HIV infection may be present,
which additionally impairs the course of the disease.

Diagnostics
The suspected diagnosis should be confirmed bacteriologically. Fresh stool samples
or freshly taken rectal swabs in a buffered transport medium (30% glycerol in 0.6%
NaCl solution), transferred to appropriate culture media as quickly as possible, are
suitable for this purpose. The samples should be obtained before antibiotic therapy,
and an antibiogram should be prepared to adjust the initiated antibiotic therapy if
necessary.
To identify the sources and routes of infection, pathogens can be typed at special-
ized reference centers (molecular biological subdifferentiation using pulsed-field gel
electrophoresis – PFGE). Some physicians recommend stool testing for shigella for
PLWH with diarrhea and STI screening for all patients with shigellosis who have not
traveled to an endemic area (Keay 2014).

Treatment
Due to its high infectivity, antibiotic treatment is recommended. According to a
Cochrane review, bacterial excretion is reduced, the duration of excretion and illness
is shortened, and symptoms are alleviated. However, regularly updated local or
regional antibiotic sensitivity patterns to different species and strains are required
to guide empiric therapy (Christopher 2010). Due to the increasing development of
resistance, treatment should follow resistance testing. In principle, antibiotics from
the quinolone group, azithromycin, trimethoprim-sulfamethoxazole, tetracycline,
doxycycline, and ampicillin are suitable for long-term treatment of shigella carriers.
Gyrase inhibitors such as ciprofloxacin (2 x 500 mg/day) for five to seven days are
the agents of choice. The choice of therapy depends on the antibiogram (Niyogi
2007, Gaudreau 2010, Hoffmann 2013, Zayet 2021, RKI 2022). In patients in good
general health, symptomatic therapy with oral fluid replacement may be sufficient.
In both very young and elderly patients, as well as in the presence of severe comor-
bidities, fluid and electrolyte losses must be compensated parenterally. Motility
inhibitors should be avoided.
430 Other Infections

Preventive and control measures

The basis of prevention is hygiene (personal, drinking water and food hygiene,
hygiene in communal facilities). Effective hand hygiene is crucial. An alcohol-based
disinfectant can supplement thorough hand washing with soap and water. In coun-
tries with poor sanitation, consider “peel it, boil it, cook it or forget it”. Condoms
do not provide adequate protection against sexual transmission. During and in the
days following diarrheal illness (until shigella excretion is ruled out), sexual contact
should be avoided.
During the entire period of illness, but also in the case of excretions, all objects and
surfaces that may have come into contact with infectious excretions must be disin-
fected. Laundry should be washed at least 60°C or soaked in suitable disinfectant
solutions for 12 hours and washed as everyday household laundry. Toilet seats, toilet
lids, bed frames, sinks, and bathtubs must be disinfected daily in healthcare facili-
ties. Darkroom operators and sex party organizers should ensure soap dispensers are
installed for hand washing. Sharing of inadequately disinfected dildos or lubricant
cans should be avoided. Hot tubs should be adequately chlorinated.
Persons who have contracted shigellosis or are suspected of having contracted
shigellosis are not allowed to work in food establishments. This also applies to the
rare cases without symptoms who shed shigella in their feces for many months after
acute infection. Return to work is possible after recovery and with three negative
stool samples 1–2 days apart. The first stool sample should be taken no earlier than
24 hours after the appearance of the formed stool or 24 hours after the end of
antibiotic therapy. In the case of prolonged excretion of pathogens, an individual
solution should be found with the health department. Contact persons must provide
evidence of a negative stool sample at the end of the incubation period.
Literature
Aragón TJ, Vugia DJ, Shallow S, et al. Case-control study of shigellosis in San Francisco: the role of sexual trans-
mission and HIV infection. Clin Infect Dis 2007, 44:327-34.
Baer JT, Vugia DJ, Reingold AL, et al. HIV infection as a risk factor for shigellosis. Emerg Infect Dis 1999; 5:820-3.
Braam JF, Bruisten SM, Hoogeland M, et al. Shigella is common in symptomatic and asymptomatic men who
have sex with men visiting a sexual health clinic in Amsterdam. Sex Transm Infect. 2022 Feb 11:sextrans-2021-
055274.
Christopher PR, David KV, John SM, Sankarapandian V. Antibiotic therapy for Shigella dysentery. Cochrane
Database Syst Rev 2010; 8:CD006784.
Daskalakis DC, Blaser MJ. Another perfect storm: Shigella, men who have sex with men, and HIV. Comment on
CID 2007, 44:327-34.
Gaudreau C, Ratnayake R, Pilon PA, Gagnon S, Roger M, Lévesque S. Ciprofloxacin-Resistant Shigella sonnei
among Men Who Have Sex with Men, Canada, 2010. Emerg Infect Dis 2011; 17:1747-50.
Hoffmann C, Sahly H, Jessen A, et al. High rates of quinolone-resistant strains of Shigella sonnei in HIV-infected
MSM. Infection 2013, 41:999-1003.
Keay R, Singh G, Abdul-Latif M, Rayment M, Nelson M. Shigella flexneri enteritis in risk-taking HIV-infected MSM.
J Infect 2014, 68:103-4.
Marcus U, Zucs P, Bremer V, et al. Shigellosis – a re-emerging sexually transmitted infection: an outbreak in men
having sex with men in Berlin. Int J STD AIDS 2004; 15:533-7.
Mohan K, Hibbert M, Rooney G, et al. What is the overlap between HIV and shigellosis epidemics in England:
further evidence of MSM transmission? Sex Transm Infect 2018, 94:67-71.
Niyogi SK. Increasing antimicrobial resistance—an emerging problem in the treatment of shigellosis. Clin
Microbiol Infect 2007; 13:1141-3.
Nüesch-Inderbinen M, Heini N, Zurfluh K, et al. Shigella Antimicrobial Drug Resistance Mechanisms, 2004–14.
Emerg Infect Dis 2016, 22:1083-5.
Zayet S, Klopfenstein T, Pierron A, et al. Shigella sonnei, an emerging multidrug-resistant sexually transmitted
pathogen in Franche-Comté, France. Emerg Microbes Infect 2021, 10:1702-1705.
HIV and sexually transmitted diseases 431

Mpox
ST E FA N E S S E R , C H R I ST I A N H O F F M A N N

The natural hosts of Mpox virus (MPXV) are various rodents. Monkeys and humans
are not required for the viral life cycle and thus are only incidental hosts. When
transmitted to humans, this zoonosis can cause pox-like symptoms. In mid-May
2022, increased cases were first described in Europe through human-to-human trans-
mission, initially in the United Kingdom, Portugal, and Spain, and shortly thereafter
in numerous other countries, with more than 85,000 cases worldwide as of January
2023 (WHO). After a sharp increase in global numbers of MPXV infections since May
2022, case numbers declined significantly from August 2022 due to intensive public
health efforts (Srivastava 2023). Only isolated cases have been reported in Europe
since mid-October 2022, with some local outbreaks in early 2023.

Affected groups
Among the 546 cases in a German MSM cohort, 256 (46.9%) were PLWH (Hoffmann
2022). Of these, most had a normal immune status with a median CD4 T-cell count
of 691/µl. Only 17% and 3% had CD4 T-cell counts of less than 500 and 350/µl,
respectively. A total of 4% were viremic at the last measurement with HIV RNA above
50 copies/mL, although only 4/10 had HIV RNA above 200 copies/mL. The second
largest affected group, with 232 (42.5%) cases, were PrEP users, and the remaining
58 cases (10.6%) were MSM without known HIV infection or PrEP. Over half of all
patients had been diagnosed with another STI recently, and one-third had been diag-
nosed concurrently with MPXV infection (Hoffmann 2022). MSM, with frequently
changing sex partners and visitors to sex parties, are particularly affected by MPXV
infections. Similar observations have been made in other cohorts worldwide (Iñigo
Martínez 2022, Tarín-Vicente 2022, Thornhill 2022). Thus, in most cases, sexual
transmission is likely involved in the current outbreak.

Clinic
Almost all those infected with MPXV suffer from skin/mucosal lesions at diagnosis
(99%), more than half have a fever, and just under half have swelling of the lymph
nodes, some painful. A few days after infection, skin lesions typically develop
synchronously, first macules and papules, then the characteristic indented vesicles
and pustules with central scabs or crusts. In the further course, erosions and ulcer-
ations, some covered with crusts or eschar, develop and may persist for more than
three weeks before the coverings fall off and spontaneous healing finally occurs (see
also picture plates). Scarring is possible, especially with ulcerations. Some lesions are
very painful; others are entirely indolent. However, besides typical smallpox, there
are lesions in which one does not expect to find MPXV. MPXV can be confused with
many other infectious diseases, especially syphilis, herpes simplex, varicella, or dell
warts, but also with non-infectious skin diseases such as erythema exsudativum
multiforme (also known as Stevens-Johnson syndrome). Thus, in suspected cases of
MPXV, appropriate differential diagnoses should be considered and diagnostically
confirmed.
By far, the majority of smallpox lesions have manifested anally or genitally. Only
12% of our own cohort had neither genital nor anal involvement (Hoffmann 2022).
Among these, cases were quite frequently found in the region of the lips or even
with isolated pharyngeal ulcers, which can be accompanied by massive lymph node
swelling and sometimes cause considerable dysphagia and pain. Only 4% were the
432 Other Infections

lesions confined to the trunk and extremities. High rates of anogenital disease
patterns have also been reported in Spain, the UK, and other countries (Thornhill
2022, Tarín-Vicente 2022, Girometti 2022). Overall, the localization of MPXV in the
2022 outbreak differs markedly from those of previous outbreaks. Previously, in
Africa, lesions were primarily localized at the face and extremities, much less genitally
and virtually none anally (Jezek 1987, Yinka-Ogunleye 2019).
In 83% of the patients in our cohort, the disease was localized with a maximum of
10 lesions. Only a few patients had 50 or more lesions. The most common general
symptoms were fever, headache, limb pain, and often painful swelling of the lymph
nodes. The duration of symptoms rarely exceeded seven days. Night sweats occurred
relatively infrequently. Extremely painful proctitis happened in some patients (15%),
and bacterial superinfections were also reported. The complications that are quite
common in Africa, such as pneumonia and involvement of the eyes or CNS, were
seen very rarely in the 2022 outbreak.
However, the spectrum of courses is broad, ranging from asymptomatic cases that
come to attention during STI screening (rare) to severe complications requiring
hospitalization. However, most illnesses to date have turned out to be relatively mild.
Unlike in previous outbreaks, where mortality ranged from 1% to 11% (Beer 2019),
less than 100 deaths have been observed worldwide. Our cohort’s hospitalization
rate was 4%, with no difference between MSM with and without HIV. However, most
patients were predominantly young, immunocompetent, and otherwise healthy.
Hospitalizations were primarily due to complications, largely massive swelling of the
lymph nodes and genitalia, extensive involvement of the entire integument, bleed-
ing, or due to refractory pain that could not be managed as an outpatient, especially
in the case of anal involvement.
Contrary to earlier reports, HIV infection per se does not appear to be a risk factor,
at least if HIV infection is treated adequately and there is no severe immunodefi-
ciency. In these situations, severe courses are undoubtedly possible (Boesecke 2022).
In a global cohort of 382 cases among PLWH with advanced immune deficiency, a
severe necrotizing form of Mpox appears to behave like an AIDS-defining condition,
with a high prevalence of fulminant dermatological and systemic manifestations
and death (Mitjà 2023). Overall, 107 (28%) of 382 cases were hospitalized, of whom
27 (25%) died. Of note, an immune reconstitution inflammatory syndrome to Mpox
was suspected in 21 (25%) of 85 people initiated or re-initiated on ART, of whom 12
(57%) the 21 died (Mitjà 2023).

Diagnostics
Diagnosing an MPXV infection is based on clinical findings and a positive PCR. In
our experience, PCR in smears of anal and genital lesions is almost always reliably
positive. However, diagnosis is also often successful from lesions located at the
extremities and trunk. In most cases, it is not necessary to open the lesions.
Sometimes, it is surprising how long the PCR remains positive. PCR from a throat
swab is also positive in about half of the cases, especially in cases of sore throat (often
reported only when asked) and especially in pharyngeal ulcers. However, Ct values
in the throat are usually significantly higher, which explains the probably very low
rate of droplet infections.
HIV and sexually transmitted diseases 433

Treatment
The focus is on preventing bacterial superinfections and symptomatic treatment,
especially local treatment (Tannosynt, zinc shake mixture) and adequate analgesia.
Drugs such as tecovirimat, cidofovir, or brincidofovir are currently unavailable in
most countries or are very limited (Hermanussen 2022, Mitjà 2023). However, they
are not needed in the vast majority of cases. More extensive studies have not demon-
strated efficacy in humans for any of these treatments.

Prevention and vaccination

In most guidelines, isolation of patients is recommended for the entire disease
duration, at least three weeks. Health departments apply the RKI recommendations
very differently in our experience. The rate of household infections is low, well below
the 8% described in a 2018 review (Beer 2018). Nevertheless, WHO reports more
than 550 MPXV cases among healthcare workers worldwide in the current outbreak,
suggesting the need for adequate protection in this population.
As there is no specific vaccine for Mpox, smallpox vaccines are used given cross-reac-
tivity in the laboratory and some encouraging results from animal studies. Laboratory
studies (Gilchuk 2016) and clinical observations (Jezek 1987, Karem 2007) suggest
that smallpox vaccination provides some, but not complete, protection against
Mpox. In the German cohort, a total of 13% were shown to have been vaccinated
against smallpox in childhood (Hoffmann 2022). The timing of smallpox vaccina-
tion was likely at least 40 years previous; compulsory vaccination ended in most
countries many years ago, mainly in the 70’s and 80’s. Preliminary data provide some
limited evidence for a milder course of disease with a history of a smallpox vacci-
nation (Hoffmann 2022).
It remains to be seen whether the smallpox vaccination campaign in sexually active
MSM (with a modified vaccinia virus Ankara) will actually provide substantial pro-
tection against severe infections and effectively prevent contagions. Breakthrough
infections are not uncommon, especially among those vaccinated only once. At least
one study suggests vaccine protection in PLWH is no worse than in HIV-negative
persons (Greenberg 2013).
In addition to the indicated vaccinations, vaccinations were recommended for
known close contacts of confirmed MPXV-infected persons and vaccinations as post-
exposure prophylaxis for asymptomatic persons up to 14 days after confirmed
contact.
However, the currently observed worldwide decline in the number of infections is
probably due less to vaccination than to the fact that MPXV is not well adapted to
humans. Transmission requires close contact (usually sex), but unlike HIV, the infec-
tivity of affected individuals is short (a few weeks, not years). In addition, MPXV
infection usually makes visible changes, and asymptomatic transmissions are rare.
Nevertheless, it seems possible that Mpox may establish itself as a new STI among
MSM.
Literature
Beer EM, Rao VB. A systematic review of the epidemiology of human monkeypox outbreaks and implications for
outbreak strategy. PLoS Negl Trop Dis 2019, 13(10):e0007791.
Boesecke C, Monin M, van Bremen K, et al. Severe monkeypox-virus infection in undiagnosed advanced HIV
infection. Infection 2022 (in press).
Gilchuk I, Gilchuk P, Sapparapu G, et al. Cross-Neutralizing and Protective Human Antibody Specificities to
Poxvirus Infections. Cell 2016, 167:684-694.e9.
Girometti N, Byrne R, Bracchi M, et al. Demographic and clinical characteristics of confirmed human monkey-
pox virus cases in individuals attending a sexual health center in London, UK: an observational analysis. Lancet
Infect Dis 2022 Jul 1:S1473-3099(22)00411-X.
434 Other Infections

Greenberg RN, Overton ET, Haas DW, et al. Safety, immunogenicity, and surrogate markers of clinical efficacy for
modified vaccinia Ankara as a smallpox vaccine in HIV-infected subjects. J Infect Dis 2013, 207:749-58.
Hermanussen L, Grewe I, Tang HT, et al. Tecovirimat therapy for severe monkeypox infection: Longitudinal assess-
ment of viral titers and clinical response pattern-A first case-series experience. J Med Virol. 2022 Sep 30.
Hoffmann C, Jessen H, Wyen C, et al. Clinical Characteristics of Monkeypox Virus Infections Among Men with
and without HIV: A Large Outbreak Cohort in Germany. HIV Medicine 2022, Sep 4.
Hoffmann C, Wolf E, Jessen H, Bickel M, Boesecke C; DAIG and DAGNAE. Is there any evidence for milder courses
of monkeypox virus infections with childhood smallpox vaccination? Infection. 2022 Sep 20.
Iñigo Martínez J, Gil Montalbán E, Jiménez Bueno S, et al. Monkeypox outbreak predominantly affecting men
who have sex with men, Madrid, Spain, 26 April to 16 June 2022. Euro Surveill 2022, 27:2200471.
Jezek Z, Szczeniowski M, Paluku KM, et al. Human monkeypox: clinical features of 282 patients. J Infect Dis 1987,
156:293-8.
Karem KL, Reynolds M, Hughes C, Braden Z, Nigam P, Crotty S, et al. Monkeypox-induced immunity and failure
of childhood smallpox vaccination to provide complete protection. Clin Vaccine Immunol 2007; 14:1318-27.
Mitjà O, Alemany A, Marks M, et al. Mpox in people with advanced HIV infection: a global case series. Lancet
2023, 401:939-949.
Srivastava S, Kumar S, Jain S, et al. The Global Monkeypox (Mpox) Outbreak: A Comprehensive Review. Vaccines
(Basel). 2023;11:1093.
Tarín-Vicente EJ, Alemany A, Agud-Dios M, et al. Clinical presentation and virological assessment of confirmed
human monkeypox virus cases in Spain: a prospective observational cohort study. Lancet 2022 Aug 8:S0140-
6736(22)01436-2.
Thornhill JP, Barkati S, Walmsley S, et al. Monkeypox Virus Infection in Humans across 16 Countries – April-June
2022. N Engl J Med. 2022 Jul 21.
435

14. Vaccinations
GEORG HÄRTER

Morbidity and mortality of some vaccine-preventable diseases can be higher in people

living with HIV (PLWH). In principle, vaccination status should be reviewed (see
chapter Checklist: The New Patient), and the standard and indicated vaccinations
should be carried out according to current recommendations (Härter 2013, Ehl 2018,
EACS 2022).
Immunologically, HIV infection leads to a loss of CD4 T-cells and a significant restric-
tion of B cell function, especially during prolonged viremia (Hu 2015). This is also
accompanied by reduced immunity to vaccinations already given. Especially in
cases of advanced immunodeficiency, it may be helpful to determine antibody titers
(Ehl 2018).

Principles of vaccination in PLWH*

• Vaccinations should be administered according to national guidelines for the
general population.
• Non-replicating vaccines (e.g., whole inactivated, polysaccharide, conjugated and
subunit vaccines, or virus-like particles) are safe in PLWH.
• Live (replicating) vaccines (e.g., MMR, VZV, yellow fever) are contraindicated in
severe immunodeficiency (CD4 T-cell count < 200/µl or < 14%).
• Vaccinations should preferably be given after HIV suppression and immune recon-
stitution, otherwise, immunogenicity is lower.
• If HIV replication is high (e.g., in acute retroviral syndrome), it is more favorable
to wait before vaccinating.
• Repeat vaccinations after immune reconstitution, if necessary, determine anti-
body levels.
• Polysaccharide vaccines should be avoided due to reduced immunogenicity.
• Rapid vaccination regimens (e.g., hepatitis B, TBE, rabies, Japanese encephalitis)
should be avoided due to possible lower vaccine response.
• In advanced immunodeficiency, the vaccination status of close contacts (partner,
family, friends) should also be checked and supplemented if necessary.
* According to EACS 2022, BHIVA 2015 Vaccination Guidelines

Practical procedures
Education: Patients must be informed about the dangers posed by the respective
disease, the extent of the protective effect, and the risks and side effects of vaccina-
tions within the setting of HIV infection.
Timing: Vaccination should preferably take place after initiation of antiretroviral
therapy, i.e., after immune reconstitution and when HIV RNA is suppressed.
Vaccination should not be given during a severe acute infection; a mild infection
without fever is not an obstacle. Live parenteral vaccines such as MMR, varicella, or
yellow fever vaccines must be applied either on the same day or at least four weeks
apart. No live vaccines, except yellow fever vaccine, should be given for three months
after immunoglobulins.
Booster versus renewed basic immunization: The latter is only necessary if no vac-
cinations are documented or remembered. A basic immunization that has been
started will also be completed at a later date (“every vaccination counts”). However,
vaccinations given in cases of clear immunodeficiency should be repeated (see above).
436 Other Infections

Vaccination risk assessment: In principle, inactivated (non-replicating) vaccines are

safe and unproblematic and can be given at any stage of HIV infection (Ehl 2018).
Live vaccines pose a risk of manifest vaccine illness, including yellow fever and
measles/mumps/rubella and varicella vaccines. Nevertheless, live vaccines are generally
not contraindicated and are feasible when CD4 T-cell counts are > 200/µl or > 14%
(EACS 2022). Transient increases in HIV RNA following vaccination have been described
after influenza vaccination but are usually not clinically relevant (Zanetti 2002).

Environmental vaccination
If immune status is poor, care should be taken to ensure that persons in the immediate
environment are vaccinated (including annual influenza vaccination). However,
there is a risk of infection with some live vaccinations, therefore:
• No oral polio vaccination or smallpox vaccination to persons who are in close
contact with PLWH with severe immune deficiency
• As the rotavirus vaccine virus is shed during the first weeks after administration of
the rotavirus vaccine, PLWH with severe immune deficiency should avoid diaper
changes in children for four weeks after rotavirus vaccination (Rubin 2014).
• They should also avoid contact with skin lesions after varicella/live-replicating
zoster vaccination; vaccine varicella can be treated prophylactically with acyclovir.

Vaccinations of HIV-positive children

Only a few variations from the recommendations apply to all children (Ehl 2018,
BHIVA 2015). The classification of immunosuppression differs in children younger
than six years from adults (Ehl 2018). In the previous CDC classification, severe
immunodeficiency was defined as a CD4 T-cell count < 15% in all children. However,
according to the newer classification, it is mainly the absolute counts that should
be considered (CDC 2014). However, the percentage threshold < 15% still applies in
many recommendations (Menson 2012).
The following procedure appears practical: live vaccinations (MMR, VZV, yellow
fever, rotavirus) are contraindicated in severe immunodeficiency. This is defined
according to CDC as follows: < 1 year: CD4 T-cell count < 750/µl (relative < 26%);
1 to < 6 years: CD4 T-cell count < 500/µl (< 22%); > 6 years: CD4 T-cell count < 200/µl
(< 14%). Above these values, live vaccination should be performed according to the
general recommendations (Ehl 2018). This explicitly includes rotavirus vaccination.
Family members of children with severe immunodeficiency should be vaccinated if
they have not already undergone the infections. Because vaccine response is reduced
and possibly shortened in children living with HIV, determining antibody levels is
recommended (Ehl 2018).

Vaccinations in detail (selected vaccinations)

Tetanus/diphtheria/pertussis/polio: After primary immunization in childhood,
booster vaccination against diphtheria and tetanus is also helpful for PLWH every
10 years. A combination vaccine with polio and/or pertussis is available. Since 2009,
a single pertussis booster has been recommended for all adults using the combina-
tion mentioned above. In addition, a vaccination against pertussis with a Tdap
combination vaccine should be given for every (!) pregnancy at the beginning of the
3rd trimester, regardless of previous vaccinations. For polio, a single booster vacci-
nation is recommended after primary immunization. In some countries, however,
an additional vaccination may be necessary (see HIV and travel).
Vaccinations 437

Pneumococcus: As there is an increased risk of invasive pneumococcal infections,

all PLWH should be vaccinated (Yin 2012, Lee 2014). Compared to pneumococcal
polysaccharide vaccines (PPSV), conjugate vaccines (PCV) provide higher and longer-
lasting protection (Nunes 2012). Most guidelines recommend a sequential use: with
no prior pneumococcal vaccination, vaccinate first with 13-valent PCV13 or PCV15
and then after 6–12 months (8 weeks at the earliest) with 23-valent PPSV23 (EACS
2022); PLWH < 200 CD4 T-cells/µl should delay the vaccination until their immu-
nity had been reconstituted with ART (Lee 2014). If available and recommended by
the national authorities, a single PCV10 can be given. If the PPSV23 vaccination was
less than six years ago, PCV13 or PCV15 is vaccinated at least 12 months apart with
a booster after six years (CDC 2012). For PPSV23 vaccination of more than six years
ago, regular sequential vaccination with PCV13 or PCV15 and PPSV23 is given.
Influenza: Given a higher risk of severe courses and increased influenza-associated
mortality for PLWH (Lin 2001), vaccination should be given annually before the start
of influenza season (Anema 2008, EACS 2022). Children under ten receive two doses
four weeks apart at the time of initial vaccination. Because influenza remains a
relevant cause of febrile respiratory illness even after vaccination (Klein 2007),
contacts in the private and medical sectors should also be vaccinated annually. As
higher immunogenicity seems achievable with adjuvanted vaccines (Durier 2013),
we believe these should be preferred, especially in PLWH with poor immune status.
Tetravalent vaccines, according to the antigen combination currently recommended
by WHO, which contain influenza A strains and the B strains of the Victoria and
Yamagata lineages, are recommended (STIKO 2022a, EACS 2022). Due to a slight
superiority of vaccine efficacy in older people, a tetravalent high-dose vaccine with
the current antigen combination recommended by WHO is now recommended for
persons over 60 in some countries (STIKO 2022a).
Hepatitis B: All PLWH with negative HBV serology should be vaccinated (Bailey
2008). However, the overall effectiveness of hepatitis B vaccination is reduced (van
den Berg 2009). Hepatitis A vaccination indications should be assessed beforehand,
as the combination vaccine may be more immunogenic (van der Wielen 2006).
Depending on current CD4 T-cells, CD4 nadir, and other factors such as viral load,
sex, and age, sufficient anti-HBs titers are achieved in only 20–70%, most likely in
those PLWH with > 350 CD4 T-cells/µl and undetectable viral load (Okwen 2014).
Multiple and/or higher doses and more effective adjuvants have been successful
(Whitaker 2012). Although an optimal vaccination strategy has not yet been clearly
defined, there is consensus regarding the following (BHIVA 2015, EACS 2022):
• If seronegative, vaccination is recommended as early as possible after HIV diag-
nosis
• Check vaccination success (anti-HBs level) 4–8 weeks after the last dose or after
vaccinations in childhood or the past.
• re-vaccination in case of missing or suboptimal vaccination success (in some coun-
tries, anti-HBs < 100, in others < 10 IU/l).
Most guidelines initially recommend the regular vaccination schedule with three
doses of 10–20 µg antigen. In the UK, a 4-dose vaccination schedule (0, 1, 2, and 6
months) is recommended (Geretti 2016). Anti-HBs should be monitored annually if
CD4 T-cell count < 350/µl and/or HIV viral load control is inadequate (Geretti 2016).
In case of non-response to standard vaccination, the following options are possible
or recommended:
• If anti-HBs titer is > 10 but < 100 IU/L, one booster vaccination (EACS 2022) with
a follow-up antibody level check.
• If the anti-HBs titer is < 10 IU/l, repeat the vaccination cycle with 3–4 applications
438 Other Infections

at months 0, 1, (2), and 6 (EACS 2022). Double-dose or the high dose vaccine
(HBVaxPro 40 µg) shows response rates of 80–90% (Launay 2011+2016) and could
be considered.
• The first vaccination cycle with 4 doses of an ASO4C-adjuvanted vaccine (Fendrix®)
could also be considered. PLWH with prior non-response showed an excellent
vaccine response at 95% and 82%, a highly protective response with anti-HBs
> 100 IU/L (de Silva 2014).
• Another possibility is a vaccination cycle with three applications (0, 1, and 6
months) with the combination vaccine (Twinrix®) in a double-dose; vaccination
response is 95% (Cardell 2008).
Individuals who still do not show an adequate vaccine response should be serolog-
ically tested for HBV annually and receive TDF- or TAF-based ART, as it is protective
regarding HBV (EACS 2022).
There are now two other vaccines that show improved response in the elderly and those
with underlying chronic diseases compared to the standard vaccine (Engerix B®):
1. The adjuvanted recombinant vaccine Heplisav-B® (EU approval in 2021) is given
only twice for primary immunization at months 0 and 1 (Jackson 2018).
2. PreHevbri® is a recombinant vaccine with the three antigens S, pre-S1, and pre-S2
HBsAg (Vesikari 2021), now licensed in Europe. Although published data in PLWH
are still lacking for both vaccines, they are attractive candidates, especially for
non-responders.
The management of “isolated” anti-HBc detection (negative HBs antigen, anti-HBs
< 10 IU/l), a frequent serological constellation in HIV infection (14–44%), is con-
troversial. The reasons could be either false positive results or loss of anti-HBs after
infection or occult hepatitis B (positive HBV DNA with negative HBs antigen). Success
rates in PLWH with three vaccinations were 40% (Chakvetadze 2010) and 52% (Piroth
2016), respectively, vs. 24% after one vaccination (Morsica 2017). Three vaccinations
can increase the response. However, vaccination is not generally recommended for
the constellation of isolated anti-HBc (EACS 2022).
Hepatitis A has an increased incidence among PLWH (Fonquernie 2001). In recent
years, outbreaks have occurred among MSM in major European cities (Werber 2017).
Vaccination status or serostatus should be checked in MSM; vaccination is recom-
mended in specific populations at risk (travelers, MSM, IVDU, hepatitis B or C co-
infection, chronic liver disease, and close contact with children) (EACS 2022). A
monovalent vaccine is usually recommended. Due to the frequent lack of response,
especially in those with poor immune status, the following dose intervals are rec-
ommended: three doses at months 0, 1, and 6 for CD4 T-cell counts < 350/µl; or two
doses at months 0 and 6–12 for CD4 T-cell counts > 350/µl (Tseng 2013, Ehl 2018).
Combination vaccination with hepatitis B is less effective than mono-vaccine when
CD4 T-cells are low and viremia is present (Jimenez 2013). Success should be mon-
itored: antibody levels > 20 mIU/mL are considered protective (Ehl 2018); below
that, a booster with the monovalent vaccine is recommended.
Measles: Because measles is often severe (Kaplan 1992), all PLWH without a history
of vaccination or infection should be vaccinated twice, at least one month apart, if
possible. Vaccination protection should also be considered when traveling abroad
(see HIV and Travel). Vaccination is possible from CD4 T-cells > 200/µl (> 14%)
(different cut-offs in children) with absent or only mild clinical HIV symptoms.
Primarily, the MMR combination vaccine is used (live vaccine!). Depending on the
risk, post-exposure immunoglobulins are indicated in some situations (STIKO 2022a).
Human papillomavirus (HPV): Vaccination is now one of the standard vaccina-
tions for female and male adolescents aged 9–17 years. However, this recommenda-
Vaccinations 439

tion does not consider sexually active people aged >17 or high-risk groups (especially
MSM). In the United States, vaccination is recommended for all adolescents/adults
up to age 26 (Kim 2017). EACS recommends vaccination for all PLWH up to age 45
(EACS 2022). A study in MSM showed a significant decrease in intraepithelial neo-
plasia (AIN) for the quadrivalent vaccine, potentially reducing the incidence of anal
carcinoma (Palefsky 2011+2017). Due to the lack of recommendations in some coun-
tries, in PLWH or persons at increased risk (e.g., MSM), vaccination can only be per-
formed after application to the health insurance company or as a pay-as-you-go
service. The 9-valent vaccine is preferred.
Varicella/herpes zoster: Similar to measles, varicella may be life-threatening in
PLWH (Perronne 1990). Individuals without a history of varicella or zoster should
be serologically screened and vaccinated if CD4 T-cells are above 200/µl (Geretti
2016, Rubin 2014). Vaccine complications can be treated with acyclovir. Vaccine
viruses can reactivate as zoster, but this occurs less frequently than with wild virus.
Herpes zoster, a complication after chickenpox infection, occurs much more fre-
quently in PLWH than in uninfected persons (Jansen 2013). The adjuvanted inacti-
vated vaccine (Shingrix®) is recommended for all persons >60 years of age and persons
with immunosuppression, including PLWH, >50 years of age. Immunogenicity and
tolerability have been shown in PLWH (Berkowitz 2015).
Meningococci: The risk of invasive meningococcal infections increases in PLWH
(Miller 2014, Cohen 2011). In some countries, the 4-valent conjugate vaccine
(ACWY) (usually one vaccination, two at two-month intervals if CD4 T-cell count
< 200/µl) and meningococcal B vaccine (2–3 doses according to vaccine manufacturer)
are recommended for persons with immunodeficiency (Ehl 2018). Because clusters
of severe infections have occurred among MSM in several major cities, vaccination
may also be considered for high-risk HIV-negative individuals, e.g., gay events like
parades (Simon 2013). Meanwhile, there is also evidence that meningococcal B
vaccination provides some protection against Neisseria gonorrhoeae (Wang 2022),
which may become interesting in PrEP counseling. Notably, only the 4CMenB vaccine
(Bexsero®) leads to potential cross-protection against gonorrhea (Ruiz Garcia 2021).
Meningococcal vaccination is essential in travel medicine (see HIV and travel).
COVID-19: Vaccines against SARS-CoV-2 have a good protective effect against severe
COVID-19 or death. There are currently eight vaccines licensed in the EU (as of July
2023):
• two mRNA vaccines (BioNTech/Pfizer’s Comirnaty® and Moderna’s Spikevax®),
• two vector-based vaccines (AstraZeneca’s Vaxzevria® and Janssen-Cilag’s Jcovden®
(previously COVID-19 Vaccine Janssen)),
• an inactivated, adjuvanted protein vaccine from Novavax (Nuvaxovid®),
• a recombinant, adjuvanted protein vaccine (VidPrevtyn Beta®),
• a recombinant, adjuvanted protein vaccine (Bimervax®) and
• an inactivated, adjuvanted whole-virus-containing vaccine (Valneva®).
Please refer to updated national recommendations and manufacturer information
for individual approvals and dosing intervals. In PLWH with suppressed viral load
and CD4 T-cell counts > 500/µl, vaccination response, humoral immune response,
and tolerability are comparable to the general population (Levy 2021, Brumme 2022,
Hensley 2022). In case of significant immunosuppression (CD4 T-cell count < 200/µl),
(multiple) booster vaccinations may be necessary (EACS 2022).
Respiratory Syncytial Virus (RSV): RSV infections substantially cause severe respi-
ratory illness, especially in older adults. In May 2023, the FDA approved the first
vaccines to prevent RSV-associated lower respiratory tract disease in adults aged
440 Other Infections

≥ 60 years. RSV vaccines have demonstrated moderate to high efficacy in prevent-

ing RSV-associated respiratory illness and potentially lower morbidity and mortality
among older adults. RSV vaccines should be administered once, preferentially given
before the seasonal peak of RSV infections (Melger 2023). Data concerning PLWH
are lacking. For older PLWH, it seems advisable to follow national guidelines.
Mpox: PLWH represented about 38–50% of the 2022 global Mpox outbreak cases.
Severe complications and deaths were more common, especially in individuals with
a CD4 T-cell count of < 100/µl. The mortality was around 14% in persons with CD4
counts < 200/µL and nearly 30% in those with CD4 counts < 100/µl (Orkin 2023).
Smallpox vaccines are considered to be effective in providing protection against
Mpox. The modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine
(Imvamune®, Imvanex® or Jynneos®) is a live, non-replicating, modified vaccinia
vaccine that is approved for use in Europe. Its use in PLWH is safe, although vaccine
response in those with uncontrolled viremia or CD4 < 100 has not been established.
Two vaccinations at least four weeks apart are recommended. Usually, one vaccina-
tion is sufficient for those vaccinated against smallpox in the past. PLWH should
receive two booster vaccinations according to the EMA product information for
Imvanex. According to the author, this applies especially to those with CD4 T-cell
counts < 200/µL. Although there is some evidence that the MVA-BN vaccination
induces only low levels of MPXV-neutralizing antibodies in healthy adults, the
correlation of these for the protection of disease remains unclear (Zaeck 2023). Case-
control studies revealed an adjusted vaccine efficacy (VE) against Mpox of 75.2% for
partial and 85.9% for complete vaccination (Dalton 2023). Additionally, another
large case-control study showed an estimated adjusted vaccine effectiveness of 66%
for two doses and 35% for one amount, respectively (Deputy 2023). As these results
suggest better protection of the two-dose vaccination route, some experts recom-
mend the two-vaccine route, irrespective of former vaccinations against smallpox,
in all PLWH at risk for Mpox. The following tables provide an overview of the current
recommendations.

Table 1: Special features and rationale for selected infections (adapted from EACS 2022). For explana-
tions, see the text.
Infection Vaccination rationale/recommendation
Influenza More frequent occurrence of pneumonia. It is explicitly recommended for all
PLWH.
Hepatitis A Indication vaccination (travel, MSM, IVD, active hepatitis B or C infection)
Hepatitis B Infection risk and pathways as for HIV. HIV accelerates the progression of liver
disease–generally, all HBV-seronegative PLWH.
Pneumococcus More common invasive disease with severe course. It is recommended for all
PLWH.
Meningococci Increased incidence. All PLWH (MenACWY and B).
Herpes zoster/ Incidence and severe courses are more common with both chickenpox and
VZV herpes zoster. HZV vaccination is recommended from age 50.
HPV Transmission routes similar to HIV. The incidence of cervical and anal carcinoma
are increased.
Hemophilus No longer generally recommended. Increased incidence only within the
influenzae type b pre-HAART era
Vaccinations 441

Table 2: Standard, indicated, and travel vaccinations (adapted from Härter 2016, EACS 2022).
See also texts and specialized information.
Vaccination Vaccination schedule Booster vaccination
against
Standard vaccinations
Tetanus/ Adults: Next Td vaccination once as Tdap Every ten years
diphtheria combination vaccination
Pertussis Next Td vaccination, once as a Tdap None, only for, e.g., women
combination vaccination of childbearing age, health
care workers every 10 years.
Pregnant women at every
pregnancy (beginning of the
3rd trimester)!
Polio Primary immunization according to national Once after basic
guidelines immunization
Measles/Mumps/ 2 vaccinations for those born after 1970, None
Rubella* minimum interval 4 weeks
Varicella* 2 doses at intervals of 6–8 weeks None
Rotavirus Recommended for infants None
Indication vaccinations are recommended for all PLWH
Hepatitis A 0 and 6–12 months, 0, 1 and 6 months, After > 25 years
respectively
Hepatitis B 0, 1, and 6 months, or rapid immunization Every 10 years or none
days 0/7/21 and 12 months)
Herpes zoster 2 vaccinations at an interval of 2–6 months Unclear
(age > 50 years)
Influenza Annually Annually
Meningococcal Once or twice in PLWH (interval > 2 months) After 5 years?
(ACW135Y), tetra-
valent conjugate
vaccine
Meningococcal 2–3 vaccinations (according to age and Unclear
group B manufacturer, see technical information)
Pneumococcus Sequentially with PCV13, PCV15, or PCV20, Every 5 years
followed by PPSV23 after 6–12 months
(only after PCV132 and PCV15)
SARS-CoV-2/ At least 3 vaccinations, preferably mRNA vaccine Annually?
COVID-19
Indication or travel vaccinations, which may be indicated according to risk
Cholera 2 vaccinations at intervals of > 1 week to Every 2 years
< 6 weeks
TBE 2 vaccinations at 1–3 month intervals and Every 3–5 years
1 vaccination after 5–12 months or rapid
immunization
442 Other Infections

Table 2: Continuation
Vaccination Vaccination schedule Booster vaccination
against
Human 2 or 3 vaccinations at 6 month intervals None
papillomaviruses (0, 1, and 6 months).
Japanese 2 vaccinations before departure (days 0/28) In case of renewed stay in an
encephalitis or rapid immunization (0 and 7), endemic area 12 months
preferably combined with rabies vaccination after primary immunization
Rabies 1 vaccination each on days 0/7/28 or 0/7/21 After 1 year (rabies vaccine
or rapid immunization (0/3/7), preferably in HDC) or 2–5 years (Rabipur®).
combination with Japanese encephalitis. After risk contact and
Alternatively, the WHO schedule with successful primary
2 vaccinations (0 and min. 7 days) immunization: 2 further
Post-exposure: active and passive according to active vaccinations (days 0/3)
exposure level and national recommendations.
Typhoid (i.m.) Once After 3 years
Typhoid (oral)* 1 capsule on days 1/3/5 3 years
Yellow fever* Once For PLWH, every 10 years
Mpox 2 vaccinations at intervals of > 4 weeks Unclear
Dengue Fever 2 vaccinations at intervals of 3 months Unclear
Respiratory Once Unclear
syncytial virus
*NOTE: Live vaccines are contraindicated in people with CD4 T-cells < 200/μl (14%).

Links
• Advisory Committee on Immunization Practices (ACIP): list of available recommendations at [Link]/
vaccines/hcp/acip-recs/[Link].
• Departmerntt of Health (UK). Immunisation Against Infectious Disease – “The Green Book”: [Link]/gov-
ernment/publications/green-book-the-complete-current-edition
• British HIV Association (for HIV patients and others): [Link]
• WHO: [Link]/immunization/en

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445

15. HIV and travel medicine

GEORG HÄRTER

People living with HIV (PLWH) are keen to travel. According to one Danish study,
about half of them took trips outside Europe; of these, only 38% received travel
medicine advice before the trip (Nielsen 2014). About 20% experienced health
problems during or after the trip. Other studies also found an increased risk of travel-
associated infections, especially gastrointestinal infections (Salit 2005, Aung 2015).
People with migrant backgrounds who visit their countries of origin, so-called
“visiting friends and relatives” (VFR), are particularly at risk. They are often over-
represented among PLWH (Sherrarf 2009, Schwartz 2015). Therefore, comprehen-
sive travel medicine advice on vaccinations and prophylaxis (especially malaria) is
essential. With a CD4 T-cell count < 200/µl and/or AIDS, the risk of severe infections
is significantly increased and reduces the response to vaccination. It is recommended
to postpone the trip until immune reconstitution (stable CD4 T-cell count > 200/µl).
Planning should begin at least 6 to 8 weeks before departure. For tropical travel,
travel medicine experts should be consulted. Current recommendations are provided
by various websites (see links at end of chapter). Long-term travelers should
familiarize themselves with the medical care available in the destination country.
ART should also be taken continuously during travel. It is essential to have sufficient
antiretroviral medication to allow for a possible delayed return. Time differences
should also be considered. Sometimes, there may be difficulties in carrying drugs to
a destination. Medical certificates in English may help.

First-aid kit, other preventive measures

In addition to ART, further medication should also be considered. Sunscreen, plasters
and bandages, wound disinfection, fever thermometer, and, if necessary, tick forceps
are essential items in a first-aid kit. Medication that contains aspirin as an analgesic
should be avoided, as it can increase the risk of bleeding in infections that cause
thrombocytopenia, especially malaria and dengue fever. Preferred analgesics include
acetaminophen, novaminsulfone, ibuprofen, or diclofenac. Anti-diarrheal agents
(see section on travel diarrhea), antiemetics, antihistamines, and ointments against
insect bites should also be included. Condoms are also recommended; according to
one study, PLWH have only about 50% “safer sex” when traveling (Salit 2005) (see
Sexually Transmitted Infections).
Thrombosis prophylaxis should also be discussed. This includes sufficient fluid intake
(no alcohol!), exercise, and, if necessary, wearing compression stockings. Travelers
with one or more risk factors for venous thromboembolism should consider gradu-
ated compression stockings and/or LMWH for flights longer than 6 hours.

Vaccinations
As part of a travel medical consultation, the vaccination status with regard to the
recommended standard and indicated vaccinations should be checked and, if
necessary, refreshed. It should be noted that influenza infections occur in the south-
ern hemisphere mainly from April to September and in the tropics throughout the
year. The indication for additional vaccinations depends on the destination,
duration, and type of travel, but should be more generous than for healthy
individuals (Chadwick 2007). Often, consultation with a tropical medical institution
is advisable.
446 Other Infections

Yellow fever: The vaccination must be documented in an international (yellow) vac-

cination certificate (“International certificates of vaccinations and vaccination
book”) or a corresponding certificate in authorized vaccination centers. A potent
vaccine (Stamaril®), based on the attenuated 17D vaccine virus strain, is a live chicken
egg protein-based vaccine. WHO assumes lifelong vaccine protection after a single
vaccination (WHO 2013). The following WHO wording is recommended in the vac-
cination card: “valid for life if the person is vaccinated”. However, this has not yet
been implemented in the entry regulations of all countries. In case of doubt, the
current recommendations should be checked on the WHO homepage (WHO 2021).
It is unclear whether lifelong immunity applies to PLWH (Gotuzzo 2013). German
authorities recommend a booster for PLWH with appropriate indications, usually
after ten years (STIKO 2022). Immunosuppression is formally a contraindication to
live vaccination. People with < 200 CD4 T-cells/µl (< 14%) should not be vaccinated;
above that, an increased adverse event rate is not expected (Barte 2014). In addition
to good immune status, viremia is critical. With undetectable or low replication, the
response is usually good (Pacanowski 2012), and vaccination is recommended only
after ART initiation with stable HIV suppression. Another limitation of yellow fever
vaccination is an age > 60 years, as an increased rate of side effects, including
neurotropic and viscerotropic side effects, has been observed. If vaccination is not
possible for medical reasons, an exemption certificate should be issued (“cannot be
vaccinated against yellow fever for medical reasons”).
Hepatitis A: Vaccination is not only very relevant when traveling to tropical coun-
tries but also when traveling to the Mediterranean or Eastern Europe (Nothdurft
2007). It has a rapid uptake, and the protective effect occurs after about 10–14 days,
while the incubation period of hepatitis A is relatively long (15–50 days). Passive
immunization with immunoglobulins is only indicated in exceptional cases. The
duration of protection after a single vaccination is 6–12 months, then the booster
> 25 years. Combination vaccines with hepatitis B and typhoid fever are available
(see Table 2).
Rabies: There are several vaccines licensed in Europe, but the regimens differ slightly
(see Table 2, chapter Vaccinations). Neutralizing antibodies persist for longer than ten
years after primary immunization. Therefore, WHO no longer recommends routine
boosters for travelers. Studies have also shown that a shortened vaccination sched-
ule (0, 3, and 7 days) provides good vaccine protection, at least in the short term;
however, it should be boostered before traveling again with potential rabies exposure
after one year (Cramer 2016). However, data on the shortened vaccination schedule
in PLWH are lacking. Another option is the so-called “WHO schedule” with only
two doses (days 0 and 7), but explicitly only in people without immunosuppression.
The author believes that the shortened “WHO regimen” and “rapid vaccination
regimen” should not be preferred in PLWH because of the lack of data. As an
alternative to pre-exposure immunization, post-exposure immunization can be
performed, but it is not always available everywhere, especially in rural areas. Post-
exposure prophylaxis must also be given after previous prophylactic vaccination,
but only two active immunizations and no passive immunizations are necessary.
Typhoid fever: is endemic, especially in countries with poor hygiene and sanitary
conditions. Especially on the Indian subcontinent and in Southeast Asia, the risk of
infection with Salmonella typhi is increased. Various vaccines are available in Europe:
the parenteral polysaccharide vaccine Typhim® or Typherix® and the oral live atten-
uated vaccine Typhoral®. For the latter, mucosal immunity is also elicited so that a
limited protective effect for Salmonella paratyphi A+B is also postulated. Live vaccines
are contraindicated with a CD4 T-cell count < 200/µl (< 14%), and a 4-week inter-
HIV and travel medicine 447

val should be maintained between them and other live vaccines (e.g., yellow fever).
The overall protective efficacy for both vaccines is limited (a 3-year protection rate
of approximately 55% for Typhim® 2-year protection rate for Typhoral® about 58%)
(Anwar 2014).
Japanese encephalitis: This arthropod-borne flavivirus infection is endemic in large
parts of Asia, especially Southeast and East Asia. It is usually asymptomatic or with
flu-like courses but rarely with severe neurological symptoms. The risk of infection
is increased, especially in rural areas and during the rainy season, but is generally
low in the usual tourist destinations. Vaccination (Ixiaro®) is recommended, espe-
cially for long-term stays in rural endemic areas (> 1 month). Risk factors are age
> 50 years, diabetes mellitus, arterial hypertension, immunodeficiency (!), chronic
kidney disease, and homozygosity for CCR5 Δ32. Rapid immunization (0 and 7 days)
has been shown to have a protective effect, as it has for rabies (Cramer 2016), but
data are lacking in PLWH. The conventional vaccination schedule should be
preferred.
TBE: Tick-borne encephalitis (TBE) is caused by flaviviruses. Transmission usually
occurs via tick bites. There are three subtypes: a European (FSME), a Siberian (RSSE),
and a Far Eastern subtype. Therefore, vaccination is recommended for risk areas in
Europe and for stays with tick exposure (e.g., outdoor activities) in Eastern Europe
and Central Asia. Two vaccines with slightly different vaccination schedules are avail-
able in Europe (following manufacturer’s instructions). The primary immunization
(3 vaccinations) should always be carried out with the same vaccine; booster
vaccinations can also be carried out with an alternative preparation.
Cholera: Two vaccines (Dukoral® and Vaxchora®) are available in Europe. They are
well-tolerated, oral inactivated vaccines. Vaccination is generally recommended for
travel to areas with current outbreaks. A certificate is required in some cases for entry
into certain countries. The induced antitoxic mucosal antibodies in the gut also
partially protect against enterotoxic E. coli (ETEC), a common pathogen of traveler’s
diarrhea. However, a meta-analysis failed to demonstrate a sufficient protective effect
against ETEC-related traveler’s diarrhea (Ahmed 2013). Vaccination must be weighed
on an individual basis.
Meningococci: Outbreaks occur mainly in the dry season (January to May) in the
so-called “meningitis belt” in Africa. Knowledge of the worldwide distribution of
different serotypes is vital for vaccination recommendations: in Africa, predomi-
nantly serotypes are A, less frequently C, X, W-135. In Europe, North America,
Australia, and New Zealand, B and C predominate (Harrison 2009). In travel medi-
cine, the tetravalent conjugate vaccine against A, C, W-135, and Y (Nimenrix® or
Menveo®) should always be used; the polysaccharide vaccines should be avoided.
Vaccination is recommended for travel to the “meningitis belt”, to countries with
recent outbreaks, and for close contact with the local population, e.g., medical
personnel and development workers. Vaccination against A, C, W-135, and Y is
mandatory for pilgrims to Mecca. Vaccination against meningococcal B (Bexsero® or
Trumenba®) may be helpful for travel to European countries, North America, and
New Zealand.
Polio: The national authorities usually recommend primary immunization and a
single booster. However, when traveling to different countries, a booster vaccination
may be necessary for individual protection and to prevent the export of circulating
virus strains. Poliovirus transmission is predominantly fecal-oral. Of the original
circulating wild polioviruses (WPV), only WPV-1 still exists. WPV-1 is endemic in
Afghanistan and Pakistan, as well as in Malawi. In addition to WPV-1, mutant
vaccine-derived polioviruses (cVDPV) circulate in many countries, for example, an
448 Other Infections

outbreak of cVDPV-2 in Nigeria with a spread in neighboring countries. WHO updates

the list of countries with special requirements every quarter (WHO 2022). The
following table summarizes the recommendations (WHO 2022).

Table 1: Country-specific recommendations for polio.

Indication Countries Vaccination recommendation
WPV1-endemic Afghanistan, Malawi, Pakistan A detection requirement exists for
cVDPV1-3 cVDPV-1: Yemen, Madagascar WP1 cVDPV-1 and cVDPV-3 in
cVDPV-3: Israel, Palestine endemic countries.
cVDPV-2: Afghanistan, Benin, •Stay ≤ 4 weeks: booster vaccination
Burkina Faso, Cameroon, Central if the last vaccination was over ten
African Republic, Chad, Djibouti, years ago
D.R. Congo, Egypt, Ethiopia, Gambia, •Stay > 4 weeks: Vaccination should
Guinea, Guinea-Bissau, Iran, Liberia, be only four weeks to 12 months
Madagascar, Mauritania, ago when leaving the affected
Mozambique, Niger, Nigeria, country
Pakistan, Rep. Congo, Senegal,
Sierra Leone, Somalia, South Sudan,
Tajikistan, Uganda, Ukraine, Yemen
Vulnerable, Algeria, Bosnia-Herzegovina, Booster vaccination if the last
politically unstable, Burundi, China, Côte d'Ivoire, vaccination was more than 10 years
or surveillance not Gabon, Ghana, Haiti, Indonesia, ago
secured Iraq, Kenya, Kiribati, Comoros, Laos,
Libya, Malaysia, Mali, Myanmar,
East Timor, Papua New Guinea,
Philippines, Romania, Sudan, Syria,
Togo, Vanuatu, Venezuela
Other Saudi Arabia Vaccination is compulsory for entry
from risk regions. The vaccination
must be 4 weeks to 12 months ago

The vaccination should be documented in the vaccination certificate as an interna-

tional certificate (analogous to yellow fever). Polio booster shots – also in the context
of travel medicine – are considered indicated vaccinations and can, therefore, be
carried out at the expense of statutory health insurance.
Influenza: is often forgotten in travel medicine. Possibly, influenza vaccination is
the most essential travel vaccination. The seasonal activity in the southern hemi-
sphere in the northern summer months should be considered! Therefore, an updated
vaccine should also be ordered and vaccinated for travelers to the southern hemi-
sphere via the international pharmacy.
COVID-19: Since the beginning of the COVID-19 pandemic, international travel has
played an essential role in the spread and infection of SARS-CoV-2. Completing
vaccination protection according to the current national recommendations is
strongly recommended (see Vaccinations). The entry restrictions, approved vaccines,
and vaccination schedules valid in the destination country should be checked on
the website of the National Foreign Offices. Vaccines approved in the EU are recog-
nized in all countries with few exceptions.
Ebola: There are now two vector virus vaccines against the Zaire ebola variant. These
are relevant for medical personnel in an outbreak area mission; vaccination does not
affect tourist travel.
HIV and travel medicine 449

Mpox: Smallpox vaccines are considered effective in protecting against Mpox. Two
vaccinations with the modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine
(Imvamune®, Imvanex® or Jynneos®) should be recommended to PLWH, especially
if traveling abroad to Gay Pride events (see Vaccinations for more details).
Dengue Fever: Dengue is a mosquito-borne viral infection that is common in
(sub-)tropical countries. Dengue outbreaks tend to have seasonal patterns, with trans-
mission often peaking during and after rainy seasons. Since the beginning of 2023,
dengue outbreaks have been recorded in the WHO Region of the Americas, with the
highest number of dengue cases in Brazil, Peru, and Bolivia. In the past, about 70%
of cases occurred in Asia, especially in Southeast Asia. Due to global warming, dengue
spreads to new areas, including Europe (WHO 2023).
Available vaccines: The first approved vaccine was a live-attenuated, quadrivalent
vaccine (Dengvaxia®). Due to several severe dengue cases after wild-type virus infec-
tion following the vaccination (Halstead B 2017), it is now licensed only in indi-
viduals 6 to 45 years of age with test-confirmed previous dengue infection. The
vaccine is not licensed and not recommended for regular travelers to endemic coun-
tries. Since the end of 2022, another live-attenuated, tetravalent vaccine has been
approved in the EU (Qdenga®). Studies showed a summarized vaccine efficacy against
dengue fever of 61.2% and against hospitalization due to severe dengue of 84.1%
(Biswal 2019, Bsiwal 2020, Lopez-Medina 2022, Rivera 2022). Subgroup analysis
revealed an insufficient efficacy against specific subtypes such as DENV-3 and -4
(Rivera 2022). In contrast to Dengvaxia®, there are no signals for severe infections
after the vaccination in seronegative individuals. Therefore, a pre-vaccination test is
not necessary. In approximately 50% of the vaccinated seronegative individuals, a
transient viremia can be seen, followed by mild symptoms with headache, chills,
and exanthema in some individuals (Tricou 2020). The vaccination schedule is two
vaccinations with a time interval of 3 months. Early counseling and vaccination
should be considered. There is evidence of (short-term?) vaccine efficacy of 81% after
the first vaccination (Biswal 2020). It should be regarded as a live vaccine; therefore,
PLWH with CD4 T-cell counts < 200/µl (< 14%) should not be vaccinated. A general
recommendation of Qdenga® at this juncture is difficult. The following persons seem
to profit from vaccination before traveling to dengue-endemic areas:
• Long-term or frequent travelers, e.g. professional ex-patriates
• Visiting friends and relatives from dengue-endemic areas for longer stays
• People who have already had a dengue virus infection
• People with a high risk for severe infections, e.g. older people, obese people, people
with coagulation disorders, or severe chronic illness.
• Women of child-bearing potential planning a pregnancy in an endemic area.
Noteworthy, due to the live-attenuated vaccine formulation, Qdenga® is contra-
indicated in pregnancy. Additionally, pregnancy should be avoided for at least four
weeks after the last vaccination.

Entry requirements and health insurance

In some countries, there are, unfortunately, still entry restrictions for PLWH,
especially for longer stays for work or study. To avoid problems, those affected should
know the entry regulations of the destination country. An overview is provided by
a database ([Link]). Travel insurance policies almost always exclude pre-
existing conditions and often explicitly reject PLWH. However, travel insurance
policies abroad include pre-existing HIV infection (e.g., World First).
450 Other Infections

Specific risks
Travel diarrhea
Enteric infections are the most common imported infections after long-distance
travel (Steffen 2015, Schlagenhauf 2015). About 10–40% of travelers have diarrhea
during a two-week stay. PLWH are at increased risk for diarrhea and pathogens such
as Cryptosporidia, Isospora belli, and Giardia lamblia (Steffen 2015). The risk varies
regionally: it is highest in Africa, the Indian subcontinent, Southeast Asia, and South
America. The most common pathogens are bacteria; however, lambliasis (Giardia
lamblia) is increasing in incidence and is often a relevant problem. The most common
bacterial pathogens worldwide are Campylobacter, Salmonella (non-typhi), and Shigella
(Schlagenhauf 2015). It should be noted that Campylobacter species are becoming
increasingly resistant to quinolones (up to 90%!), especially on the Indian
subcontinent and in Southeast Asia (Ricotta 2014). In addition, the selection of
extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae with the use
of antibiotics for traveler’s diarrhea is an increasing problem. In particular, the com-
bination of loperamide and antibiotics showed evidence of ESBL in 71% of travel-
ers’ diarrhea patients in one study (Kantele 2016). In Europe, there have also been
several outbreaks of enteritis in MSM with the detection of highly resistant strains
of Shigella (ECDC 2022).
The standard recommendation, “Boil it, cook it, peel it, or forget it” makes sense,
but studies have not proven the effectiveness. Additionally, in tropical countries,
avoid ice cubes in bars or restaurants, as they can be contaminated. The benefit of
prophylactic intake of probiotics is not proven. The prophylactic use of antibiotics,
especially quinolones, is not recommended due to resistance. However, the non-
absorbable antibiotic rifaximin can undoubtedly reduce the incidence of traveler’s
diarrhea, although there is no protection against invasive bacterial pathogens (Steffen
2015).
In addition to oral rehydration, preparations containing tannin albuminate and
ethacridine lactate (Tannacomp®) are suitable for self-therapy in short, mild courses.
Motility inhibitors (loperamide) may also be used temporarily, but prolonged use
should be discouraged. Antibiotic self-therapy should be used in moderate or more
severe courses with systemic symptoms (fever and/or bloody diarrhea). Due to the
increasing quinolone resistance, especially in Campylobacter species, azithromycin is
a good choice; relevant resistance is rare (Steffen 2015, Tribble 2007).

Malaria prophylaxis
Malaria occurs in tropical and subtropical regions of Africa, South America, Central
America, and Asia. The vector mosquitoes are females of the Anopheles species. The
most common forms are malaria tropica and malaria tertiana. The latter is essential
to consider because late relapses can also occur in malaria tertiana due to forms of
the pathogen that can persist in the liver (hypnozoites) for up to 1 year. PLWH are
at increased risk for malaria and complicated cases. On the other hand, malaria can
adversely affect the course of HIV infection (Flateau 2011, van Geertruden 2014).
Therefore, counseling on malaria prophylaxis is essential. The basis for this is
exposure prophylaxis with consistent mosquito protection. This can reduce the risk
by up to 90%. In addition, other arthropod-borne infections are also prevented, e.g.,
dengue fever, chikungunya, Zika virus, or tick-borne diseases. Exposure prophylaxis
includes consistently using repellents on uncovered skin areas during the day and
at night. Preferred repellents are those with DEET or icaridin as the active ingredi-
ent. In addition, skin-covering, light-colored clothing should be worn during the
HIV and travel medicine 451

twilight hours. Other essential measures are sleeping under mosquito nets (prefer-
ably impregnated) and/or sleeping in rooms with air conditioning. Due to wide-
spread resistance to chloroquine and sulfadoxine/pyrimethamine, prophylaxis with
atovaquone/proguanil or doxycycline is additionally recommended in high-risk
areas. Mefloquine can only be recommended to a limited extent and for specific indi-
cations (e.g., long-term stays, pregnant women, children) due to neuropsychiatric
side effects. However, chemoprophylaxis does not fully protect against malaria.
Therefore, malaria should always be ruled out in cases of fever after a tropical stay.
In some areas with low or moderate malaria risk, emergency self-treatment
(“standby”) is recommended as an alternative. Consider relevant interactions with
antiretroviral agents (see [Link]). Doxycycline has the lowest
potential (Abgrall 2013), but phototoxicity may be problematic.
Visiting friends and relatives (VFRs) are an essential group in malaria consultation.
These have frequently experienced malaria episodes in their country of origin in
decreasing disease intensity and are often negligent with chemoprophylaxis.
However, acquired partial immunity to malaria is lost with stays of more than six
months outside the endemic areas.

Respiratory infections, TB
Respiratory infections are among the most common health problems after travel
(Schlagenhauf 2015). Therefore, sufficient vaccination protection against pneumo-
coccus and influenza (seasonal activity in the southern hemisphere in the northern
summer months!) should always be ensured.
The risk of tuberculosis is significantly higher in almost all (sub-) tropical countries.
An interferon assay (IGRA) is helpful before and after longer trips (Rieder 2001,
Bhadelia 2007). People with reactive tests (or after known high-risk exposure) should
be treated like latent tuberculosis if necessary (see TB). High-risk areas such as
hospitals, prisons, or homeless shelters should be avoided, or appropriate masks
should be worn.

Measles
According to WHO, more than 20 million cases and about 600,000 deaths world-
wide in 2002. Measles occurs more frequently and is more severe in PLWH, and the
virus is shed for longer, a particular problem in Africa (Moss 2006). Studies from the
US showed a high mortality rate, mainly due to giant cell pneumonitis (Kaplan 1996).
For non-immune PLWH, active or passive immunization is recommended before
traveling to areas with an increased risk of measles (see Vaccinations).

Leishmaniasis
Visceral leishmaniasis (kala azar) is a feared opportunistic disease because of its life-
threatening course, often delayed diagnosis, and limited treatment options (see OI).
In northern Europe, most cases are imported from Mediterranean countries, espe-
cially during long journeys. PLWH have a higher risk of infection (Weitzel 2005),
especially with CD4 T-cells below 200/µl (Kaplan 1996). Infection may be latent and
not manifest until many years after exposure. Particularly in cases of poor immune
status, the risk in Mediterranean countries should be underlined. To avoid it,
mosquito protection measures should be followed (see above); because of the small
size of the vectors, a fine-mesh mosquito net with impregnation is advisable.
452 Other Infections

Endemic mycoses
These are rare but can be life-threatening and manifest themselves even years after
residence in an endemic area. Infections with Penicillium marneffei, Histoplasma
capsulatum, or Cryptococcus neoformans are among the most common opportunistic
infections in the corresponding endemic areas and are thus frequent indicator
diseases (Lortholary 2013) (see OI). Particular exposure risks, including with dust or
soil (construction sites, agriculture, gardening, or excavations), should be avoided
by immunodeficient individuals. In individual cases (especially with advanced
immunodeficiency), primary prophylaxis may be considered with fluconazole or
itraconazole, depending on the pathogen.

Sexually transmitted infections (STDs)

Travel is associated with more frequent sexual contact and less frequent condom use
(Matteelli 2001). STD risk is significantly increased (Richens 2006). Twenty-three
percent of HIV-positive travelers reported sexual contact with new partners, with
only 58% using a condom (Salit 2005). Travelers should be aware of STDs, and
condoms should be recommended.

Other parasites
The following parasitic pathogens are relevant:
Strongyloides stercoralis, a nematode found in the tropics/subtropics, is transmitted
by cutaneous invasion of larvae on contact with contaminated soil. Immuno-
compromised individuals may develop an often lethal “hyperinfection syndrome.”
It is relatively rare in PLWH; risk factors are therapy with corticosteroids or HTLV-1
infections (Toledo 2015).
Trypanosoma cruzi, the causative agent of Chagas disease, is endemic in Latin America
and is transmitted by predatory bugs. Oral infections through contaminated fruit or
sugarcane juice are also possible. In cases of severe immunodeficiency, chronic
infection can lead to severe encephalitides, with lesions resembling cerebral toxo-
plasmosis in terms of image morphology (Rocha 1994).
Babesia sp. are globally occurring protozoa transmitted by ticks. Life-threatening
diseases clinically resembling malaria occur frequently in immunodeficient individ-
uals (Falagas 1996).
Free-living amoebae are inhabitants of wetlands worldwide. Acanthamoeba sp. and
Balamuthia mandrillaris, as opportunistic pathogens, can cause granulomatous
encephalitis and severe local infections of the skin and cornea in PLWH (Barratt
2010).
Schistosoma sp., the causative agent of schistosomiasis, is less effective in treating
PLWH (Kallestrup 2006) and, like other worm infections, has a negative impact on
HIV infection via chronic immune stimulation (Secor 2006). Freshwater bathing in
regions with endemic schistosomiasis (especially Africa, Southeast Asia, and South
America) should be discouraged.

Medical problems after the trip

Any illness that is temporally related to a trip should be clarified immediately. The
rarity of many tropical diseases often leads to delayed diagnosis (Weitzel 2005). In
addition, tropical diseases often manifest themselves atypically in HIV (Karp 1999).
HIV and travel medicine 453

The already broad differential diagnosis is even more complex after travel abroad
and requires close cooperation between HIV specialists and tropical medicine insti-
tutions.

Links
World Health Organization, WHO: current news, country information, information on vaccinations, etc.:
[Link]
ProMedMail: International Society for Infectious Diseases page with current outbreaks: [Link]
[Link]/
Global database in cooperation with the European Aids Treatment Group on restrictions for HIV-infected persons:
[Link]
Example of travel insurance with HIV: [Link]

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455

16. HIV-2 infection

DI R K B ERZOW AN D C H R ISTIAN HOFFMAN N

HIV-2 is less prevalent than HIV-1, with approximately 1–2 million people infected
with HIV-2 living predominantly in West Africa (Gottlieb 2018). The following
summarizes the significantly limited data compared to HIV-1.

Discovery and origin

In 1986, Luc Montagnier and colleagues isolated a new human retrovirus from
patients of West African origin (Guinea-Bissau and Cape Verde Islands). These
patients presented clinically with the full symptoms of AIDS, but the sera did not
react at all or weakly with the env or gag epitopes of HIV-1 (Clavel 1986). The virus
was named HIV-2, another primate lentivirus in addition to HIV-1. At the amino
acid level, there is a 60% match in the chains coding the gag and pol proteins and
a 30–40% match in the chains coding for the env proteins (Guyader 1987). HIV-2
originated from a cross-species transmission of SIV from sooty mangabeys to humans
in West Africa. Nine subtypes are known to date. The most common, subtype A,
occurs primarily in Senegal, Gambia, Guinea-Bissau, Côte d’Ivoire, Ghana, and the
Cape Verde Islands; subtype B occurs in Côte d’Ivoire, Ghana, Burkina Faso, and
Mali. Subtypes C-I are extremely rare (“dead-end infections”). To date, there is no
evidence of differences between subtypes with regard to clinical course or treatment
(Visseaux 2016).

Epidemiology
In the country with the highest HIV-2 prevalence worldwide, Guinea-Bissau, there
is a decreasing trend. In 1987, adult prevalence was estimated at 8.9%; in 2017, it
was 3.4%. During the same time, the prevalence of HIV-1 increased from 0 to 4%
(Jespersen 2020). Senegal, Gambia, Sierra Leone, and Côte d’Ivoire are reported to
have a 1–5% prevalence. Other West African countries have a prevalence of below
1% (Visseaux 2016). In Europe, the countries with the highest HIV-2 case numbers
are Portugal (with an n of approximately 2000), France (around 1200), and Spain
(about 400). HIV-2 cases also occur in European countries such as Great Britain,
Belgium, the Netherlands, Italy, and Germany, and countries such as Mozambique,
Angola, Brazil, India (Goa region), and the United States (Berzow 2020). In the
Portuguese CHLO cohort (Centro Hospitalar de Lisboa Ocidental, n=180), 64% of
the individuals are female, with a mean age of 43 years at diagnosis (Perpetua Gomez,
personal communication).

Diagnostics
Today’s 4th generation screening tests (antibody and antigen immunoassays) contain
HIV-1 and HIV-2 antigens, and HIV-2 antibodies are reliably detected. However, the
time between infection and seroconversion may be several weeks longer. In addi-
tion, a lower sensitivity can be assumed for antigen detection (p26 instead of p24!).
In case of a positive HIV screening test without detection of HIV-1 RNA or in case
of very low HIV-1 RNA, explicit testing for HIV-2 antibodies should be performed –
especially in West African patients and their potential partners. Standardized
HIV-1/HIV-2 immunoblots or other antibody differentiation tests should be used as
confirmation. Nucleic acid assays such as HIV-2 RNA PCR are unsuitable as confir-
matory tests since there is often no measurable viral load, even without therapy.
456 Other Infections

Occasionally, it can be problematic to distinguish HIV-2 mono-infection from dual

(HIV-1/HIV-2) infection. However, dual infection is rare in Europe. With modern
antibody differentiation tests, their proportion was only 0.1% of new HIV-2 infec-
tions in one French study (CNdS 2017). Dual infection could be missed if HIV-1 and
HIV-2 are not differentiated in the confirmatory test. In this case, ART inappropriate
for HIV-2 may fail to achieve immunologic success despite a drop in HIV-1 viral load.
In this case, it is advisable to reconsider dual infection and to contact specialized
laboratories.

Transmission
HIV-2, like HIV-1, is transmitted sexually, perinatally, and hematogenously. However,
the sexual transmission rate is 3–9 times lower (Gilbert 2003). As in peripheral blood,
less virus is detectable in seminal fluid and genital secretions in HIV-2 (Gottlieb
2006). Transmission at birth or through breastfeeding is also several times less
frequent (O’Donovan 2000). In the French ANRS cohort, only two vertical trans-
missions occurred among 223 pregnant women living with HIV-2 between 1986 and
2007, although only 57% of the women were receiving ART and 68% delivered vagi-
nally (Burgard 2010).

Features of pathogenesis and course

Disease progression in HIV-2 infection is different from that in HIV-1. Both the pro-
portion of “progressors” and the speed are lower. In African cohorts, many infected
individuals remained clinically asymptomatic for the first few years (Berry 2002).
However, this asymptomatic phase is also not indefinite. Over a more extended
period, disease progression eventually occurs in most cases. In the French cohort,
6% remained asymptomatic over eight years, and 9% remained without detectable
viral load over ten years (Thiebaut 2011). About 55% were already in need of
treatment for disease progression at the time of diagnosis (Drylewicz 2008). In a long-
term cohort study from Guinea-Bissau, 40% of 464 HIV-2-positive persons had
developed AIDS after ten years, compared with 80% of 404 HIV-1-positive persons.
Rates after 15 years were 50% and 90%, respectively. With HIV-2, AIDS, and death
occurred after an average of 14.3 and 15.6 years, compared with 6.3 and 8.2 years
with HIV-1 (Esbjörnsson 2018). In the case of progression, HIV-2 also shows the
typical spectrum of opportunistic infections and AIDS disease (Jaffar 2004).
Another distinctive feature of HIV-2 is the approximately 30–100-fold lower viremia
than HIV-1 (MacNeil 2007). In contrast, the amount of proviral DNA is about the
same, with about 200 copies per 10,000 PBMC (Popper 2000, Matheron 2003).
Replication of HIV-2 is thought to be blocked during late transcription to mRNA
(Soares 2012).
In the French HIV-2 cohort, plasma RNA averaged only 1,000 copies/mL, and 52%
had no detectable viral load (Matheron 2003). A plasma viral load above 1,000
copies/mL is considered high. It is a positive predictor of disease progression. PLWH
with low viral load (< 100 copies/mL) are usually “non-progressors,” with minimal
immune activation and T cell impairment. Highly viremic individuals with HIV-2
(> 1,000 copies/mL) show no differences, immunologically or clinically, compared
to people with HIV-1 (Hegedus 2014, Hansmann 2005). Because disease progression
can occur in approximately 20% even without viremia (Hoenge 2019), CD4 T-cell
count remains an essential parameter for monitoring (before and during therapy).
In untreated individuals, the average annual drop in CD4 T-cells is 9/µl yearly
(Drylewicz 2008), about one-fifth of the usual decline in HIV-1 (Matheron 2003).
This drop correlates with the viral load level and the immune activation degree
HIV-2 infection 457

(Soares 2011). A continuous drop of more than 10% per year (Hansmann 2005) or
a drop to less than 200/µl (Matheron 2003) is associated with disease progression
and mortality (Schim van der Loeff 2010, Hegedus 2014). In a study from Guinea-
Bissau, the CD4 T-cell count at first diagnosis of AIDS with HIV-2 was 237/µl, com-
pared with 137/µl for HIV-1 (Esbjörnsson 2018).
Some immunological correlates have been found for the clinical differences with
HIV-1 infection. For example, T cells’ functionality and regenerative capacity (espe-
cially CD8 T-cells) are better preserved in HIV-2 infection. HIV-2 induces lower
immune activation, lower ß2-microglobulin levels, and lower expression of apopto-
sis markers than HIV-1, although immune activation is similar at higher levels of
viremia (Nyamweya 2013, Angin 2016, Buggert 2017). Neutralizing antibodies are
often better in HIV-2 regarding breadth and binding strength (Marcelino 2012).
In vitro tests showed a low cross-neutralization activity between HIV-2 and HIV-1
antibodies (Rodriguez 2007).

Dual infection with HIV-1 and HIV-2

Dual infections occur especially in high-incidence areas. According to one meta-
analysis, mortality is similar to HIV-1 mono-infection (Prince 2014). Without treat-
ment, HIV-1 appears to “outcompete” HIV-2 during progression: in a Senegalese
cohort, both viruses were often detectable in blood and genital secretions initially.
The more advanced the infection, the more likely it was that only HIV-1 was found
(Raugi 2013). Superinfections are also possible. A patient from Portugal has been
described, with immune recovery and virological suppression for over a decade, who
presented with a severe decline in the CD4 T-cell count secondary to HIV-2 super-
infection (Ceia 2019). This case suggests that HIV-2 superinfection should be con-
sidered in the presence of an unexplained and sustained decline in CD4 T-cell count
in HIV-1 infection with viral load suppression.

Antiretroviral therapy for HIV-2 infection

All antiretroviral drugs were developed against HIV-1 only. Given the numerous poly-
morphisms in HIV-2, it is essential to note that not all agents used with HIV-1 are
sufficiently adequate for HIV-2 (Ekouevi 2014, Menendez-Arias 2014, Berzow 2020).
Not effective against HIV-2 are:
• All approved NNRTIs
• The fusion inhibitor T-20 (enfuvirtide)
• The entry inhibitor fostemsavir, probably due to polymorphisms (Mendoza 2020)
• Some PIs (no efficacy of nelfinavir, ritonavir, fosamprenavir, tipranavir, insufficient
efficacy of indinavir and atazanavir)
Effective against HIV-2 are:
• All NRTIs
• The PIs darunavir, lopinavir, and boosted saquinavir
• All integrase inhibitors (INSTIs)
• The co-receptor antagonist maraviroc (for R5 tropism)
For new agents, data is still scarc (only in vitro data):
• The INSTI cabotegravir appears to have the same activity as dolutegravir and
bictegravir (Le Hingrat 2020) but is not an option for HIV-2 because of the fixed
combination with the NNRTI rilpivirine.
• Ibalizumab is effective but expensive and difficult to obtain in many countries (Le
Hingrat 2020).
458 Other Infections

• The capsid inhibitor lenacapavir shows activity in vitro (Yant 2019). However, in
cell cultures, the EC50 is higher than for HIV-1. According to the SmPC (Summary
of Product Characteristics), lenacapavir is “15- to 25-fold less active against HIV-2
isolates.”
• The NRTTI islatravir showed good activity against HIV-2 in vitro (Wu 2017).
• There are no published data on maturation inhibitors.

Treatment recommendations and guidelines

Despite the modest data situation, there are now recommendations and guidelines
(based on comparatively small studies, case reports, and in vitro data), such as:
• French guidelines from 2016 (CNdS 2016)
• British BHIVA guidelines 2021 (Reeves 2021)
• Spanish “Guidelines for Non-Endemic Regions” 2020 (Mendoza 2020)
• Recommendations for Europe of an “EU Expert Group” 2020 (Berzow 2020)
• US Guidelines (National Institute of Health 2019, New York State Department of
Health AIDS Institute 2022) and
• Global guidelines (Gottlieb 2018)
A summary of these recommendations is presented below.

Monitoring before starting therapy

Plasma RNA and CD4 T-cells should be measured every 3–6 months, depending on
individual clinical and immune status, and if disease progression is suspected. Any
HIV-2 RNA above the limit of detection should be confirmed promptly.

Resistance testing
The prevalence of transferred primary resistance was 5% in the French cohort.
(Charpentier 2013) and 2% in Portugal. If possible, initial resistance testing (or
subsequent testing if not available) should always be performed. If plasma RNA is
too low, resistance testing from proviral DNA can be attempted.

Start of therapy
Unlike HIV-1, there is no consensus for an optimal starting point. Since 2019, US
and British guidelines recommend treatment for all HIV-2-infected persons (DHSS
2019). This strategy (treatment upon diagnosis) is also recommended by renowned
experts as the basis for achieving the UN 90-90-90 targets (Gottlieb 2018). Other
European guidelines consider that there are limited treatment options for HIV-2.
Moreover, regarding potential “elite controllers”, therapy should primarily be initi-
ated when it is “really” necessary for clinical, virological, and immunological reasons.
On the other hand, there is a caveat regarding starting too late, especially since
immune reconstitution (increase in CD4 T-cells) is often much lower under ART
according to older studies (Benard 2011, Matheron 2006). According to these con-
siderations, initiation of ART is
• mandatory for patients with symptoms (CDC category B and C) or with dual infection
• recommended for patients with less than 500 CD4 T-cells/µl and/or a drop of more
than 30/µl per year for at least three years (only recommended by the “EU expert
group”), repeated detection of HIV-2 RNA in plasma, co-morbidities such as chronic
hepatitis B, primary HIV infection, and during pregnancy
• ART can be deferred in patients with the following criteria: absent symptoms and
criteria for non-progression, i.e., stable CD4 T-cells above 500/µl and an HIV-2 RNA
permanently below the detection limit.
HIV-2 infection 459

Treatment
First-line treatment of HIV-2 should consist of a combination of two NRTIs and either
an INSTI or one of the effective boosted PIs.
Table 1: Recommended first-line therapy for HIV-2 (for women, follow warnings and dosing instructions
regarding pregnancy).
Backbone (NRTI) Third agent
TAF/FTC or TDF/FTC INSTI: Dolutegravir or Bictegravir
Alternatives: plus Alternative: Raltegravir, Elvitegravir/c
TAF/3TC or TDF/3TC or
or ABC/3TC PI: Darunavir/r/c
Alternative: Lopinavir/r
Booster drugs: c: Cobicistat, r: Ritonavir

Available data:
PI-based regimens in HIV-2
In one study, 126 patients showed an excellent immunological response and an
average CD4 T-cell increase of 88/µl after one year on boosted PIs, mostly in
lopinavir/r (Benard 2011). The increase in the West African IeDEA cohort of 287
patients was as high as 191/µl (Balestre 2016). Both studies showed that boosted PI
regimens were superior to a combination of three NRTI or unboosted PI. Data for
good in vitro efficacy are available for darunavir/r, ranked first among PIs in the guide-
lines. In most cases, darunavir can be given once daily at 800 mg (with 100 mg riton-
avir); for resistance-associated mutations such as I84V and/or L90M, darunavir/r
should be given twice daily (2 x 600/100 mg). Although data on cobicistat and HIV-2
are not yet available, comparable boosting can be assumed.

INSTI-based regimens in HIV-2

Raltegravir: 30 patients treated with TDF/FTC experienced a CD4 T-cell increase of
87/µl after one year. Only one patient developed virological failure (Matheron 2018).
Elvitegravir/c: 30 patients treated with TDF/FTC experienced a CD4 T-cell increase
of 161/µl after one year. Only one patient had > 50 copies of HIV-2 RNA/mL after
week 36 (Ba 2017).
Dolutegravir: was used in 62 Indian patients. The mean CD4 T-cell increase was
72 cells/µl after 18 months; 7 patients showed virological failure, and three clinical
events occurred (Pujari 2020). In 24 French ANRS HIV-2 cohort patients, the mean
CD4 gain was 54 cells/µl over 28 months. Overall, 23 patients had an HIV-2 RNA
< 40 copies/mL, and one discontinued dolutegravir due to weight increase (Joly 2023).
Bictegravir/TAF/FTC: was used successfully in 62 patients in a Portuguese open-label
phase II trial. The median CD4 increase after one year was 96 cells/µl, with no viro-
logical failure (Pacheco 2023).
In vitro studies suggest that second-generation INSTIs are more effective against HIV-2
(Le Hingrat 2018, Reeves 2021).

Monitoring before therapy

Under ART, treatment success should be monitored by HIV-2 plasma RNA and CD4
T-cells as follows:
• After starting or switching therapy, at months 1, 3, and 6.
460 Other Infections

• With CD4 T-cell count below 200/µl every three months, with CD4 between 201
and 499/µl every 3 to 6 months (depending on adherence and clinical situation),
and with CD4 T-cells above 500/µl every six months.
• If disease progression is suspected, immediately.
• In case of pregnancy, every three months and monthly in the last trimester.

Treatment failure
Viral load alone is not a sufficient parameter for therapeutic success, and it may not
be detectable even before ART initiation. CD4 T-cell progression and clinical condi-
tion are much more critical. Treatment failure is likely if (Berzow 2020):
• HIV-associated symptoms occur or do not improve while on ART,
• CD4 T-cells continue to decline in number, and/or
HIV-2 plasma RNA is detectable while on ART.
In these cases, testing for resistance to NRTI, PI, and INSTI should be initiated imme-
diately. If plasma RNA is low and undetectable, a resistance test from proviral DNA
can be attempted.

Recommended agents – second-line treatment

Second-line treatment should consider genotypic resistance testing, tolerability, and
adherence. If a PI was used in first-line treatment, a switch to an INSTI is recom-
mended (and vice versa). Maraviroc, AZT, saquinavir/r, and effective new substances
may also be considered. With maraviroc, a genotypic tropism test should be done.
A biomathematical tool for interpretation (sequence analysis of the V3 loop) is avail-
able online via [Link].

Resistance
The differences between HIV-2 and HIV-1 in the amino acid sequence in the pol gene
explain the variable efficacy of antiretroviral agents (Camacho 2012). Resistance
pathways for HIV-2 have been described for NRTIs, PIs, and INSTIs (Moranguinho
2023). Polymorphisms in the RT region at positions 181(I), 188(L), and 190(A) explain
the ineffectiveness of NNRTIs (Colson 2005).
NRTIs: Typical polymorphisms of the HIV-2 RT are T69N, V75I, V118I, L210N, T215S
and K219E (Menendez-Arias 2014). The mechanism of “pyrophosphorolysis-medi-
ated primer unblocking” while on AZT, leading to the emergence of TAMs in HIV-1,
does not appear to play a role in HIV-2 (Menendez-Arias 2014). The following resist-
ance mutations occur most frequently (most of which arose from the use of older
regimens with AZT, d4T, and ddI): Q151M (50%), K65R (13%), M184V (25%), L74V,
and V115Y (Trevino 2011). In the Portuguese ADR resistance cohort (153 cases with
resistance mutations, 2007–2019), RT mutations involved M184V/I in 58%, Q151M
in 18%, and K65R in 15% (Perpetua Gomez, personal communication).
The multi-resistance mutation Q151M is seen more frequently and earlier than in
HIV-1. In contrast, S215ACFLYV (this position is highly polymorphic in HIV-2) is
observed less often or only after prolonged administration of AZT and d4T
(Menendez-Arias 2014, Tzou 2020).
The viral fitness of HIV-2 is reduced by M184V, as in HIV-1 (Deuzing 2015), but the
efficacy of AZT is not reinforced (Smith 2009). V111I is a mutation typical of HIV-2.
It increases the imprecision of RT and leads to a higher mutation rate but simulta-
neously “restores” the limited viral fitness at K65R and Q151M (Deuzing 2015).
PIs: Polymorphisms were seen at 47 of 95 amino acid positions in another French
study (Damond 2005). The major polymorphisms affecting the substrate binding
site are V32I, I47V, L76M, and V82I (Menendez-Arias 2014). Common resistance
mutations include V47A, G48V, I54M, I82F, L90M, and L99F (Charpentier 2014).
HIV-2 infection 461

Resistance can occur more rapidly (Camacho 2012, Menendez-Arias 2014). At some
positions, even one mutation seems to be enough (Trevino 2011, Raugi 2013,
Charpentier 2014). This concerns V47A (lopinavir), I50V (darunavir), I54M (lopinavir
and darunavir), and L90M (saquinavir). The combination I54M+I84V+L90M can lead
to high-level resistance to all PIs. In the Portuguese ADR cohort, PI resistance occurred
with the following frequency: L90M 26%, I54M 14%, I50V 8%, V47A 6%, I82F and
I84V 2% (Perpetua Gomez, oral communication).
Integrase inhibitors (INSTIs): Polymorphisms were found at 33% of amino acid
positions in therapy-naive patients (Perez-Bercoff 2010). Under raltegravir, the
known resistance mutations T92Q, T97A, Y143C/G, Q148H/K/R, and N155H were
found (Charpentier 2011, Smith 2012); under elvitegravir, E92G/Q, T97A, Q148K/R,
Y143C, and N155H (Smith 2012). For dolutegravir, resistance-associated mutations
have been described at positions E92Q, T97A, G104S+Q148R, Q148K, and N155H,
among others (Descamps 2015, Smith 2015). Bictegravir is thought to have a very
similar resistance profile (Smith 2019, Obermeier 2022). Insertion 231ins causes
high-level resistance to raltegravir, elvitegravir, dolutegravir, and partial resistance
to bictegravir (Le Hingrat 2019).
CCR5 antagonists: HIV-2 can use diverse co-receptors. CCR5 and CXCR4 are the
most important, as in HIV-1. X4-tropic isolates are found only in advanced-stage and
low CD4 T-cells (Visseaux 2014). In vivo, there are case reports for maraviroc in salvage
therapy (Descampes 2015).

Interpretation rules and algorithms for HIV-2 resistance mutations

Table 2 shows an assessment of the most important resistance mutations based on
study data and case reports by the European HIV-2EU Group (Charpentier 2015,
updated 2022). These algorithms are available as a continuously updated internet
tool for entering the entire nucleotide sequence after sequencing and for entering
the known resistance mutations (HIV2EU tool, [Link]
The listed therapy-induced resistance mutations have been confirmed by a more con-
siderable recent work (analysis of gene sequences from 739 PI-, 611 NRTI-, and 321
INSTI-treated individuals before and after initiation of therapy) (Tzou 2020).

Treatment of dual infection

The start of therapy should be based on the same criteria as for HIV-1 infection. The
choice of drugs should consider that there is good activity against HIV-2. A Spanish
study of 20 patients with dual infection showed a virologic response (for both viruses)
at 80%. There was an average CD4 T-cell increase of 212/µl over 13–48 months
(Requena 2019).
Table 2: HIV-2 RAMs (according to "HIV-2EU group resistance interpretation rule set").
NRTI Resistance Partial resistance
AZT Q151M S215ACFLYV
S215ACFLYV + another mutation from
(N69ST, K70R, V115F, K223R)
3TC/FTC M184V K65R
ABC K65R two mutations (D67N, K70RN, M184V,
Q151M S215ACFLYV)
M184V + one mutation from (L74V, Y115Y)
TDF/TAF K65R
Q151 + V111I
462 Other Infections

Table 2: Continuation
PI High level of resistance Medium resistance
SQV G48V I84V
L90M
LPV V47A V62A+L99F
I54M I82F
Two RAMs out of (I82F, I84V, L90M) I84V
L90M
DRV I50V I84V
I54M L90M
I84V + L90M
INSTIs High level of resistance Medium resistance
RAL E92Q + T97A E92Q
Q148HKR Y143CGR
N155HR
One of (E92Q, T97A) + Y143CGR
231ins
EVG E92QG Y143C
T97A + Y143C
Q148HKR
N155H
231ins
DTG Q148K E92Q
E92Q + N155H T97A + Y143C
T97A + N155H Q148R
G140S + Q148HR N155H
231ins
BIC Q148K E92Q
E92Q + N155H T97A + Y143C
T97A + N155H Q148R
G140S + Q148HR N155H
231ins

Literature
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CD8 + T Cells in HIV-2-Infected Controllers. J Immunol 2016; 197:2787-2795.
Ba S, Raugi D, Smith R, et al. A trial of fixed dose combination of elvitegravir, cobicistat, emtricitabine, tenofovir
disoproxil fumarate for the initial treatment of HIV- 2 infections: 48 week results from Senegal, West Africa.
Abstract #MOPEB0294, 9th IAS 2017, Paris.
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SECTION 5

Women and
Children
466

17. HIV and women

ANNETTE HABERL

Sex and gender-specific factors significantly impact the prevention and treatment of
HIV. Of note, a distinction must be made between the genetically determined
biological sex and gender and the “social sex” which is determined by socially and
culturally ascribed characteristics.
More than half, about 20,7 of the 39,0 million PLWH globally, are female. Women
and girls accounted for 46% of all new infections in 2022 (UNAIDS 2023). In the
high-prevalence countries of sub-Saharan Africa, young women aged 15–24 account
for 25% of new HIV infections. Among men of the same age, the infection rate is
8%. One reason for the increased transmission risk among young women is the sexual
violence they still face in many countries (UNAIDS 2018). In addition, women are
anatomically at higher risk of infection than men during unprotected sexual contact.
The mucosal surface of the female genital tract is larger and more sensitive than that
of men. Microtrauma of the vaginal and cervical mucosa occurs quickly and increases
the risk of infection.
In Western Europe, the proportion of women among PLWH is 30% on average.
In Germany and Spain, it is comparatively low at 20%, while in France, it is highest
at 39% (WAVE 2017). Women account for about one-third of new HIV diagnoses
in Europe. Older women, in particular, are at risk of being diagnosed late
([Link]). The main transmission route among women is unprotected het-
erosexual contact.
The course of an untreated HIV infection can be different in women and men. During
acute infection, HIV is taken up by dendritic cells (plasmacytoid dendritic cells pDC).
These cells belong to the antigen-presenting cells that can recognize HIV with a
Toll-like receptor (TLR7). The DC respond with the release of interferon-alpha, a
signaling substance for activation of CD8-positive T cells. The female sex hormone
progesterone can increase interferon-alpha production in the DC, which explains
the greater immune activation in women during the early phase of HIV infection.
As a result, viral load is initially lower in women than men. However, the more robust
immune activation leads to more rapid disease progression during untreated infec-
tion (Meier 2009). Sex-specific differences in immune activation were also seen in
treated HIV infection. Inflammatory markers decreased to a lesser extent in women
with ART than in men (Mathad 2014).

Menopause and HIV

While the focus in the care of women living with HIV has been on child-bearing
and pregnancy issues for a long time, the transition from pre- to post-menopause is
now becoming increasingly important. Numerous studies have described differences
in the course of menopause compared to HIV-negative women. In the Women
Interagency HIV Study (WIHS), the age at onset of menopause was 47.7 versus 48.0
years (Cejtin 2012). Other studies saw an even earlier onset of menopause. In one
study, the risk was increased by 73% (Schoembaum 2005), but in another, prema-
ture menopause was found in only 12% (Pommerol 2011). Women with HIV are
more likely to experience menopausal symptoms (Ferreira 2007, Looby 2014). In the
PRIME (Positive Transitions Through the Menopause) study, conducted in the UK
from June 2015 to April 2018, 89% of approximately 1000 study participants expe-
rienced menopausal symptoms. Strikingly, only 10% received hormone therapy.
Physicians feared potential interactions between ART and hormone replacement
HIV and women 467

therapy as the primary reason for their reluctance (Tariq 2019). This concern is
unwarranted because the potential interactions are well-known from experience with
oral contraceptives, and in addition, interaction tables for menopausal therapy are
available online ([Link]). In clinical practice, interdisciplinary
care of peri- and post-menopausal women living with HIV should be aimed at in
order to classifying symptoms and treating them early.

Antiretroviral therapy
To date, there are no specific recommendations for HIV treatment in women. No
gender-specific differences were found in a meta-analysis by the FDA, which analyzed
treatment responses in 43 randomized trials from 2000–2008. However, women
accounted for only 20% of the more than 20,000 study participants (Soon 2012).
Due to the low proportion of women in clinical trials investigating new HIV drugs,
there is an ongoing lack of sex-specific data. In addition, the desire to have children
and the onset of pregnancy have been exclusion criteria for participation in
registration trials. Sex- and gender-specific differences often only become apparent
in everyday clinical practice and usually years after a drug has been approved. In the
meantime, however, the regulatory authorities explicitly demand study data. At the
same time, regulations are being revised to make it easier for women of childbear-
ing age to participate in studies and thus generate data more quickly.
There are also sex- and gender differences in the occurrence of adverse events.
Gastrointestinal side effects were more likely to manifest as nausea and vomiting in
women, whereas men more frequently complained of tolerable diarrhea due to pre-
viously prescribed ART (Floridia 2008, Squires 2011). Differences are also still evident
with newer HIV drugs. In a German study, for example, the discontinuation rate of
dolutegravir due to neuropsychiatric side effects was threefold higher in women
(Hoffmann 2017). Concerning weight gain, possibly due to integrase inhibitors,
female sex is an independent risk factor (Kerchberger 2020, Venter 2020). Sex
differences in pharmacokinetics may influence efficacy and tolerability and are
multifactorial. Body weight, proportion of fat, and the influence of hormones on
plasma protein binding are essential. Differences in diet and exposition time in the
gastrointestinal tract are significant for bioavailability. The female hormone proges-
terone may increase the activity of the CYP3A4 system in the liver. Finally, organ
size plays a role in the elimination of a drug. Relevant differences between women
and men are possible in all of the above. Unfortunately, it takes an average of six
years after the approval of an HIV drug for data on pharmacokinetics in pregnancy
to become available – for data on breastfeeding, i.e., the lactability of the drugs, even
eight years (Orkin 2019).
ART for women of childbearing potential – or, given the high rate of unplanned
pregnancies – ART for young women as a whole remains a particular challenge.
Ideally, young women living with HIV should receive a treatment that can be
continued at the onset of pregnancy. However, forming an intersection of adult and
pregnancy guideline recommendations still results in limited treatment options for
young women. New drugs and administrations may be eliminated due to limited or
no knowledge about their use in pregnancy. In clinical practice, it is a balancing act
taking into account both the woman’s needs and the potential risks to the unborn
child. Data from the German HIV Pregnancy Registry show that women who became
pregnant while on ongoing ART were 44% treated with a PI-based regimen. If ART
was not initiated until pregnancy, the proportion of PI regimens increased to 62%.
Integrase inhibitors were used pre-conceptually in 25% of women. That proportion
increased to 37% when ART was started upon pregnancy (Haberl 2023).
468 Women and Children

HIV pre-exposure prophylaxis (PrEP) has so far hardly been used by women in
Germany and also in other European countries (Fitzgerald 2023), although data on
its effectiveness and tolerability are available, and guidelines recommend PrEP for
women with a high transmission risk ([Link]; [Link]). The
main barrier is the lack of information for potential female PrEP users. Women are
not reached through the network of HIV focus centers but need counseling in gyne-
cological and primary care practices or even in travel medicine. When prescribing
PrEP, it should be noted that the protective effect starts later in women than in men.
This delayed effectiveness can be explained by the poorer accumulation of tenofovir
(TDF) in the vaginal tissue compared to the rectal mucosa (Patterson 2011). Therefore,
on-demand PrEP is not considered for women. An alternative to oral PrEP for women
in the near future may be intramuscular cabotegravir (CAB). The HPTN 084 study
showed the superiority of CAB IM in women compared to oral PrEP with TDF/FTC
(Delany-Moretlwe 2022).
The higher rate of treatment discontinuation in women with HIV compared to men
has been investigated in numerous studies. Side effects, but also socioeconomic and
psychosocial factors, had an impact on continuous adherence. In particular, depres-
sion, which is more common in women anyway, and lack of support in the social
environment have a negative impact on treatment success. The GRACE study
identified childcare responsibilities, unemployment, and transportation problems as
major causes of adherence problems among women (Squires 2013). A prospective
study of health-related quality of life in the Frankfurt HIV cohort showed significant
differences between women and men. In the Mental Health Score (MCS) men and
women with HIV scored significantly lower overall than the general population.
However, there was also a significant difference between HIV+ women and men,
with a lower score for women (Kuhlen 2018).
Fear of HIV-related discrimination continues to burden especially women with HIV.
Most of them lead a strenuous double life for fear of HIV disclosure. In addition to
effective HIV treatment, reducing stigmatization and discrimination is a decisive
factor for a good quality of life in women living with HIV.
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disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-
1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial. Lancet HIV 2020: e666-
e676.
470

18. HIV and gynecology

ANKE REITTER AND ANNETTE HABERL

Gynecologists are particularly important for preventing, diagnosing, and treating

HIV infection. Women see them regularly from their youth, and sexual health is on
the agenda anyway. It makes sense to address sexually transmitted infections such
as HIV in gynecological practice. This works well in the context of prenatal care, and
HIV testing rates of over 85% are now achieved in Germany (Beermann 2020).
Beyond childbearing and pregnancy, however, HIV testing could be offered more
frequently in gynecological practices than it has been to date. Especially in women
over 50, HIV diagnosis is too often made only at an advanced stage of infection
([Link]).
Gynecologists also play a crucial role in HIV pre-exposure prophylaxis (PrEP). The
success of PrEP depends mainly on how well potential users can be reached. While
men with a high risk are informed about PrEP via HIV care centers, organizations,
or internet forums, there is a lack of comparable forums for women. This preven-
tion tool will be available for women only if information on PrEP is also located in
gynecological practices. As the protective effect of PrEP starts later in women than
in men, PrEP on demand is not an option for women. Intramuscular cabotegravir
(CAB) could make PrEP more attractive to women. PrEP approval of this INSTI has
already been granted in the US and has been applied for in Europe.
Cooperation between gynecological centers and HIV centers should always be
sought. Contact persons should be known at the local level. If, for example, an initial
HIV diagnosis is made in the gynecological practice, this requires the fastest possible
presentation at an HIV focus center. This way, possible interactions between anti-
retroviral therapy and hormone preparations can be clarified quickly.

Gynecological screening
Women living with HIV are at increased risk for cervical dysplasia and carcinoma,
genital ulcers, vaginal infections, and genital condylomas if untreated. ART reduces
AIDS-defining diseases, including cervical carcinoma, via sustained viral load sup-
pression and immune reconstitution.
Gynecological examination with a Pap smear is obligatory for all women. Cells are
taken from the cervix and microscopically classified using a special stain (Table 1).
When HIV infection is first diagnosed, the importance of gynecologic screening
should be explained, and regular participation in screening examinations should be
recommended. Particular attention should be given to contraception in younger
women and in older women, to postmenopausal issues.
Guidelines for cancer screening may differ markedly between countries. There is
considerable variation in screening methods, starting age, stopping age, and screen-
ing interval between countries. In Germany, the following gynecological check-ups
are offered by health insurance, depending on age:
• From age 20–34, annual cervical cancer screening (Pap smear).
• From age 35, an additional test (“co-test”) for HPV is optional in addition to the
existing annual Pap smear. If the results are normal, the screening interval is then
extended to three years.
• Annual examination for chlamydia (in urine) until age 25.
• After age 30, a palpation examination and a lymph node scan of the breast once a year.
• From age 50 to 70, a mammography every two years.
• At or after age 35, baseline mammography/sonography can be performed.
HIV and gynecology 471

Given the risk of cervical and anal dysplasia, screening, especially Pap smears of the
cervix and anus, is of great importance for all women, including those living with
HIV. Recommended intervals vary depending on findings and risk status. The risk
of breast cancer is not increased by HIV infection. The usual further preventive exam-
inations are colon cancer screening from age 50 (examination for occult blood;
colonoscopy from age 55) and skin cancer screening every two years.

Human papillomaviruses (HPV)

Over 50% of sexually active people have had contact with one or more of the more
than 100 HPV subtypes. The infection usually resolves within a few months in
immunocompetent individuals. Chronic HPV infection can lead to genital warts,
condylomata acuminata (mostly “low-risk” LR-HPV, subtypes 6 or 11), and intra-
epithelial and invasive neoplasms in the lower female genital tract (the “high-risk”
HR-HPV subtypes 16 and 18).
The diagnosis of condylomata acuminata is usually visual. A biopsy is necessary if
the diagnosis is unclear, the condylomas do not respond to therapy or are progres-
sive, or if the warts are pigmented, indurated, fixed, or ulcerated. Simple genital warts
of the vulva or vagina (LR-HPV types 6, 11, less commonly types 42, 43, and 44) can
be treated initially with podophyllin or imiquimod. In case of extensive infestation
or recurrence, laser vaporization should be considered.

HPV vaccination
Around 125 countries have introduced HPV vaccines, many offering access to girls
(and boys) aged 9–14 worldwide (2–3 vaccinations at months 0, 2, and 6). The CDC
recommends vaccination for all PLWH until the end of the 26th year of life (CDC
2015, Meites 2019). In Germany and some other countries, however, general health
insurances currently do not cover vaccination of adults. HIV-positive children and
adolescents should be vaccinated before their first sexual contact.

HPV and cervical cancer

Cervical carcinoma is a squamous cell carcinoma in more than 80%, and in more
than 98%, the carcinogenic HR-HPV types 16, 18, but also 31, 33, 35, 58, etc. are
involved. If the HPV test is positive, clarification with cytology is the international
standard. If cytology is abnormal, up to 40% of cervical intraepithelial neoplasia
(CIN) III can be detected by colposcopy and biopsy, depending on the severity of
the Pap result. CIN III risk with a cytology-negative but HPV-positive result is present
in 4–9%, necessitating further smear checks (Ronco 2014, Cruickshank 2019).

HPV self-test
In principle, HPV self-testing is also possible today, but it does not replace screen-
ing with regular inspection of the cervix (Arbyn 2014, Zhang 2019). Alternatively,
many guidelines on cervical cancer screening recommend immunocytochemical
testing for the biomarker p16/Ki-67, which appears more accurate than the Pap test.
Still, there is not yet as much data on this.
With increasing ART duration and improvement in CD4 T-cell count, HR-HPV preva-
lence appears to decrease. This also reduces the prevalence of CIN II and CIN III
(Menon 2017). A high CD4 T-cell count potentially has a protective effect against
cervical neoplasia, but the direct impact of ART is not established (Kelly 2017,
Zhang 2020). However, a recent meta-analysis shows that early ART initiation with
good adherence reduces the incidence and progression of cervical dysplasia to cervical
carcinoma (Kelly 2018).
472 Women and Children

Rapid virological control with functional, complete local strengthening of the

mucous membranes seems to be essential. In the case of poor adherence and HIV
disease progression, gynecologic screening must be more closely performed, as in
these cases, infections with HR-HPV types and progression of dysplasias are more
likely (Kelly 2018).

Treatment of cervical dysplasia

The treatment of cervical dysplasia (cervical intraepithelial neoplasia/CIN) and
cervical carcinoma is the same in HIV-positive and -negative women. However, PLWH
have an increased risk of recurrence and should be monitored closely (Heard 2005).
The goal of surgical therapy for cervical dysplasia is the complete removal of the
transformation zone with all neoplastic lesions.

Table 1: Management according to cervical cytology (Pap findings), histological classification, and HPV
status (modified according to German guidelines on prevention of cervical carcinoma, 2017).
Pap smear Management OP procedure Conservative/Controls
Histology
I Annual/triennial checks HPV as co-test
II Often, inflammatory Local treatment of the
cell changes infection/remediation
Control after three months of the flora
IIID Colposcopic cytological Loop conization, laser Up to 24 months
CIN I (mild control every 6 months conization/vaporization (only relevant in case of
dysplasia) * (only in case of HPV-HR (in case of persistence HPV-HR positivity)
positivity) of findings, HPV-HR
positivity, and wish of
the patient)
IIID Colposcopic cytological Loop conization, laser, Up to 12 months
CIN II (moderate control every 6 months laser conisation/ (only relevant in case of
dysplasia) (only in case of HPV-HR vaporization (in case of HPV-HR positivity)
positivity). persistence of findings,
HPV-HR positivity, and
wish of the patient)
IVa/IVb Therapy Conization (loop, laser, In pregnancy, close
(CIN III severe needle, knife) monitoring with biopsy
dysplasia) or extended treatment
postpartum
* In the case of CIN I and histologically expressed suspicion of endocervical involvement, close cytolo-
gical/colposcopic controls and, if necessary, conization should be performed (especially in the case of
HR-HPV positivity).

Anal dysplasias
In PLWH, HPV infection is often multifocally localized. The risk of concurrent cervical
and anal dysplasias is increased (Holly 2001). Unlike cervical dysplasia, there is no
regular screening program for anal dysplasia. Anal HPV infection also initially results
in local dysplasia, which may progress to anal carcinoma after years. Anal carcino-
mas develop in 90% from dysplastic precursors called anal intraepithelial neoplasia
(AIN) due to HR-HPV (Forman 2012). The risk of anal carcinoma is increased 7- to
HIV and gynecology 473

28-fold compared to HIV-negative women. This has not yet led to increased attention
to screening everywhere (Wells 2020, Rodriquez 2021). CD4 T-cell counts normalized
by ART appear to reduce the risk of disease; a direct effect of ART is controversial
(Gonzalez-Ruiz 2004). A thorough inspection of the anal region and, if necessary,
smear/HPV diagnostics are recommended.

Cycle and menopause

Whether HIV affects the female cycle is still a matter of controversy. It is equally
unclear whether HIV accelerates the onset of menopause. Studies show contradic-
tory results (Imai 2013, Van Ommen 2021). The average age of onset of menopause
in the general population in many Western countries is between 50 and 52.
Diagnostic workup is the same as for HIV-negative women. ART interactions with
menopausal hormone therapy are possible when boosted substances are used. Hot
flashes, sleep disturbances, and mood swings are reported as the most common symp-
toms of menopause (Ferreira 2007). The expression of symptoms may be increased
in women living with HIV (Tariq 2019). The duration of vasomotor symptoms is
approximately 7–8 years and begins on average 4.5 years before the last menstrual
period (Avis 2015).
Post-menopausal bone and lipid metabolism changes may be exacerbated by HIV
infection or its treatment, possibly increasing the risk of osteoporosis and cardio-
vascular disease.
Menopausal hormone therapy is always an individual decision after weighing the
advantages and disadvantages. HIV infection is not a contraindication to hormone
therapy (Haberl 2018). Interactions with ART should be considered ([Link]-drug-
[Link]).

Contraception
Women with a completely suppressed viral load who do not use a condom should
be advised individually on contraception. The condom, which can protect partners
of untreated women from HIV transmission, has a comparatively low contraceptive
effect: the Pearl index (number of pregnancies in 100 patient-years) is 2–12 com-
pared to 0,1–0,9 for ovulation inhibitors. Spermicides are also not recommended.
Nanoxynol-9 damages the vaginal mucosa.
The following methods are available: combined oral contraception (COC), patch,
ring, progesterone-only pill (POP), copper IUD, hormonal IUD, hormonal injection,
and implant. These contraceptive methods do not affect the course of HIV infection
(Phillips 2013). When choosing a method or preparation, general contraindications
should be considered (e.g., age, obesity, smoking, thrombophilia, post-thrombo-
sis/embolism, diabetes mellitus, hypertension, migraine, liver tumors).
Possible interactions of hormonal contraceptives with ART should be considered
([Link] No interactions with hormonal contracep-
tives are seen with NRTIs; the newer NNRTIs etravirine, rilpivirine, and doravirine,
the integrase strand transfer inhibitors (INSTIs) raltegravir, bictegravir, dolutegravir,
and cabotegravir IM, and the CCR5 antagonist maraviroc. Boosted protease
inhibitors, the boosted INSTI elvitegravir, and the old NNRTIs efavirenz and
nevirapine interact with ethinylestradiol and progestin via cytochrome P450.
Enzyme inducers for CYP3A4 (including rifampicin, rifabutin, and some antiepileptic
drugs) are also problematic, and the effects of the interactions are hardly predictable
due to lack of data (Robinson 2012).
When prescribing hormonal contraceptives, the risk of inadequate contraceptive
474 Women and Children

protection due to interactions with ART should be considered, and, if necessary, a

preparation with a high estrogen or progestin dose should be selected. Metabolic
effects must also be considered: progestogen-only preparations have a particularly
unfavorable effect on lipid and insulin metabolism in women living with HIV
(Womack 2009).
Many studies have investigated whether contraception increases the risk of HIV trans-
mission. Hormonal contraception, copper intrauterine devices (IUDs), and lev-
onorgestrel-containing IUDs do not increase the risk (Patel 2017, Stringer 2007,
Heikinheimo 2006). Conflicting data are available on the “three-month injection,”
which contains 150 mg of medroxyprogesterone acetate (Polis 2014, WHO 2015,
Ralph 2015).

Other infections
Before the introduction of antiretroviral therapies, recurrent genital tract infections,
bacterial vaginosis, genital herpes, and vulvovaginal candidiasis were very common.
Frequency and severity correlated with immune status and viral load. Other sexu-
ally transmitted infections besides HIV are also diagnosed more frequently. The
therapy of women living with HIV does not differ from that of HIV-negative patients.
Common to all genital infections is the damage or weakening of the mucosa caused
by the infection and thus an increased permeability with the risk of further infec-
tions and an increased risk of transmission of HIV.

Table 2: Common genital infections: Diagnosis, therapy and unique features.

Bacterial vaginosis Genital herpes Vulvovaginal candidiasis
Diagnosis Thin fluorine Amine Painful Thin fluorine Amine odor
odor of fluorine blisters/ulcerations of fluorine
White grayish Serological/virological Whitish fluorine
Smear (smear) Itching
Microscopic ("Clue cells") Burning
Native preparation Colposcopic
Amine test (drops 10% Smear/culture
KOH typical odor) Urine
Most common Gardnerella vaginalis Human herpes virus Candida albicans
pathogens type 2 (HSV-2)
Therapy Metronidazole systemic Acyclovir Local azole for 1–3 days
Tablet (2 x 500 mg/day local/systemic (e.g., clotrimazole 2% cream
for 7 days or 2 g once or 5 g intravaginally 1 x daily
2x2 g within 48 hours) for 3 days or miconazole
Local: Clindamycin vaginal suppositories
vaginal cream 200 mg 1 x daily for 3 days)
Differential Trichomonads Lues, "Chancroid" Trichomonads
diagnosis (haemophilus ducreyi)
Prevention Local strengthening, Prophylaxis with Use prophylaxis fluconazole
e.g., lactobacilli Acyclovir 200–400 mg 1 x 200 mg/week
x 1 daily orally
Partner Not mandatory Barrier method during Only in case of complaints
treatment intercourse until healing, co-treatment
treatment for symptoms
HIV and gynecology 475

Practically, therapy should always disinfect and strengthen the local milieu, e.g., by
supplying lactic acid bacteria suppositories, and vitamin C locally (Vagiflor®, Vagi-Hex®,
Fluomizin®). For example, vaccination with Lactobacillus strains to reconstitute the
physiological Döderlein flora may be considered in recurrent non-specific colpitis.
Study data from large study collectives are available on this, but not for women living
with HIV. In HIV-negative women, these preparations can reduce the recurrence rate
by up to 80% (e.g., Gynatren®, Lyseen®).

Summary
Gynecologists play a crucial role in the prevention and treatment of HIV infection.
Collaboration with HIV centers ensures optimal care. PLWH should be aware of the
early detection and treatment options for genital HPV-associated dysplasia and
neoplasia. Effective HIV therapy can now reduce the risk of cervical dysplasia/
neoplasia to the level of HIV-negative women. At least annual screening, including
screening for anal dysplasia, is recommended for all women.
Interactions of HIV drugs with hormone preparations are now well studied. They
may be clinically relevant in individual cases. Individual therapy modifications
ensure the success of contraceptive or hormonal therapies. A new topic for gyne-
cological practice is PrEP. Gynecologists have a central role in reaching those women
who could benefit from this prevention method.

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477

19. Pregnancy and HIV

Therapy for the mother and prophylaxis for the newborn baby
MEC HTH I LD VOC KS-HAUC K

HIV infection of the newborn has become rare in Western Europe and the United
States since the introduction of antiretroviral transmission prophylaxis and elective
sectio. While the perinatal HIV transmission rate in Europe was approximately 15%
in the early 1990s, it is now less than 1% (Connor 1994, Townsend 2014, DHHS
2023). HIV infections postpartum are preventable unless mothers with HIV infection
breastfeed without prophylaxis.
Current ART guidelines primarily recommend integrase inhibitors (INSTIs) in initial
therapy. There have been restrictions on this substance class due to potential embry-
otoxicity. Since approximately 75% of HIV-positive women in Western industrial-
ized nations become pregnant. At the same time, already on ART and a large part of
embryogenesis has already been completed by the time pregnancy is established,
this restriction has implications primarily for the preconceptional choice of therapy.
As a rule, the existing therapy is continued during pregnancy.
In the following, the American and European guidelines (EACS 2021, DHHS 2023)
for HIV therapy in pregnancy summarized, the German-Austrian recommendations are
also taken into account (DAIG 2020). Constantly updated recommendations can be found
at [Link] or at [Link]/[Link].

ART before and during pregnancy

Pre- and periconceptional ART
INSTIs are preferred in many adult primary therapy guidelines, in part because of
the high resistance barrier of dolutegravir and bictegravir (EACS 2022, DHHS 2023).
Dolutegravir and raltegravir are also preferred in pregnant women, and dolutegravir
is unreservedly preferred in DHSS guidelines. However, the current EACS guidelines
recommend “discussing” the use of dolutegravir because of a low (non-significant)
risk of neural tube defects (NTDs) in the first 6 weeks (EACS 2022). Women without
safe anticonception should be fully informed of the inconclusive, rare NTD risks of
neural tube defects with dolutegravir at the time of conception: In the Tsepamo trial,
the initial prevalence of NTD dropped from 0.94% (4/426) by 2018 to 0.15% (9/5860)
by 2021, compared with 0.07% (22/22475) under other regimens not containing
dolutegravir and also 0.07% among those not exposed to HIV (APR 2023). Bictegravir
cannot yet be recommended due to insufficient data (approximately 140 pregnancies).
Data on raltegravir are known from more than 400 pregnancies with periconcep-
tional exposure. Elvitegravir/c is not well suited due to insufficient levels during preg-
nancy. Data from pregnancies under cabotegravir are not available. The recom-
mended PIs are darunavir/r (BID) and atazanavir/r (QD). The NNRTIs rilpivirine and
efavirenz are recommended as alternatives. Doravirine is not (yet) established, and
the resistance barrier is higher than for rilpivirine. Nevirapine is no longer recom-
mended; dual and cobicistat-boosted therapies are not recommended for pregnancy.

Continuation of ART during pregnancy

Existing ART with INSTIs – including dolutegravir – can be left in the first trimester
according to DHHS guidelines (DHHS 2023), as pregnancy is usually confirmed after
the first four to six weeks of development. Neural tube defects may develop during
this period. According to the EACS guidelines, it should be discussed whether
478 Women and Children

dolutegravir therapy should be modified in the first six weeks (EACS 2022). If a
change in therapy is decided in the first trimester, it is likely to be safe regarding
viral suppression and neonatal outcomes (Peyronnet 2019) (see below). Raltegravir
(400 mg BD) can be left in place. Substances containing cobicistat as an enhancer
can be exchanged or continued under close plasma level and viral load monitoring
in the second and third trimesters. This should also be considered for single-dose
darunavir/r and, if appropriate, for sufficient dual therapies. Efavirenz may be
continued based on recent embryotoxicity results. Rilpivirine (RPV) has been without
apparent embryotoxicity in over 500 documented exposures. No pregnancy out-
comes have yet been documented for rilpivirine long-acting. For doravirine, there is
data from a placental perfusion model with evidence of high placental transfer and
accumulation (Pencolé 2020).
If the initial diagnosis of HIV infection is made late, e.g., in the third trimester, it requires
immediate therapy, preferably with INSTIs such as dolutegravir and raltegravir, to
rapidly reduce viral load and achieve complete suppression by the time of delivery.
With complete suppression to below 50 HIV RNA copies/mL by 34–36 weeks of
gestation at the latest, perinatal transmission becomes unlikely. In these cases, intra-
partum intravenous transmission prophylaxis with AZT is not necessary (DAIG 2020).
Vaginal delivery is then performed. If the viral load was undetectable throughout
the pregnancy, neonatal postexposure prophylaxis (neo-PEP) may also be omitted.
If viral load was detectable just before delivery, pre/intrapartum ART is boosted with
i.v. AZT for transmission prophylaxis during delivery. Sectio is performed, and post-
natal mono-exposure prophylaxis with AZT is extended to combination prophylaxis
in the child (see below).

Start of ART during pregnancy

Approximately one-quarter of pregnant women with HIV infection are first diagnosed
during prenatal care. European and American guidelines recommend treatment
irrespective of immune status and viral load. Before starting therapy, a resistance test
and, if necessary, subtyping should be performed. It should be noted that despite
the lack of approval, NRTIs other than AZT are preferred as part of the therapy,
provided that the resistance test and expected toxicity do not contradict this. If HIV
is diagnosed in the first trimester, ART should be started as soon as possible. However,
the urgency of the indication depends on the viral load level and CD4 T-cell count.
If the values are good, it should be considered to wait for the first 6–8 weeks. In
principle, the choice of agents should be the same as for non-pregnant women. AZT
is usually discontinued. Dual therapies are not recommended in pregnancy due to
lack of data but may be continued with monthly viral load monitoring.
Dolutegravir is the drug of choice in the DHSS recommendations. Because of the
minimal increase neural tube defects (NTDs) in an early study in Botswana, EACS
guidelines recommend waiting until (approximately eight weeks gestation). As
shown above, bictegravir is not (yet) recommended due to lack of data. No increased
malformation rates have been reported with raltegravir (BID) in over 400 documented
pregnancies. Elvitegravir boosted with cobicistat is not recommended in pregnancy
due to low active levels. As an NNRTI, rilpivirine is preferred for viral loads less than
100,000 copies/mL and CD4 T-cell counts greater than 200/µL (DAIG 2020).
Viral loads should also be carefully controlled because of approximately 20–50% low
total and trough levels. Efavirenz is recommended as an alternative. Periconceptional
teratogenicity in primates has not been confirmed in humans in over 1,300 preg-
nancies. Nevirapine is now mentioned only by DAIG (2020) as an alternative NNRTI.
Data on doravirine are lacking. The PIs darunavir (twice daily) and atazanavir boosted
with ritonavir are considered alternatives.
Pregnancy and HIV 479

Table 1: Special features of ART in pregnancy.

Resistance testing, if necessary, HIV subtyping before starting therapy
Dolutegravir in the first trimester, if necessary, only from 8 weeks of gestation (initial 2018 Tsepamo
study with increased incidence of neural tube defects)
Bictegravir has no data; therefore, it is not recommended.
In the 2nd and 3rd trimesters, Raltegravir 400 mg BID
Cobicistat in 2nd and 3rd trimesters has insufficient plasma levels, especially with Elvitegravi/c,
so avoid or monitor viral load closely
Replace darunavir/c with darunavir/r BID or close viral load monitoring
If taken preconception, continue raltegravir (400 mg BID), rilpivirine, or darunavir/r
Efavirenz (Sustiva®) has no embryotoxicity (no neural tube defects)
Nevirapine is not recommended due to increased toxicity (v.a. >250 CD4 T-cells/μl) but may be
continued if pre-conceptional therapy is in place
Rilpivirine has decreased plasma levels, close viral load monitoring during 2nd/3rd trimester
Checking hemoglobin and liver values about monthly
Viral load every two months: prepartum in 34–36 weeks of gestation
Risk disclosure Teratogenicity: Only AZT is approved for perinatal transmission prophylaxis, but it is
rarely used anymore
If viral load <50 reached at the latest 34–36 weeks of gestation: no i.v. AZT intrapartum

Prophylaxis in antiretrovirally pre-treated pregnant women

In the case of efficient ART (<50 copies/mL) with fixed combination preparations,
this is left in place, and AZT is dispensed with as a component of combination
prophylaxis (“non-AZT prophylaxis”). The NRTI backbone usually consists of
TAF/FTC, TDF/FTC, or ABC/3TC.

Interruption of therapy in the first trimester

Women who have to interrupt their ART, e.g., because of hyperemesis, should not
resume it until the medication is expected to be tolerated again. Especially if the
pregnancy is diagnosed very early, fear of possible embryotoxic effects may lead to
interruption until after the first trimester. However, there are indications that after
interruption of therapy during pregnancy, complete viral suppression may be more
difficult in the further course.
If ART is interrupted, NRTIs, PIs, or INSTIs should be discontinued and restarted
simultaneously to avoid resistance. Because the gestational age can usually not be
determined precisely, the restart is usually scheduled after 13+0 weeks of gestation.
Due to their long half-life, NNRTIs should be discontinued up to three weeks before
NRTIs to avoid resistance; alternatively, the NNRTI can be replaced by an INSTI, or
a PI boosted with ritonavir beforehand.

ART for initial HIV diagnosis in the 2nd and 3rd trimesters
For later initial diagnosis, mainly if this occurs at the end of the second and in the
third trimester, dolutegravir or raltegravir are preferably recommended for rapid viral
load reduction, in each case in combination with two NRTIs.
Potential fetotoxicity due to accumulation, especially with pre/intrapartum admin-
istration, and perinatal transmission risk must be carefully weighed. For women
whose viral load is detectable on existing ART due to compliance or resistance issues,
resistance testing is performed and, if possible, switched to a combination with
480 Women and Children

dolutegravir or raltegravir or added to existing therapy. The rapid viral load reduction
typical of INSTIs is essential to minimize the risk of transmission.

Therapy monitoring
Especially in case of reduced immune status, ART is continued with careful labora-
tory and ultrasound controls. If necessary, the viral load and CD4 T-cell count should
be checked bi-monthly (at the beginning monthly), and the remaining pregnancy
support should be carried out according to general pregnancy guidelines and obstetric
criteria.
Always viral load should be measured in 34 to 36 weeks of gestation to plan the
mode of delivery. Hemoglobin and transaminases are checked monthly. If treated
with PIs, glucose levels should be monitored closely. Resistance and plasma levels,
if applicable, are determined at therapy initiation and failure.

Hepatitis B and/or C co-infection

An NRTI combination of TAF or TDF and FTC or 3TC should preferably be used as
a backbone in HBV coinfection (Funk 2020). The newborn is actively and passively
immunized against hepatitis B within 12 hours. There is little data on treating HCV
coinfection with oral DAAs in pregnancy. A phase I study of sofosbuvir/ledipasvir in
28 pregnant women with HCV genotype 1 mono-infection showed an SVR 12 of
100% (Chappell 2019). However, there is usually no urgency, and HCV therapy can
be deferred until after pregnancy. Interferon is contraindicated, and ribavirin is
considered embryo- and fetotoxic. Hepatitis coinfection may be associated with
increased liver toxicity from ART. Therefore, it is recommended that liver values be
checked approximately every four weeks (DAIG 2020, DHHS 2023). The mode of
delivery for both coinfections depends on the HIV situation (see below).

HIV drugs during pregnancy

NRTIs (nucleoside analogs)
Nucleoside analogs are placentally acceptable. For NRTIs such as AZT, 3TC/FTC,
abacavir, and TDF, the teratogenicity risk should certainly not exceed 1.5-fold
(Antiretroviral Pregnancy Registry 2023). Most experience is with AZT, but it is now
considered only an alternative. Follow-up of more than 20,000 infants revealed no
serious adverse effects from AZT prophylaxis despite the potential mitochondrial
toxicity described (The Perinatal Safety Review Working Group 2000), even with
exposure in the embryonic period. The combinations of ABC/3TC and TDF/FTC have
not resulted in increased congenital malformation rates. With abacavir, hypersensi-
tivity reaction (HSR) should be considered (see chapter ART), and HLA-B*5701 testing
before initiation of therapy is mandatory. No HSR-related complications have been
reported in abacavir-exposed fetuses. Since most women with HIV become pregnant
while on existing ART, toxicities of individual agents can now only be detected in
large prospective studies. Further studies are needed on long-term effects in HIV- and
ART-exposed, uninfected children (see below).
TDF and FTC also have good placental clearance. A meta-analysis of 17 studies found
TDF to be safe for pregnant women and infants (Nachega 2017, Lockman 2021).
A previously reported lower neonatal bone density and low birth weight of up to
19% with TDF in combination with various PIs (Rough 2018, Sebkiari 2019, PROMISE
077BF/FF) have not been conclusively resolved. With tenofovir-based PrEP in
pregnancy, no growth disturbances were observed in newborns or in the first year
of life in a small study (Heffron 2018).
Pregnancy and HIV 481

Human placental transfer of TAF is low (Brooks 2021). No increased teratogenicity

could be demonstrated in animal experiments. TAF is preferred over TDF in current
DHHS recommendations. Despite greater weight gain with dolutegravir and TAF,
gestational diabetes did not develop, and pregnancy outcome was superior to
efavirenz and TDF (Chinula 2022, Lockman 2021). However, due to insufficient data,
the BHIVA 2020 recommends TAF only from the 2nd trimester.

NNRTIs
Nevirapine is no longer used as first-line therapy (DHHS 2023). If pregnancy occurs
while on nevirapine, it can be continued regardless of CD4 T-cell count and poten-
tial hepatotoxicity monitored. If there is an increased perinatal risk of transmission,
the newborn receives one dose of nevirapine immediately after birth, another after
48–72 hours, and a third after another 96 hours. In addition to prophylactic, empiric
therapeutic doses are used in neonates (see below). Efavirenz has not been confirmed
to have potential human embryotoxicity (Martinez de Tejada 2018). The Tsepamo
study from Botswana also found a low NTD rate of 0.04 in children born to women
who had taken efavirenz periconceptually. However, a twofold increased risk of
microcephaly was reported in a study of 141 children (Williams 2020). As a recom-
mended alternative, oral rilpivirine is moderately placental (cord blood/maternal
ratio 0.35–0.81), and plasma concentrations were 20–50% lower in the last trimester
than postpartum. There is insufficient data on long-acting injectable (LA) rilpivirine
(see below: LA cabotegravir). Etravirine showed 34% increased plasma concentra-
tions in the third trimester, and the placental transfer rate was 0.52 (variable from
0.19 to 4.25) (Mulligan 2016); fetotoxicity was estimated to be low. Doravirine
showed no reproductive toxicity in animal experiments. Insufficient human in vivo
data are available. People with suppressed viral load may continue doravirine with
frequent viral load monitoring or switch to an ARV regimen recommended for use
in pregnancy.

Protease inhibitors (PIs)

PIs are also considered alternative ART in pregnancy. Possible diabetogenic effects
and hepatotoxicity should be monitored every one to two months, especially in
advanced pregnancy. Unlike darunavir and atazanavir, lopinavir/r is no longer rec-
ommended due to side effects.
Mild hyperbilirubinemia of approximately 1.5 mg/dl in neonates has been described
with atazanavir/r at a placental transfer rate of approximately 20%. Intracellular
levels were not significantly decreased during pregnancy. Increased risks for congeni-
tal skin anomalies and musculoskeletal malformations were not observed in approx-
imately 1,500 first-trimester exposures, for an overall malformation rate of 2.11%.
Darunavir/r is the preferred protease inhibitor when a PI-based regimen is indicated
(DHHS 2023). DRV has low placental clearance; despite decreasing plasma levels
during pregnancy, dose adjustment is usually unnecessary (Schalkwijk 2019).
However, a dose of 800/100 mg darunavir/r is considered suboptimal, with a 33–44%
decrease in plasma concentrations during pregnancy and a 17–27% decrease with a
single dose. Therefore, darunavir/r is recommended at 600/100 BD if therapy is con-
tinued in pregnancy. NRTI-sparing monotherapies resulted in 92.8% HIV suppres-
sion in a pilot study (Mandelbrot 2021). Darunavir/c is not recommended in the
second and third trimesters because plasma levels of darunavir were 56 and 50%
lower under cobicistat and 63% and 59% lower for cobicistat than postpartum
(Crauwels 2019). ATV/r is an alternative PI regimen with once-daily dosing.
An increase in preterm births with PI-containing ART (Townsend 2010, Powis 2011,
Sibiude 2012, Watts 2013, Schneidman 2023) has been confirmed in several studies.
482 Women and Children

Alfa-fetoprotein levels and progesterone are reported to be decreased under PI regimens,

but unconjugated estriol and human chorionic gonadotropin levels are not.

Entry and fusion inhibitors

The placental toxicity of maraviroc is moderate, with a ratio of 0.25. Like T-20, the
substance is now hardly needed. Fostemsavir (FTR) is placentally acceptable in animal
experiments.

Integrase inhibitors
The good placental clearance of INSTI is an advantage for late-onset transmission
prophylaxis. With dolutegravir, trough plasma levels were not significantly decreased
in the third trimester. The unbound component appeared elevated in the third
trimester compared with postpartum concentrations (Colbers 2019). The fetomaternal
ratio is 1.38 (0.63–1.81) (Colbers 2019). Accumulation was reported in a preterm
infant because of a fourfold longer half-life and twofold longer in mature neonates.
Dolutegravir is preferred over raltegravir for acute infections because of its lower
resistance rates (DHHS 2023). In a prospective study in Botswana of dolutegravir in
early pregnancy, an initially significant risk of neural tube defects was not seen later
in larger numbers of cases – incidence was 0.3 versus 0.1% with ART regimens without
dolutegravir.

Table 2: HIV medications in pregnancy (GW = week of gestation).

NRTIs TAF/TDF + FTC Bone density ↓ in newborns at TDF
(placenta-permeable) ABC + 3TC o. FTC Because of HSR: HLAB5701 test is obligatory
AZT + 3TC Only alternative, AZT is metabolized in the placenta
Risk for mitochondriopathy:
DDI>D4T>AZT>3TC>>ABC>TDF/TAF
NNRTIs Efavirenz No neural tube defects, usable in the 1st trimester
(placenta-permeable) Etravirine Variable transfer ratio 0.52 (0.19–4.25),
PK in pregnancy unchanged
Nevirapine No longer recommended, hepatotoxicity ↑,
especially with > 250 CD4 T-cells; rapid resistance
Rilpivirine AUC 30% ↓ ; placental transfer 0.5 (0.35–0.81)
Doravirine Placental transfer 0.5, insufficient data
PIs (low Darunavir/r Low placental toxicity, 2 x daily dosage
placenta-permeable) Darunavir/c Low levels, therefore avoid or close VL monitoring
Atazanavir/r Alternative recommended PI, alternative ARV,
hyperbilirubinemia,
Lopinavir/r 2 x daily dosing, dose increase if necessary, lipids ↑
Integrase inhibitors Dolutegravir Rather not before 8 weeks of gestation due to
(high placental neural tube defects; placental transfer 1.38 (0.63–1.81),
transfer) HWZ ↑ at NG, higher resistance barrier than RAL
Raltegravir Rapid reduction of viral load, half life ↑ in NG, BID
Elvitegravir/c Low levels; not recommended as initial therapy
Bictegravir High placental transfer in individual cases
PM transfer, insufficient data
Cabotegravir IM Long half-life, insufficient data on pregnancy
Pregnancy and HIV 483

Raltegravir is now recommended as an alternative rather than preferred ARVs for use
in pregnancy (DHHS 2023). It also shows good placental transfer and rapid viral load
reduction. In vitro, it does not affect neonatal hyperbilirubinemia. Compared with
efavirenz, it showed no differences in neonatal size and weight. If raltegravir is taken
during pregnancy, before and during delivery, there is a risk of accumulation in the
neonate. Therefore, potentially subsequent neonatal PEP with raltegravir is not
recommended until 1–2 days. Elvitegravir/c is not used for initial therapy due to
lowered plasma levels in the 2nd and 3rd trimesters. No toxicities have been reported
with bictegravir from 235 pregnancies. No embryofetotoxicity has been reported in
animal experiments. Placental transfer was low in ex vivo models, as it was for
cabotegravir. In contrast, high placental transfer was present for bictegravir, with a
fetomaternal ratio of 1.42 (Bukkems 2021). According to pharmacokinetics models,
dose adjustment in pregnancy is unnecessary (Atoyebi 2022). However, due to
insufficient data about the use of bictegravir in pregnancy, people who present on
this regimen with a suppressed viral load may continue their current treatment with
frequent viral load monitoring or switch to an ARV regimen that is recommended
for use in pregnancy (DHHS 2023). Some pregnancy data exist for long-acting
injectable cabotegravir and rilpivirine (Patel 2023). Counseling is recommended to
support informed decisions about whether to continue with frequent viral load
monitoring or consider switching to a three-drug regimen recommended for use in
pregnancy.

Teratogenicity and long-term effects in children after intrauterine ART exposure

Overall, embryonic and fetal toxicity appears low (APR 2023). However, long-term
data are incomplete. In a prospective study of 2,644 ART-exposed, uninfected
children, neurologic symptoms were seen in 0.26%, and language development
delays were seen in other follow-up (Wedderburn 2019). Delays in auditory evoked
potentials and nonspecific changes in cerebral MRIs of children perinatally exposed
to AZT and 3TC were described. In another study, no developmental delays could
be demonstrated in children exposed to HIV and in 64% exposed to AZT at 24 months
of age compared with children not exposed to HIV and/or ART (Chaudhury 2017).
Cardiac changes were transient (Garcia-Otero 2016) or undetectable. Elevated lactate
levels, impaired hematopoiesis, and metabolic changes regarding hyperlactatemia
syndrome can be detected in children long after antiretroviral prophylaxis. A meta-
analysis of 22 studies found increased mortality in HIV- and ART-exposed children.
Mitochondrial toxicities associated with prenatal ART exposure have been described
(Poirier 2015) as having immunologic defects and a higher incidence of severe infec-
tions and hospitalizations (Slogrove 2017). Furthermore, growth disturbances have
been noted in children with prenatal ART exposure (Sudfeld 2016) and persistent
lower weight curves in the first year of life (Le Roux 2019). Alterations in lipid
metabolism were reported by Williams 2016. Overweighed HIV-exposed adolescents
were at greater risk for elevated blood pressure compared with overweighed children
and adolescents in the general population (Jao 2019). Furthermore, neurocognitive
impairment has been reported in prenatally ART-exposed children. However, many
studies are inconsistent and methodologically inadequate, and high-quality long-
term studies are needed.

Risk of perinatal HIV infection

About 75% of HIV is transmitted during or in the last weeks before birth. About 10%
of vertical HIV infections occur before the third trimester, and 10–15% occur through
breastfeeding. The likelihood of HIV transmission correlates with viral load and treat-
484 Women and Children

ment duration. This is also true for women on ART (Table 3). The probability is
extremely low if the viral load is below the detection limit. Vaginal births have thus
become possible, as has the omission of post-exposure prophylaxis in the newborn
(neo-PEP). In contrast, lack of or inadequate HIV suppression increases the risk of
transmission. The combination of plasma viremia and prematurity and/or prema-
ture rupture of membranes poses an additional transmission risk. It is, therefore,
essential to reduce plasma viremia and improve the mother’s immune status. ART
should also be taken at the prescribed times during delivery, if possible. Resistance
is still thought to be involved in about 20% of the current HIV transmission rate of
less than 2%. The risk is increased in women infected with HIV perinatally, but it
remains below 1% even here.

Table 3: Risk factors of perinatal HIV transmission.

High maternal viral load, low CD4 T-cell count

Mother's disease
Vaginal delivery if ≥ 50 HIV RNA copies/mL without ART (DHHS: if >1000 copies/mL)
Premature rupture of membranes of more than four hours in HI viremia
Premature birth with viremia (< 37th week of pregnancy)
Breastfeeding in the setting of viremia

Medical prevention, in addition to maternal ART, includes:

• Antiretroviral prophylaxis before and during birth (with HI viral load >50 copies/mL
in 36 weeks of gestation) by INSTIs (dolutegravir, raltegravir) and AZT intravenously
• The primary cesarean section on the laborless uterus, as vaginal delivery increases
the risk of transmission at a viral load of ≥50 copies/mL
• The postnatal antiretroviral postexposure prophylaxis of children (escalated).
• The avoidance of breastfeeding

Transmission prophylaxis pre/intrapartum at <50 copies/mL:

low transmission risk
Combination therapy of pregnant women with two NRTIs and either INSTI, boosted
PI, or NNRTI is sufficient as preexposure prophylaxis of perinatal HIV transmission,
provided the viral load is below 50 copies/mL (<1,000 copies/mL according to US
guidelines). Intravenous AZT administration during delivery is not recommended.
Neonatal PEP can also be omitted if the viral load is consistently below 50 copies/mL
before and during pregnancy (DAIG 2020).

Prophylaxis for ≥ 50 copies/mL: increased risk of transmission

If there is a standard risk and the viral load is above 50 copies/mL prepartum, resist-
ance testing is performed, adherence is evaluated, and ART is escalated with an INSTI
if necessary. At parturition, intravenous AZT is administered. While the transmis-
sion rate was 0.05 and 0.3% for less than 50 copies/mL, it is 1.1 and 1.5% between
50 and 399 copies/mL, and 2.8 and 4.1% for a prepartum viral load of >400 copies/mL
(Townsend 2014). Delivery is by sectio. Neonatal combination prophylaxis is prob-
ably reasonable. Depending on the assessment of risk, mono-PEP with AZT for four
weeks is given to the infant or dual- or triple-combination prophylaxis is given.

Intrapartum prophylaxis/therapy without prior treatment

If HIV infection is not known until the time of birth, mother and newborn receive
dual or triple prophylaxis with AZT (plus FTC/3TC as well as an INSTI and/or
Pregnancy and HIV 485

nevirapine (in the newborn) (increased risk with low viral load or significantly
increased risk with high viral load and/or obstetric complications). The 2022 US
guidelines recommend dolutegravir as an alternative for acute HIV infection in preg-
nancy because of lower HIV resistance rates than raltegravir.

Table 4: Transmission prophylaxis for prepartum viral load ≥ 50 HIV RNA copies/mL.
Resistance testing, if necessary, therapy escalation, e.g., with an INSTI
Two NRTI + plus INSTI or PI/r
During delivery (elective sectio at the earliest from 37 + 0 weeks of gestation), AZT is infused
intravenously into the mother for standard prophylaxis if VL > 50 (DHHS: > 1,000) copies/mL*:
2 mg/kg i.v. as "loading dose" over 1 hour approx. 3 hours preoperatively/prepartum).
1 mg/kg i.v. intraoperatively/intrapartum) until the child develops
In the newborn, AZT monoprophylaxis within 6 hours postpartum:
2 (4) mg/kg orally every 6 (12) hours for 4** weeks or if orally intolerant:
1.5 mg/kg i.v. every 6 hours for 10 days
In case of additional risk factors, extended postnatal prophylaxis (combination Neo-PEP).
* The benefit of intravenous AZT at viral load <50 (<1,000) copies/mL is not specific (DAIG 2020, DHHS
2023, EACS 2022). Therefore, AZT can then be omitted
** 4 weeks e.g. at >50 to <1,000 copies/mL. In case of additional risk factors, extended PEP (see below).

Treatment during birth

Prerequisites for a vaginal delivery mode
If the viral load is less than 50 copies/mL before delivery (viral load negative at 34
to 36 weeks of gestation), the advantage of elective (primary) sectio over vaginal
delivery is no longer demonstrable (Townsend 2014). Therefore, in most countries,
unless obstetric complications are anticipated, these women are scheduled for a
vaginal delivery, which is lower risk compared with a sectio. The rate of vaginal deliv-
eries in Western Europe is approximately 50%. In the American guidelines, vaginal
delivery is recommended if the viral load is less than 1,000 copies/mL, if necessary
with intravenous AZT administration.
No increased risk has been demonstrated with surgical vaginal delivery (e.g., vacuum
extraction). Similarly, premature rupture of the membranes, amniotic infection syn-
drome, and prematurity are not thought to pose an increased risk of transmission if
the viral load is negative. Even extreme prematurity of <30 weeks of gestation is
unlikely to pose an increased risk if viral load is consistently negative. Previous studies
on transmission risk have sometimes reached divergent results (Townsend 2010).
Therefore, even in preterm infants, monoexposure prophylaxis with AZT for 2 (to
4) weeks is sufficient. Neonatal PEP can be dispensed if the viral load is constantly
undetectable during pregnancy.

Elective caesarian section for elevated viral load prepartum

If there is a risk of transmission due to incomplete reduction of the viral load (non-
compliance, later prepartum HIV diagnosis), ART is started or escalated if time permits
(see above), and AZT is infused intravenously as transmission prophylaxis during
delivery. Sectio is performed electively before the onset of labor and at the earliest
from 37+0 weeks of gestation using a low-bleeding surgical technique, according to
Misgav-Ladach, swiftly and by experienced gynecologists. Blunt dissection and devel-
opment of the child in the standing amniotic sac are considered ideal.
486 Women and Children

Table 5: Prophylaxis for low transmission risk in preterm and mature infants and prepartum viral
load (VL) <50 HIV RNA copies/mL.
Low risk Mother Child
≥ 35 weeks of Combination, e.g., TDF + FTC (3TC) Within 6 hrs postpartum
gestation of mothers or ABC/(AZT) + FTC (3TC) plus AZT 2 x 4 mg/kg orally 2(–4) weeks,
with HI-VL prepartum INSTI, alternatively PI/r, NNRTIs alternative: i.v. 2 x 3mg/kg*
<50 without possible if indicated, vaginal Sustained VL below 50 copies/mL during
adherence pregnancy: Neo-PEP dispensable
problems
Premature birth Combination, e.g. 2 x 2 mg/kg orally or 2 x 1.5 mg/kg i.v.,
30+0–34+6 weeks of AZT + FTC (3TC) or from day 15: 2 x 3 mg/kg orally
gestation and VL <50 TDF + FTC (3TC) plus AZT 2–4 weeks for preterm birth
Premature birth ** INSTI, alternatively PI/r, <30+0 weeks of gestation from day 29
< 30+0 weeks if necessary NNRTI
of gestation and Mode of birth according to
VL < 50 obstetric criteria; see above
* For oral feeding problems; p.p. = postpartum. VL = viral load, HIV RNA copies/mL.

Table 6: Prophylaxis for increased risk: viral load ≥ 50 copies/mL.

Increased risk Mother Child
Mother without sufficient If necessary, ≥35 weeks of gestation: AZT 2 x 4 mg/kg
HIV therapy before and escalation of orally: AZT dosage for preterm birth <35+0
during delivery ART with, e.g., weeks of gestation: 2 x 2 mg/kg orally or
(viral load ≥ 50 copies/mL): Dolutegravir or 2 x 1.5 mg/kg i.v., from day 15: 2 x 3 mg/kg
Especially after vaginal delivery Raltegravir orally (for preterm birth <30+0 weeks of
No ART pre- and/or intrapartum gestation from day 29) for 4–6 weeks plus if
necessary 3TC** 2 x 2 mg/kg over 2 weeks
plus Nevirapine* 2 mg/kg within 2 h to 48 h +
2nd dose 48 h after 1st ***
Or if appropriate, raltegravir**** 1.5 mg/kg
up to 7 days, 2 x 3 mg/kg 8-28 days,
> 4 wks u. >3kg 2 x 6 mg/kg
*See chapter NNRTIs. **Caution: neutropenia in combination with AZT, in preterm infants: rather not
use 3TC; *** according to DHHS 2023: 1st dose: after birth until 48 h, 2nd dose: 48 h after 1st, 3rd
dose: 96 h after 2nd **** Approval for newborns ≥37 weeks of gestation ≥2 kg.

In the case of premature birth, the caesarian (C-) section is also essential for obstet-
ric reasons to avoid hypoxia of the premature baby; the specifics for prophylaxis are
listed above. In case of premature rupture of membranes of less than four hours, a
C-section is reasonable if the situation still allows it. If it takes more than four hours,
there is no advantage over vaginal delivery. However, this should be done quickly,
as the risk of HIV transmission increases by about 2% per hour, depending on viral
load. It is then essential to extend precautions to the child (Table 6).

Unknown HIV status

If the HIV status is unknown at the time of birth and a suspicion exists, a rapid HIV
test is recommended. Because of the high but insufficient specificity, using two rapid
tests from different manufacturers is advisable. If one test is negative, there is prob-
ably no infection.
Pregnancy and HIV 487

Treatment of the newborn

Standard postnatal prophylaxis for VL < 50 copies/mL: low risk
Postnatal transmission prophylaxis in the case of negative viral load and low risk of
transmission begins, if possible, within the first 4–6 hours after birth with oral or
intravenous AZT prophylaxis in the case of gastrointestinal symptoms. The duration
of standard oral prophylaxis is two (to four) weeks (Vocks-Hauck 2001, Neubert 2013).
For negative viral load, DAIG (2020) and the British HIV Association (BHIVA 2020)
suggest two weeks in newborns whose mothers have been on antiretroviral treat-
ment for at least 10 weeks and in whom a negative viral load has been documented
at least twice, most recently four weeks or later before delivery (at or after 36 weeks
of gestation), and four weeks in the United States. If HIV was already undetectable
preconceptually up to delivery, neonatal PEP may be omitted entirely (DAIG 2020).

Prophylaxis for increased transmission risk with VL ≥ 50 copies/mL

An increased risk exists at a viral load above 50 copies/mL. In the US guidelines, a
viral load of 1,000 copies/mL is considered the limit for increased risk of transmis-
sion. Still, escalation of Neo-PEP is considered reasonable at a prepartum viral load
of 50 to 1,000 copies/mL. Additional risks such as prematurity, premature rupture
of the membranes, amniotic infection syndrome, viral load far above 1,000 copies/mL
before birth, lack of transmission prophylaxis, cut injury to the child during sectio,
and aspiration of bloody amniotic fluid from the gastrointestinal or respiratory tract
if the mother’s viral load is detectable before delivery are criteria for escalation.
In children with these additional transmission risks, combination prophylaxis of
AZT+3TC and three administrations of nevirapine are recommended. In the first
week, this is administered immediately after birth, 48 hours after the first dose, and
96 hours after the second dose. Newborns receive prolonged AZT prophylaxis (see
below) for four to six weeks. Because of the increased toxicity with the combination,
3TC is recommended for only two weeks. In very small preterm infants, dose
recommendations exist for AZT and NVP, so only dual prophylaxis may be possible
here. Raltegravir has approval in neonates >37 weeks of gestation and weighing more
than 2 kg. If INSTIs were given long-term during pregnancy or before birth, there is
a risk of accumulation in the newborn. Therefore, it is recommended that INSTI-PEP
not be started in the newborn until the second or third day of life. If late initiation
of prenatal therapy has failed to prevent an intrauterine infection that has already
occurred, empiric combination therapy started neonatally will transition to ART in
the infant. Dolutegravir is approved in infants weighing 3 kg or more and four weeks
of age.
The UK guidelines recommend nevirapine, raltegravir, and TDF in double doses intra-
partum to achieve an initial dose in the preterm infant if the woman is at risk of
preterm birth and presents late in pregnancy.
Data on PIs are limited to neonates. Lopinavir/r was associated with increased cardiac
toxicity in preterm infants. Adrenal insufficiency was also observed in neonates who
were prenatally exposed to lopinavir/r and received postnatal PEP for 30 days.
Therefore, it is used in the first two weeks of life only in exceptional cases. In
premature infants, administration is not recommended until two weeks after the
expected date of birth.

Procedure in the absence of pre- and intranatal prophylaxis

Combination prophylaxis with AZT(+3TC) begins as early as possible within the first
6 to 12 hours after birth. In addition, postnatal nevirapine prophylaxis is given in
three doses or raltegravir. Because of the toxicity of lopinavir/r, its use in mature
488 Women and Children

Table 7: Studies of antiretroviral prophylaxis in neonates.

Short name Medium Most common Studies/Approval
Daily dose Side effects in newborns
AZT 2 x 4 mg/kg, 2 x 2 mg/kg Anemia, neutropenia (P)ACTG 076, 316,
Retrovir® for premature infants in combination with 3TC, 321, 331 (FG) 353,
<35 weeks of gestation, mitochondriopathy 354, 358,HIVNET
from day 15: 2 x 3 mg/kg, 012 III
for < 30 weeks of gestation Approval
from day 29
3TC 2 x 2(3) mg/kg in newborns Gastrointestinal symptoms, PACTG 358
Epivir® (< 30 days), 2 x 4 mg/kg in mitochondriopathy in NICHD/HPTN 040/
≥ 4 wks combination intolerance in PACTG1043
premature infants Limited data
FTC 1 mg/kg immediately post- Gastrointestinal symptoms, ANRS 12109
Emtriva® natal or 2 mg/kg after 12 h; mitochondriopathy Gilead PK Study
3 mg/kg for neonates < 3 mo
ABC 1 x 2–4 mg/kg; Hypersensitivity reaction, PACTG 321
Ziagen® > 1 mo. 2 x 8 mg/kg (study). mitochondriopathy,
lactic acidosis
TDF Mother 600 mg intrapartum; Osteopenia, NCT00120471
Viread® newborn 6 mg p.n. daily nephrotoxicity HPTN 057;
(1st week); 1 x 8 mg in ANRS12109 (step 2)
children ≥ 2 years
NVP 14 days 1 x 2–4 mg/kg Hepatotoxicity, PACTG 316,356,
Viramune® or 1 x 120 mg/m2, then exanthema, HIVNET 012
2 x 3.5–4 mg/kg or hyperbilirubinemia
2 x 120 mg/m2 (maximum
2 x 200 mg), 6 mg/kg
Lopinavir/r 2 x 300/75 mg/m2 in children Gastrointestinal, cardiotoxic PACTG P 1030
Kaletra® >2 < 6 weeks; in premature and adrenal insufficiency IMPAACTG P1060
infants >2 wks after in newborns, not in new- Admission:
calculated date borns <2 wk; in premature Children >2 Wo
infants not until 2 wk after
the calculated date
Dolutegravir Approx.1 mg/kg children Gastrointestinal and CNS IMPAACT P 1093
Tivicay® ≥ 3–6 kg u. 4 wks = 5 mg adverse events
Raltegravir 1x1.5 mg/kg up to 7 days for newborns: half-life ↑ IMPAACT P 1066
Isentress® (>2 kg), 2x3 mg/kg day 8-28, IMPAACT P 1110
then 2 x 6 mg/kg Admission 2019
children ≥ 4 wk ≥3 kg
(P)ACTG = (Pediatric) AIDS Clinical Trials Group; IMPAACTG = International Maternal Pediatric
Adolescent ACTG; HIV-NAT = HIV-Netherlands Australia Thailand Research Collaboration; ANRS =
Agence Nationale de Recherche sur le Sida; HPTN = HIV Prevention Trials Network; NCT = NIAID
(National Institute of Allergy and Infectious Diseases) Clinical Trials.
Note: Except for AZT in mature infants, dosages were taken from studies. Unapproved substances
should be used in neonates only in studies.
Pregnancy and HIV 489

infants has not been recommended until two weeks of age and in preterm infants
until two weeks after the calculated date of birth. If HIV infection is unknown until
after birth, early initiation of combination prophylaxis/therapy appears significantly
more effective. Because of potential accumulation, combination PEP/start with
raltegravir is not initiated until 1–2 days after birth.

Counseling and care for women breastfeeding under ART

In countries without limited access to safe drinking water and where substitute foods
are readily available, breastfeeding continues to be discouraged. Even with a negative
viral load, there is a residual risk of HIV transmission, and ART toxicity may be
prolonged (Yuhin 2016).
In several European countries such as Germany, 83% of all children without HIV
exposure were initially breastfed in 2007–2011, on average for eight months. Women
with HIV infection expressed the wish to breastfeed their child in 38% of cases
(Kahlert 2018). This was implemented and documented under the professional super-
vision of interdisciplinary teams of midwives, psychologists, and physicians.
Infections did not occur in this group of more than 50 mother-infant pairs (Haberl
2021). In 72 people who breastfed in the US and Canada, there was no HIV trans-
mission to the child (Levison 2023). The transfer of well-breastfed antiretroviral
agents (Waitt 2019) into the infant’s plasma is low. It is 3–8% of the maternal
concentration. Breast milk transfer studies of efavirenz (BM/P ratio 0.82, Olagunju
2019), etravirine (3.21, Spencer 2019), FTC (3.01), and TDF (0.015, Waitt 2018) and
TAF each resulted in low or undetectable levels in the infant. In women taking PrEP
while breastfeeding, estimated plasma levels of TDF/FTC were <0.01 and 0.5%,
respectively, compared to the pediatric doses (Mugwanya 2016).

Further studies on HIV prevention in newborns

A review of neonatal pharmacokinetics studies is provided in Table 7. Careful
documentation of clinical data is needed to improve ART during pregnancy and pro-
phylaxis of perinatal HIV infection ([Link]).
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493

20. Antiretroviral therapy in children

TI M N I E H U E S, C H R I STO P H KÖ N I G S

Viral dynamics, clinical course, transmission routes

The clinical course of natural untreated HIV infection in infants and young children
is more aggressive than in adults. The viral load in untreated children often rises to
over 1,000,000 copies/mL and then decreases only hesitantly over 4–5 years. Possible
reasons are the developing lymphatic system and the inability of the somewhat naive,
immature immune system to develop an adequate HIV-specific immune response.
Typically, there are specific clinical manifestations that are included in the CDC
classification of HIV infection in childhood (Table 1). Infants without ART show
rapid progression with AIDS-defining symptoms in about 10–25% (see below). The
infection is fatal if untreated: an infant at six months of age with 15% CD4 T-cells
has a 20% risk of dying within 12 months (Dunn 2013). A particularly feared
complication in infancy is HIV-related encephalopathy with opisthotonos, cognitive
defects, loss of milestones, and hyperreflexia. National and international guidelines
recommend starting ART immediately after diagnosis in all children and adolescents,
regardless of CD4 T-cell count and viral load.
Perinatal HIV infections occur mainly when the mother’s HIV status remains
unknown during pregnancy, transmission prevention is incomplete, or the mother
has no access to healthcare. Over 95% of children are infected vertically through the
mother. Horizontal routes of transmission (sexual intercourse, sexual abuse, drug use)
are exceptions. The transmission rate in children of untreated mothers was approx-
imately 20–30% in Europe. These infections are considered 35–45% peri- or intra-
partum and 10–25% in utero. Breastfeeding transmits HIV in another 35–40%, depend-
ing on duration. In suppressed maternal viral load cases, transmission during
pregnancy, childbirth, or breastfeeding occurs rarely.

Diagnosis
The diagnosis of HIV infection is critical to enable a prompt start of treatment,
particularly in infants. PCR is a highly sensitive and specific method for detecting
HIV-specific DNA in lymphocytes and/or HIV-RNA in plasma. The methods for
confirming the diagnosis are adapted to the child’s age.
In children under 24 months of age with peri- and postnatal exposure, HIV detection
must be performed by PCR. Maternal IgG HIV antibodies are actively transmitted to
the child transplacentally. They persist into the second year of life due to the high
titers in infected mothers. Consequently, the antibody test is always positive in
mature, exposed children – even HIV-negative ones. Umbilical cord blood is of limited
use for diagnosis, as maternal cells or contamination may give a false positive result.
Early postnatal testing is helpful if there is a high risk of transmission (e.g., untreated
HIV infection during pregnancy) or if breastfeeding is desired. A positive PCR should
be confirmed immediately in a second blood sample. However, within 48 hours after
birth, PCR remains negative in 62% of all HIV-infected infants and 11% after four
weeks (Burgard 2012).
To exclude HIV infection, at least two PCR tests from independent samples should
be available in breastfed children at one month and three months of age. The control
after three months is necessary because the PCR can be negative even longer after
the end of the transmission prophylaxis. In breastfed infants, further testing is
required every eight weeks and one and three months after cessation of breastfeed-
ing due to the potential exposure to HIV during breastfeeding.
494 Women and Children

In children of at least 24 months of age and with perinatal HIV exposure or

suspected horizontal infection, a combined HIV antigen/antibody test should be
performed. See also the chapter on HIV testing.

Indication for antiretroviral therapy

Updated recommendations of the European PENTA group (Paediatric European
Network for Treatment of AIDS) within EACS (European AIDS Clinical Society) and
WHO are freely available online. The recommendations include the approach for
adolescents and hepatitis B, hepatitis C, and tuberculosis co-infections.
• Europe (EACS): [Link]
• US: [Link]
• WHO: [Link]

Premature infants (< 37th week of gestation)

The limited data on dosages and safety are based on case reports. Some toxicities
have been described. For example, lopinavir/r can lead to metabolic derailment and
cardiac or endocrinologic problems, and raltegravir can exacerbate hyperbilirubinemia.

Children < 3 years

In infancy, the risk of dying from AIDS is exceptionally high if the start of therapy
is delayed (Violari 2008, Judd 2011). This is due to poorer control of HIV infection
up to the age of 3. Therefore, initiation of therapy is always recommended in the
first three years of life, regardless of virologic, immunologic, and clinical criteria.

Children ≥ 3 years
Starting ART in older children is not an emergency. Given the presumably lifelong
treatment, limited options, and potential side effects, premature “consumption” of
effective therapies makes little sense. However, starting therapy too late could result
in a larger reservoir of latent HIV-infected cells in the body and irreversible damage
to the immune system and CNS due to continuous, subclinical inflammation. The
START trial in adults showed that early initiation of therapy above 500 CD4 T-cells/µl
is superior to later initiation at 350 cells/µl (Insight 2015).
Although such data is lacking for children > 3 years of age, European and American
guidelines recommend treatment for all children and adolescents, regardless of clin-
ical, virologic, and immunologic status. Priority for a rapid treatment start is given
to children < 3 years, adolescents, and children and adolescents with symptoms or
low CD4 T-cells (American guidelines: “treat” and “urgent treatment”).
In older asymptomatic children (37 months to the end of 12 years of age), the German
guidelines do not advocate a general therapy recommendation in the absence of clin-
ical, immunological, or virological indications (see below). At this age, a lower disease
progression can be assumed. In the PREDICT trial, in which children aged > 1 year
(mean age 6.4 years) were treated either immediately or delayed (CD4 T-cell-based
decision), no clear clinical difference was demonstrated (Puthanakit 2012). To the
extent that initiation of therapy is delayed in this age group, ART should be started
immediately if clinical symptoms, immunodeficiency, and viral loads >100,000
copies/mL are present.
From the age of 12, the guidelines also advocate an immediate start of therapy. In
addition to the individual clinical benefit, another benefit is the prevention of further
infections since people with a negative viral load do not transmit the virus (U = U,
undetectable = untransmittable).
Antiretroviral therapy in children 495

Immunological and clinical criteria

In infancy, there is an age-dependent interpretation of the CD4 T-cell count (Table
1). Example: A value of 700 CD4 T-cells/µl, which appears normal in adults, is highly
pathological in infants and indicates a severe immunodeficiency. Therefore, per-
centages should also be considered. The predictive value of viral load for AIDS and
mortality is less significant than the combination of viral load and CD4 T-cells. For
older adolescents, the recommendations for adults apply (see chapter ART).

Table 1: Immunological stages according to the 2014 CDC classification for childhood HIV infection,
based on absolute or relative CD4 T-cell counts.
Immunological <1 year 1 to <6 years ≥6 years
stage* Cell count/μl (%) Cell count/μl (%) Cell count/μl (%)
1 ≥1,500 ≥34 ≥1,000 ≥30 ≥500 ≥26
2 750–1,499 26–33 500–999 22–29 200–499 14–25
3 <750 <26 <500 <22 <200 <14
* Centers for Disease Control and Prevention. MMWR 2014; 63(Rr-03):1-10.

Table 2: Clinical stages according to the CDC classification for childhood HIV infection
([Link]
CDC stage Clinical symptoms
Stage N: Children who have no symptoms or clinical signs of HIV infection or only one
of the symptoms listed under stage A
Stage A: Children with two or more of the following symptoms but none of the
Early symptoms symptoms listed in stages B and C.
• Lymphadenopathy, hepatomegaly, splenomegaly
• Dermatitis
• Parotitis
• Recurrent upper respiratory tract infections, sinusitis or otitis
Stage B: Children who have symptoms other than those listed in stage A and C.
Moderately Examples of stage B symptoms are:
severe symptoms • Anemia (Hb <8 g/dL), neutropenia (<1,000/μL), thrombocytopenia
(<100,000/μL) for >30 days
• Bacterial meningitis, pneumonia, sepsis (one episode)
• Oropharyngeal candidiasis, persistent for >6 months in children
• Cardiomyopathy
• CMV infection with onset in the first month of life
• Diarrhea, recurrent or chronic
• Hepatitis
• Herpes simplex (HSV) stomatitis, more than two episodes per year
• HSV bronchitis, pneumonitis, or esophagitis in the first month of life
• Herpes zoster (>2 episodes on >1 dermatoma), dissemin. Varicella
• Leiomyosarcoma
• Lymphoid interstitial pneumonia (LIP)*.
• Nephropathy
• Persistent fever >1 month duration
• Toxoplasmosis in the first month of life; nocardiosis
496 Women and Children

Table 2: Continuation
CDC stage Clinical symptoms
Stage C: • More than one severe culturally proven infection with common bacteria
Severe within two years
symptoms, AIDS • HIV encephalopathy
• Wasting syndrome, cachexia
• Pneumocystis jiroveci (formerly "carinii") pneumonia (PCP)
• Cerebral toxoplasmosis in children >1 month of age.
• Cryptosporidiosis with diarrhea >1 month duration
• Isosporidiasis with diarrhea >1 month duration
• Various lymphomas, including CNS lymphomas
• Kaposi's sarcoma
• Progressive multifocal leukoencephalopathy
• HSV-related mucocutaneous ulcers (duration >1 month) or bronchitis,
pneumonia, or esophagitis due to HSV in children aged >1 month
• Lymphoid interstitial pneumonia caused by EBV
• CMV: retinitis, esophagitis, and colitis in children >1 month of age
• Candidiasis of the esophagus, the tracheobronchial system
• Extrapulmonary cryptococcosis
• Disseminated or extrapulmonary histoplasmosis
• Tuberculosis, atypical mycobacterioses
* LIP is classified as B but is still considered an AIDS-defining condition when reported.

Therapy requirements and practical procedures

HIV infection in childhood is very rare. It is recommended to cooperate with an
experienced center. The most essential prerequisite for successful therapy is sufficient
adherence, i.e., adherence to jointly defined therapy goals. Depending on the child’s
age, this is only achieved in 70% of cases (MacDonell 2013). The GEPIC cohort
showed treatment success (<50 copies/mL) in 91% of children and adolescents treated
in Germany. Adherence of pubescent adolescents is described as problematic. Even
in this age group, the viral load in the GEPIC cohort was below 50 copies/mL in
92%. Nevertheless, more individualized therapeutic approaches are needed. In ado-
lescents and young adults, the BREATHER study of the PENTA group compared
reduced administration to 5 intakes/week (break on weekends) of efavirenz-based
ART with administration on 7 days/week: There was no increased risk for the reduced
administration (Butler 2015). The extent to which this strategy holds outside of
strictly controlled trial conditions is unclear and is currently not recommended.
Because of the stigmatization, the high burden of the family with the diagnosis of
HIV, and the constant need to improve therapy adherence, intensive, multidiscipli-
nary team care with personnel from nursing, psychology, and social work would be
indispensable but is often not implemented in clinics due to a lack of funding for
human resources.
Establishing a peer group, if possible, or contact with other affected adolescents is
beneficial. ART should be optimally integrated into the daily routine of children and
adolescents. Taking the medication in the evening before going to bed can be useful
to place peak levels and thus undesirable drug effects in the sleep phase. Morning
intake may be more beneficial for medications with frequent sleep disturbances or
nightmares, such as efavirenz or dolutegravir. The morning routine is often more
regular than the evening for school-aged adolescents. Apps, phone alarms, or
electronic pill boxes can be helpful. Taking tablets/bad-tasting suspensions (e.g.,
Antiretroviral therapy in children 497

lopinavir/r) can be difficult, especially in young children; mixing them into some
milk, syrup, juice, or similar may help. There are several resources with practical tips
that can help with difficulties ([Link]
https:// [Link]/resources/pill-swallowing-podcasts).
Inpatient admission at the start or change of therapy may be necessary to monitor
intake by trained nurses and to manage side effects. Critical prerequisites for suc-
cessful ART are knowledge of adverse drug reactions and an understanding of phar-
macology in children (Waalewijn 2019). Pharmacokinetics can vary significantly
from child to child (Kearns 2003). As in adults, interactions should be considered
(see below). Determining plasma levels at longer intervals may be useful to docu-
ment poor adherence, ingestion errors, and underdosing. Care should be taken to
ensure that children do not “outgrow” their dose and that the dose is adjusted reg-
ularly (Menson 2006).

Treatment strategies
HIV eradication in children and adolescents is currently not possible. In some chil-
dren, sero-reversion may occur after early treatment – HIV-specific antibodies are no
longer found after early therapy initiation. However, with ultrasensitive RNA or cDNA
assays, HIV can usually still be detected in the end – when ART is discontinued, viral
load increases regularly (Butler 2015). In difficult situations (e.g., treatment failure),
it is highly advisable to discuss cases in a multidisciplinary team virtual clinic (link
see EACS guideline (PVC))
A combination with a so-called “backbone” of two NRTIs plus an NNRTI, PI, or INSTI
is recommended as first-line therapy (Table 3). Due to the small number of cases, all
children should be included in clinical registries if possible. Resistance testing should
be performed before starting antiviral therapy.

Classes of Drugs
Drugs are presented with regard to indication, mode of administration, and dose.
Adverse effects such as headache, fatigue, gastrointestinal complaints, or skin rash
are known for all. In children and adolescents, it should be noted that both infec-
tion and therapies can affect growth and development. In the following, toxicities
are listed only if they are particularly relevant in childhood and adolescence.
Dyslipidemias are observed in a proportion of children (Jacobson 2011). In some
adolescents and young adults on long-term ART, changes in coronary vessels have
been found on MR angiography (Mikhail 2011); the long-term consequences are
unknown.
Dosing is mainly by body weight, partly by body surface area, and increasingly by
weight ranges (so-called “weight bands”) [Link]/hiv/paediatric/generic-
tool/en. The dosing intervals commonly used in Anglo-Saxon countries (QD = 1 x
daily, BID = 2 x daily, TID = 3 x daily) are adopted here for reasons of space.

NRTIs
The combination of two NRTIs as part of ART (“backbone”) is usually well tolerated.
The preferred combination initially is ABC+3TC, once daily from the age of 3 months.
Fixed dose combinations exist, some of which can be used in older children (see
Table 4). Substance class-sparing regimens or regimens of two substances (dolute-
gravir/3TC or dolutegravir/rilpivirine) are now approved from 12 years of age; clin-
ical trials are ongoing “D3” study, PENTA 21 or published (Compagnucci 2023),
498 Women and Children

Table 3: Preferred and Alternative First-Line Options in Children and Adolescents

(Pediatric EACS guidelines [Link]
Backbone 3rd Agent (in alphabetical order)
Age Preferred Alternative Preferred Alternative
0 – 4 weeks AZT1 + 3TC – LPV/r2,3 –
NVP3
RAL3
4 weeks – 3 years ABC4 + 3TC5 AZT1 + 3TC6 DTG8 LPV/r
TDF7 + 3TC NVP
RAL
3 – 6 years ABC4 + 3TC5 TDF7 + XTC9 DTG8 DRV/r
AZT + XTC9 EFV
LPV/r
NVP
RAL
6 – 12 years ABC4 + 3TC5 TDF7 + XTC9 DTG8 DRV/r
TAF10+ XTC9 EFV
EVG/c
RAL
> 12 years ABC4 + 3TC5 TDF7 + XTC9 BIC11 DRV/b
TAF10 + XTC9 DTG8 EFV12
RAL12
RPV12

Notes
1. Given potential long-term toxicity, any child on AZT should be switched to ABC (preferred for younger children) or

TAF/TDF (alternative for younger children, with renal/bone toxicity monitoring with TDF) once age and/or weight
increase makes licensed formulations available. When ABC is contraindicated in young children, it is recommen-
ded that treatment options are discussed on a case-by-case basis
2. LPV/r should not be administered to neonates before a postmenstrual age of 42 weeks and a postnatal age of at

least 14 days. However, it may be considered if there is a risk of transmitted NVP resistance and appropriate INSTI
formulations are unavailable. In these circumstances, the neonate should be monitored closely for LPV/r-related
toxicity (e.g., metabolic, endocrine, cardiac)
3. If starting a non-DTG third agent in the neonatal period, it is acceptable to continue this option. However, when

over 4 weeks and 3 kg, a switch to DTG is recommended if and when an appropriate formulation is available
4. ABC should NOT be prescribed to HLA-B*57:01 positive individuals (where screening is available). ABC is not licen-

sed for children under 3 months of age, but dosing data for younger children are available from the WHO and
DHHS
5. At HIV-VL > 100,000 copies/mL, ABC + 3TC should not be combined with EFV as third agent
6. If using NVP as a third agent in children aged 2 weeks to 3 years, consider using 3 NRTI backbone (ABC + AZT +

3TC) until VL consistently < 50 copies/mL

7. TDF is only licensed from 2 years of age. Given concerns about the potential impact on bone development and

renal toxicity, TAF is preferred to TDF at all ages (if available)

8. DTG is licensed from 4 weeks and 3 kg. DTG has been associated with excessive weight gain in adults, especially

with TAF. This has not yet been demonstrated in pediatric and adolescent observational studies or trials. However,
the possibility of this should be considered when DTG is used. Families and young people should be counseled
regarding this, and weight should be monitored
9. XTC indicates circumstances when FTC or 3TC may be used interchangeably
10. TAF is only licensed in Europe for the treatment of HIV in combination with FTC from 12 years of age and 35 kg in

TAF/FTC and from 6 years of age and 25 kg in TAF/FTC/EVG/c. TAF is licensed for younger ages and weights, so that
it can be included as a preferred option. TAF has been associated with excessive weight gain in adults, especially
in combination with DTG. This has not yet been demonstrated in pediatric and adolescent observational studies
or trials. However, the possibility of this should be considered when TAF is used. Families and young people should
be counseled regarding this, and weight should be monitored
11. BIC is a preferred first-line option in adults. It is not licensed under 18 years of age but may be considered in those

aged less than 18 years following discussion at MDT/PVC

12. Due to predicted poor adherence in adolescence, if preferred third agents (BIC or DTG) are not available, DRV/b is

favored due to a higher resistance barrier compared to EFV, RAL or RPV

Antiretroviral therapy in children 499

Lamivudine (3TC) is available as tablets and suspension or generics. Child dosing

(≥3 months) for suspension is 4 mg/kg BID or 8 mg/kg QD (max dose 300 mg per
day). Child dosing for tablets (150 mg) is (≥3 years): (14-21 kg): ½ tablet BID or
1 tablet QD; (>21-30 kg): ½ tablet morning + 1 tablet afternoon or 1½ tablet QD;
(>30 kg): 1 tablet BID or 2 tablets QD; Dosage for adults is: (≥12 years): 150 mg BID
or 300 mg QD. Given HBV activity, it may be appropriate to add 3TC to ART for
chronic hepatitis B. In HIV-negative children with chronic hepatitis B (especially
<7 years of age), early use of 3TC achieves a high HBe/HBs seroconversion rate (Choe
2007). No systematic data are available on HBV/HIV-coinfected children. It should
be kept in mind that long-term 3TC therapy carries the risk of HBV resistance. Again,
combination therapy is recommended.
Abacavir (ABC) is available as a tablet and suspension. Child dosing (≥3 months) is
8 mg/kg BID or 16 mg/kg QD (maximum dose: 600 mg per day). Child dosing with
the tablet of 300 mg: (14-21 kg): ½ tablet BID or 1 tablet QD; (>21-30 kg): ½ tablet
in the morning + 1 tablet in the afternoon or 1½ tablet QD; (>30 kg): 1 tablet BID
or 2 tablets QD; Dosage adults: (≥12 years): 300 mg BID or 600 mg QD. The
disadvantage is the hypersensitivity reaction (HSR) risk associated with HLA-B57. If
positive, abacavir is contraindicated. Because HSR is not entirely ruled out, even in
the presence of B57 negativity, parents should be educated about HSR. If HSR is
suspected, abacavir must be permanently discontinued; re-exposure can be fatal
(single observations in adults).
Emtricitabine (FTC) is available as capsules and suspension. Child dosing for
suspension in children: (≥4 months): 6 mg/kg QD (maximum dose 240 mg QD);
Child dosing for capsules (≥33 kg): 200 mg QD; dose in adults: Capsule (≥33 kg):
200 mg QD; Suspension: 240 mg QD. FTC is equally effective against HBV.
Tenofovir disoproxil fumarate (TDF) is available as tablets (123/163/204/245 mg
TDF) and as granules containing 33 mg/g TDF (1 scoop = 1 g). It is approved for chil-
dren >2 years of age and 3kg of weight. All of the following dosages are based on
TDF. Child dosing for granules is (≥2 years) 6.5 mg/kg QD. Dosage for tablets in chil-
dren is: (≥2 years) (17-22 kg): 123 mg QD; (22-28 kg): 163 mg QD; (28-35 kg):
204 mg QD; (≥35 kg): 245 mg QD; Dose in adults is: (≥35 kg) 245 mg QD. Intake of
meals is required. Tenofovir may significantly affect renal and bone metabolism in
children (Gafni 2006, Purdy 2008). It is also effective against HBV and can be used
in coinfected children.
Tenofovir alafenamide (TAF) is available as 25 mg (without a booster) and as 10 mg
tablets (in combination with cobicistat or ritonavir). It is approved for children
12 years of age and older and >35 kg body weight. TAF is found in coformulations
with FTC and elvitegravir/c, bictegravir, rilpivirine, or darunavir/c. Ingestion with
food is required. TAF appears to be somewhat better tolerated than TDF and should
be preferred when possible. A slightly higher virologic potency is discussed.
Zidovudine (AZT) is available as capsules, suspensions, tablets, and ampoules. Given
potential long-term toxicity, AZT should be switched to ABC or TAF/TDF if possible.
Dosage (caveat: transmission prophylaxis: other dosages!): Child dosing for suspen-
sion is: (4-9 kg): 12 mg/kg BID; (9-30 kg): 9 mg/kg BID; (≥30 kg): 300 mg BID; Child
dosing for capsules is: (8-13 kg): 100 mg BID; (14-21 kg): 100 mg morning + 200 mg
afternoon/evening (22-30 kg): 200 mg BID; (≥30 kg): 300 mg BID; adults: 300 mg
BID; intravenous dosing of 120 mg/m2 QD may be considered for very sick children
with intestinal failure.
500 Women and Children

NNRTIs
Within a few weeks, cross-class resistance may occur. However, newer substances
have a higher resistance barrier. Children usually prefer the liquid preparations of
the NNRTIs in terms of taste over the liquid PI solutions. Nevirapine is the preferred
NNRTI in children <3 years of age, and efavirenz is the preferred NNRTI in ≥3 years.
NNRTIs are contraindicated in patients with hepatic dysfunction.
Efavirenz (EFV) is approved for use from 3 years of age. At HIV-RNA >100,000
copies/mL, EFV should not be combined with ABC+XTC (Table 3). Capsules,
suspensions, and sprinkles are available. Under standard dosing, levels are highly
variable, and children are sometimes underdosed. Child dosing is QD: ≥3-5 years:
(13-15 kg): 360 mg; (15-20 kg): 390 mg; (20-25 kg): 450 mg; (25-32 kg): 510 mg;
≥5 years: (13-15 kg): 270 mg; (15-20 kg): 300 mg; (20-25 kg): 360 mg; (25-32.5 kg):
450 mg; (32.5-40 kg); 510 mg; (≥40 kg): 720 mg.
Child dosing for capsules: ≥3 years (13-15 kg): 200 mg; (15-20 kg): 250 mg; (20-25 kg):
300 mg; (25-32.5 kg): 350 mg; (32.5-40 kg): 400 mg; (≥40 kg): 600 mg; adults:
(≥40 kg): 600 mg (suspension: 720 mg). It should be taken in the evening on an
empty stomach. High-fat meals should be avoided; in some cases, increases in serum
lipids have been observed. The suspension must be dosed 20% higher than the capsules.
Nevirapine (NVP) is available as “immediate” and “extended-release” tablets (IR,
XR) and solutions. In children aged > 2 months to 3 years, using a backbone with 3
NRTIs may be considered. The dosage for the IR formulation by body weight is 4 mg/kg
QD for 14 days (max. 200 mg/day), then (<8 years) 7 mg/kg BID or (≥8 years) 4 mg/kg
BID (max. 400 mg/day) in the absence of exanthema or hepatic dysfunction; dosing
for XR formulation ≥3 years is: 0.58-0.83 m2 body surface area: 200 mg QD; 0.84-
1.16 m2: 300 mg QD; ≥1.17m2: 400 mg QD. All patients must start IR formulation
for 14 days;
Etravirine (ETV) is approved for use from ≥2 years of age and is available as tablets
(25 mg, 100 mg, and 200 mg). Child dosing is ≥10-<20 kg: 100 mg BID; ≥20-<25 kg:
125 mg BID; ≥25-<30 kg: 150 mg BID; ≥30 kg: 200 mg BID (same as adults).
Rilpivirine (RPV) is approved in adolescents >12 years of age as a single agent and
in combinations and is available as a 25 mg tablet. The dosage is 25 mg QD.
Doravirine (DOR) is approved in adolescents >12 years of age and ≥35 kg as a single
agent and part of combination therapies at 100 mg QD.

Protease inhibitors
Compared to NNRTIs, resistance develops less rapidly with boosted PIs. To achieve
adequate plasma levels, PIs are boosted with ritonavir (/r) or cobicistat (/c). Lopinavir
and atazanavir are the only PIs approved under 2 years of age. QD doses are avail-
able from 6 years of age for atazanavir and 3 years for darunavir. A study in children
and adolescents showed the inferiority of QD vs. BID for lopinavir/r.
Lopinavir/r (LPV/r) is available as tablets containing 200 mg lopinavir/50 mg
ritonavir tablets and 100 mg/25 mg as a suspension. The suspension tastes foul, must
be refrigerated, contains 42% alcohol (153 mg/mL) and propylene glycol, and is
contraindicated for premature infants and newborns. Lopinavir/r is approved from
2 weeks of age (Simon 2011). The suspension is taken with meals; this is not necessary
for the tablets. Comedication with efavirenz or nevirapine requires approximately
30% higher dosing of lopinavir/r. Lopinavir/r is very effective in treatment-naive and
intensively pretreated children and infants under 6 months of age (Saez-Llorens 2003,
Antiretroviral therapy in children 501

Fraaij 2004, Resino 2005, Chadwick 2011). LPV should not be given to neonates
before 14 days of age, as endocrine, metabolic, and cardiac toxicity has been reported
in this age group. Child dosing is: (≥14 days to 6 months) 300/75 mg/m2 BID or
16/4 mg/kg body weight; (≥6 months to 18 years) 230/57.5 mg/m2 BID or (<15 kg)
12/3 mg/kg BID; (≥15-40 kg) 10/2.5 mg/kg BID (max 400/100 mg BID). Dosage for
tablets is: (15-25 kg or 0.5-0.9 m2): 200/50 mg BID; (25-35 kg or 0.9-1.4 m2): 300/
75 mg BID; (>35 kg or ≥1.4 m2): 400/100 mg BID; in neonates and infants ≥6 weeks,
dosing is probably even higher than 2 x 300 mg/m² (Chadwick 2011). QD adminis-
tration was inferior to BID administration in children and adolescents (KONCERT
study, PENTA 18).
Fosamprenavir (FPV) is approved for patients 6 years of age and older, weighing
25 kg in combination with ritonavir, and is available as a suspension (50 mg/mL)
and 700 mg tablets. The combined dose is given at mealtimes. Dosage for suspension
in children is: (≥6 years) (25-32 kg): 18 mg/kg BID+RTV 3 mg/kg BID; (33-38 kg):
18 mg/kg BID+RTV 100 mg BID; (≥39 kg) 700 mg BID+RTV 100 mg BID; dosage for
tablets is: (≥39 kg) 700 mg BID+RTV 100 mg BID; (≥18 years or ≥39 kg): 700 mg
BID+RTV 100 mg BID.
Atazanavir (ATV) is available as a powder in 100, 150, 200, and 300 mg capsules.
It is recommended once daily with meals. ATV is approved starting at 3 months of
age and 5 kg body weight in combination with ritonavir. Dosage powder: (5-<15 kg)
200 mg and 80 mg ritonavir; (15-<35 kg) 250 mg and 80 mg ritonavir, (>35 kg)
300 mg and 100 mg ritonavir. Dosage capsules: (≥15-<20 kg) 150 mg and 100 mg
ritonavir QD; (≥20-<40 kg) 200 mg and 100 mg ritonavir QD; (≥40 kg) 300 mg and
100 mg ritonavir QD. Administration of proton pump inhibitors is contraindicated.
The option of once-daily administration is attractive. Since late 2015, atazanavir can
be used without a booster in adults under certain conditions (e.g., >6 months viral
load below detection limit).
Darunavir (DRV) is available as 75, 150, 400, 600, 800 mg tablets and as a suspen-
sion (100 mg/mL). It is recommended to be taken with food. Darunavir is approved
for >3 years of age and a body weight of at least 15 kg in combination with riton-
avir or cobicistat (12 years and older). Dosage for therapy-naive or therapy-experi-
enced children is QD: (≥15-30 kg) 600 mg+ritonavir 100 mg; (≥30-<40 kg):
675 mg+ritonavir 100 mg; (≥40 kg): 800 mg+ritonavir 100 mg or cobicistat 150 mg.
Dosage for treatment-experienced children with darunavir resistance is BID: (≥15-30 kg)
380 mg BID+ritonavir 50 mg BID; (≥30-<40 kg): 460 mg BID+ritonavir 60 mg BID,
(≥40 kg): 600 mg BID+ritonavir 100 mg BID or QD is: (≥15-30 kg) 600 mg BID+
ritonavir 100 mg BID; (≥30-<40 kg): 675 mg BID+ritonavir 100 mg BID, (≥40 kg):
800 mg BID+ritonavir 100 mg BID or cobicistat 150 mg BID.

Integrase inhibitors
More frequent CNS side effects have been described for some INSTIs than other anti-
retroviral drugs. In addition, there have been case reports of myocarditis. A meta-
analysis found an increased risk of insomnia with dolutegravir (Hill 2018).
Cardiovascular risks or increased rates of suicidality were not found.
Raltegravir (RAL) is available as granules and as 25 mg, 100 mg, 400 mg, and 600 mg
tablets. It is approved from birth. Child dosing for granules in the first week of life
(from birth): (2-<3 kg) 4 mg QD; (3-<4 kg) 5 mg QD; (4-<5 kg): 7 mg QD. Child
dosing from the first to 4th week of life: (2-<3 kg) 8 mg BID; (3-<4 kg) 10 mg BID;
(4-<5 kg): 15 mg BID. Dosage from 5. Week of life: (3-<4 kg) 25 mg BID; (4-<6 kg)
30 mg BID; (6-<8 kg) 40 mg BID; (8-<11 kg) 60 mg BID; (11-<14 kg) 80 mg BID;
502 Women and Children

(14-<20 kg) 100 mg BID; Dosage for chewable tablets in children: (11-<14 kg): 75 mg
BID; (14-<20 kg) 100 mg BID; (20-<28 kg): 150 mg BID; (28-<40 kg): 200 mg BID;
(>40 kg): 300 mg BID; Dosage for film-coated tablets in children: (≥6 years and >25 kg
or ≥12 years) 400 mg BID. QD administration of the 600 mg tablet is approved for
40 kg and above.
Dolutegravir (DTG) is available as 5, 10, 25, and 50 mg tablets. It is approved from
4 weeks of age and a weight of ≥3 kg. Dosage is: (3-<6kg): 5 mg QD, (6-<10kg, under
6 months): 10 mg QD, (6-<10kg, ≥6 months): 15 mg QD, (10-<14kg): 20 mg QD,
(14-<20kg): 25 mg or 40 mg film-coated tablet QD, (≥20kg): 50 mg QD. In cases of
INSTI resistance, a dosage of 50 mg BID is discussed for patients weighing 40 kg or
more. In the ODYSSEY trial (Penta 20), DTG-containing regimens were superior to
standard regimens regarding viral load suppression (Turkova 2021). DTG has been
associated with excessive weight gain in adults, especially in combination with TAF.
This adverse effect may also affect children; parents should be educated accordingly.
Elvitegravir (EVG) is available in Germany only as a fixed-dose combination.
EVG/c/FTC/TAF is approved from 2 years and ≥14 kg for once-daily administration
and is available in doses of 150/150/200/10 mg and 90/90/120/6 mg. The latter
should be used in children between 14 and 25 kg. EVG/c/FTC/TAF is approved from
12 years of age and a body weight of ≥35 kg, also for once-daily administration.
Bictegravir (BIC) is approved only in a fixed combination for adults and is a preferred
first-line option. However, it is not yet licensed for children <18. The combination
drug has been tested in trials in children >6 years and ≥25 kg and adolescents
>12 years and ≥35 kg. Bictegravir/FTC/TAF is now the preferred first-line therapy in
US guidelines from 12 years and >35 kg.

Fusion and entry inhibitors

Enfuvirtide (ENF) is approved for use in children 6 years and older and adminis-
tered subcutaneously. Child dosing is: (6 -16 years): 2 mg/kg BID (maximum dose
90 mg BID); (11.0-15.5 kg): 27 mg BID; (15.6-20.0 kg): 36 mg BID; (20.1-24.5 kg): 45 mg
BID; (24.6-29.0 kg): 54 mg BID; (29.1-33.5 kg): 63 mg BID; (33.6-38.0): 72 mg BID;
(38.1-42.5 kg): 81 mg BID, (≥42.6 kg): 90 mg BID; adult dosage is: (≥16 years): 90 mg
BID. Controlled studies in children are lacking.
Maraviroc (MRV) is available as 25-, 75-, 150-, and 300-mg tablets and as a solution
(20 mg/mL) and is approved for 2 years of age and >10 kg. Child dosing is: (10-<20 kg)
50 mg BID; (20-<30 kg) 75 mg BID; (30-<40 kg), 100 mg BID with potent CYP3A4
inhibitors and 300 mg without strong CYP3A4 inhibitors; (>40 kg) 150 mg BID with
potent CYP3A4 inhibitors (eg., clarithromycin, itraconazole, ketoconazole, PIs) and
300 mg without potent CYP3A4 inhibitors. A tropism test to clarify efficacy should
be performed before initiation of therapy.

Fixed Dose Combinations (FDC)

There are now numerous fixed combinations and, in some cases, complete ART
regimens. A use for younger children is limited by size, dosage, and license.

Many drug interactions can complicate therapies and their management (see also
the chapter Interactions; [Link] A particular
problem is the management of concomitant infections (TB, CMV, etc.). It is recom-
mended to consult a center that has experience with ART in childhood.
Antiretroviral therapy in children 503

Table 4: Antiretroviral formulations useful for pediatric and adolescent dosing and Administration
[Link]
NRTI
ABC tablets (300 mg), solution (20 mg/mL)
FTC capsules (200 mg), solution (10 mg/mL)
3TC tablets (300, 150 mg), solution (10 mg/mL)
TDF tablets (245, 204, 163, 123 mg), granules (33 mg/g)
ZDV capsules (250 mg, 100 mg), solution (10 mg/mL) iv infusion: 10 mg/mL (20 mL/vial)
TAF/FTC tablets (25/200 mg and 10/200 mg)
TDF/FTC tablets (300/200 mg)
ABC/3TC tablets (600/300 mg)
ZDV/3TC tablets (300/150 mg)
NNRTI
EFV tablets (600 mg), capsules (200, 100, 50 mg)
NVP tablets (200 mg), extended-release tablets (400, 100 mg), suspension (10 mg/mL)
RPV tablets (25 mg)
TDF/FTC/EFV tablets (300/200/600 mg)
TAF/FTC/RPV tablets (25/200/25 mg)
TDF/FTC/RPV tablets (300/200/25 mg)
PI
DRV tablets (800, 600, 400, 150, 75 mg), solution (100 mg/mL)
DRV/c tablets (800/150 mg)
LPV/r tablets (200/50 mg and 100/25 mg), solution (80/20 mg/mL)
RTV tablets (100 mg), powder for oral suspension (100 mg sachet)
TAF/FTC/DRV/c tablets (10/200/800/150 mg)
INSTI
DTG tablets (50, 25, 10 mg), dispersible tablets (5 mg)
RAL tablets (600 mg, 400 mg), chewable tablets (100, 25 mg), granules for oral
suspension (100 mg)
ABC/3TC/DTG tablets (600/300/50 mg)
TAF/FTC/BIC tablets (25/200/50 mg)
TAF/FTC/EVG/c tablets (10/200/150/150 mg)
TDF/FTC/EVG/c tablets (300/200/150/150 mg)

Therapy effectiveness, failure, and conversion

The effectiveness of ART is measured in children by virological and immunological
response and, more importantly, by growth and development: Normalization of
growth velocity can be expected approximately two years after ART initiation
(Nachman 2005a). Data regarding neuropsychological status are conflicting. Infected
children sometimes perform worse on neuropsychological tests despite ART and are
at increased risk for psychiatric disorders (Laughton 2013). A small German study
showed that early, sufficient initiation of therapy could enable normal cognitive
development: the intelligence quotient in this study correlated inversely with viral
loads in the first years of life (Weber 2017). Many children can be treated with the
first combination for many years without complications, and the first regimen
succeeds in keeping viral loads below the detection limit for more than five years.
A change in therapy may be appropriate despite viral load suppression to reduce the
number of tablets, simplify intake, and reduce actual or potential long-term side
504 Women and Children

effects. Therapy failure is almost always a result of inadequate adherence. It can be

assessed with systematic questioning, monitoring of prescribed medications, plasma
level determinations, and resistance testing. Discussing the case in a PVC can help
(see link EACS guideline 2022).
The following points indicate virologic treatment failure: a repeatedly measured
rebound of plasma HIV RNA or failure to reach the detection limit of <50 copies/mL
after six months. In infants and young children, achievement of complete viral sup-
pression <50 copies/mL may take longer. Despite detectable viral replication on ART,
most children are usually immunologically and clinically stable. The risk of further
resistance developing with viral replication must be considered. The PENPACT 1
study (see above) investigated in 263 children whether it makes a difference whether
switching is already above 1,000 or only above 30,000 copies/mL (PENPACT study
2011). Interestingly, over a 5-year observation period, there was no significant dif-
ference in viral load reduction and no increased risk of PI or NNRTI resistance when
therapy was switched at higher viral loads. Immunologic criteria of treatment failure
are CD4 T-cells decreasing beyond physiologic levels. The guideline is a decrease of
at least 30% of the absolute value in less than six months. In children with relative
CD4 T-cell counts of less than 15%, a decrease of more than 5% may also be con-
sidered a treatment failure.
Clinical treatment failure is defined as drug toxicity, clinical progression, striking
accumulation of trivial infections without change in the CDC stage, onset of
encephalopathy, or failure to thrive.
A resistance test should be performed before each start and switch. Usually, the first
regimen contains two NRTIs (e.g., ABC+3TC). It then makes sense to select new NRTIs
(e.g., AZT+TDF) according to a resistance test and introduce a new substance class if
possible. Integrase inhibitors offer new possibilities here. There are very few prospec-
tive data on the value of resistance testing-guided therapy in children and adoles-
cents. For example, in the presence of an M184V mutation (3TC/FTC resistance) and
the absence of alternatives, it may be justifiable to maintain ART, including 3TC/FTC,
as part of treatment optimization.

Supportive therapy and prophylaxis

With timely diagnosis and treatment of perinatal HIV infection, common infections
are no more frequent than in immunocompromised children. Clinically stable chil-
dren on successful ART and with good immune status can receive live vaccines (Ehl
2018). Immunoglobulin substitution is usually not necessary anymore (Nachman
2005b). Antibiotic prophylaxis (e.g., PCP prophylaxis) is based on immune status. If
ART is not yet effective and immune reconstitution is not yet sufficient, AIDS still
occurs, especially in infants (see chapter AIDS, presentation of all OIs in children at
[Link]/mmwr/preview/mmwrhtml/[Link]).

Summary
Clinical management in children and adolescents differs from HIV infection in
adults. Infants, in particular, are highly vulnerable and must be diagnosed and treated
expeditiously. The goal is to individually manage ART for maximum effectiveness
while avoiding long-term side effects in growing children and adolescents. Long-
term success is achieved through
• Development of child-friendly forms of application (e.g., granules or tasteless juices
for young children)
Antiretroviral therapy in children 505

• Intersectoral and interdisciplinary collaboration (pediatrician in the practice and

at the center, gynecologist in the practice and at the clinic, psychosocial team,
virology, infectiology, pharmacology).
• Standardized PVCs, evidence-based approach along national guidelines, and par-
ticipation in multicenter trials (e.g., German-Austrian Guideline on Antiretroviral
Therapy of HIV Infection in Children and Adolescents; Pediatric European Network
Trial in AIDS PENTA).
• Development of new substance classes (e.g., monoclonal antibodies, capsid
inhibitors) and strategies (e.g., long-term injectables induction and continuous
therapy)
In the majority of children and adolescents in Western countries, HIV has changed
from a mostly fatal infection to a chronic one that allows them to lead largely normal
lives.
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SECTION 6

Organs ·
Interdisciplinary
Medicine
508

21. Checklist: the new patient

B E R N H A R D S C H A A F, M A R T I N H O W E R , M A R K U S U N N E W E H R

One aim of the initial contact with a new patient is to gain a comprehensive overview
of the health and social situation of the patient to assess whether and how urgently
opportunistic infections, concomitant diseases, and the HIV infection itself need to
be treated. Furthermore, these first encounters include general information about
the disease and establishing a trusting relationship. Nowadays, starting treatment
immediately at the first presentation can be considered.

What the patient should know after the first consultation

• How HIV destroys the immune system.
• The difference between HIV infection and AIDS disease.
• The significance of CD4 T-cells and viral load.
• The risk of infecting other persons and how to avoid transmission.
• The efficacy, effectiveness, and success of the HIV treatment.
• The need to take tablets (or injections) regularly.
• Good prognosis: with ART, everyday life is quite possible.
• Aspects of partnership, family planning, and professional activities.
• The risk of additional sexually transmitted infections (STIs) and viral hepatitis. Both
can worsen the course of HIV infection.
• The patient should be able to speak freely about the symptoms of an STI.
• It is possible to become infected again with a different, more pathogenic, or resistant
HIV strain.
• A healthy diet and physical exercise can improve prognosis.
• Smoking increases the risk of a variety of complications markedly.
• Information sources, support groups, NGOs, community-based organizations, and
other facilities for the support of people with HIV.
• Other diagnostic tests and why they may need to happen.

What the doctor should know after the first consultation

Infection and risk
• What are the circumstances of the initial diagnosis? Are there additional diagnoses
at the time of the initial diagnosis? Are there any current complaints?
• When, where, and why was the HIV test performed? (When) Was there a negative
test before? What risks have been taken since then?
• Are stimulants being used? Are there any sexual function disorders? A sexual history
is essential to detect STIs and advise on prevention.
• Are there any sexual partners who should be tested and treated for STIs?
• Has the patient traveled recently, and what is his geographical background (preva-
lence of infections may vary by region)?
• Use of legal and illegal drugs (including oral, inhalation, intravenous).
• Smoking status and the cumulative amount of smoking (pack-years).
• Family history, including diabetes mellitus, heart disease, cancer, tuberculosis
(-contact), and other infections.
Checklist: The new patient 509

Concomitant illnesses
• Illnesses other than HIV.
• Previous infections such as STIs, viral hepatitis, pneumonia, TB, zoster, and candidiasis.
• Any medication, including painkillers and sleeping pills, injections, inhaled agents,
dietary supplements, and ovulation inhibitors.
• Was PREP or PEP (HIV pre/post-exposure prophylaxis) used?
• Allergies or intolerances.
• Participation in disease screening programs and vaccination status (vaccination
certificate).

Social
• What is the patient’s social background? Is there a partnership? Is there a partner
test? Are there children, or is there a wish to have children?
• What is the patient’s (former) profession? Shift work?
• How is the financial situation? Are there any economic or social obligations?
Can payments for prescriptions or medications happen?
• Re: migration issues: residency and legal status, health care insurance.
• Is there a relevant religious background? Will this affect medication use, sexual
orientation, or risk behavior?
• Who knows about the infection? Who can help if necessary? With whom can
concerns be discussed? Are there infected persons in the circle of friends? Is the
patient interested in contacting social workers or support groups?
• How will the patient cope with the diagnosis? Is psychiatric/psychotherapeutic
support necessary?
• Is there a legal guardianship?

Laboratory tests
Reasonable baseline testing for all PLWH
• Confirmation of the HIV infection in a second blood sample.
• Full blood count (30–40% of untreated patients have anemia, neutropenia,
thrombocytopenia).
• Total lymphocyte count, CD4 T-cell count, percentage, and CD4/CD8 ratio (less
variable).
• Plasma HIV RNA (viral load) and resistance test (genotype).
• HLA-B*5701 test before starting abacavir treatment.
• Tropism testing before starting maraviroc treatment.
• Electrolytes, creatinine, calculated creatinine clearance, urine test, AST (GOT), ALT
(GPT), γGT, lipase, total protein and protein electrophoresis.
• Fasting blood glucose and lipid profile (total cholesterol, LDL, HDL, triglycerides)
• Hepatitis serology: A, B (if B positive, then D), C, (E). Take vaccinations into account.
Consider PCR test in case of acute infections.
• Lues serology: TPHA test, VDRL if necessary, FTA abs IgM, IgG (depending on the
laboratory).
• STI screening with (pooled) tissue swabs (gonorrhea, chlamydia, and Mycoplasma
genitalium if applicable).
• Toxoplasmosis: IgG serology. If negative: prevention (avoid raw meats and contact
with cats). If positive and < 200 CD4 T-cells/µl: prophylaxis.
• Varicella, measles, rubella IgG serology (immunity?).
• Tuberculosis: interferon-gamma assay (IGRA test). Caveat: False-negative results are
possible in case of severe immunodeficiency. Mendel-Mantoux skin test is less
sensitive and specific.
510 Organs · Interdisciplinary Medicine

Additional examinations in case of suspicion or low CD4 T-cell count

• CMV: IgG serology. If positive and < 100 CD4 T-cells/µl: fundoscopy, CMV-PCR as
activity marker.
• Cryptococcus: Antigen test for neurological symptoms.
• Folic acid, vitamins B12 and D (often low).
• Blood cultures in case of acute infections.
• Sputum diagnostics for mycobacteria.

Further investigations
• Physical examination (general condition, lungs, heart, skin, lymph nodes), height,
weight, BMI, exploratory neurological examination, vibration sensitivity, and
cognitive test (e.g., MiniMental, DemTect, clock drawing test).
• Neurological impairment should prompt a CT or MRI scan of the brain to check
for cerebral infections or malignancies.
• Chest X-ray, if IGRA is positive, and in case of suspicion of diseases of the thoracic
organs (in smokers, also low-dose CT should be considered).
• Sonography of the abdomen if necessary. It also serves as a baseline examination
of the liver, spleen, kidney, and lymph nodes.
• ECG and pulmonary function test (especially in smokers) in case of suspected or
existing diseases. Nt-pro-BNP and/or echocardiography for cardiac assessment; risk
score for CHD; baseline QTc interval before starting ART.
• In female patients: cervical PAP smear for CIN at initial HIV diagnosis, after six
months, then once a year if negative.
• In all patients: anal PAP smear. Proctological examination (condylomata
acuminata, genitoanal dys-/neoplasia) is recommended.
• Ophthalmic fundoscopy: Especially when < 100 CD4 T-cells/µl and/or visual
impairment.
• Estimate osteoporosis risk by obtaining vitamin D levels and, if necessary, bone
density measurement.
• Check vaccinations and vaccination counseling.
511

22. HIV and cardiopulmonary disease

MARKUS UN N EWEH R, JAN BÖRGEL, BERN HARD SCHAAF

Lung diseases
The lung is one of the major organs of manifestation of HIV. The spectrum of possible
disease includes HIV-typical complications such as tuberculosis (TB), Pneumocystis
jirovecii (PCP), bacterial pneumonia, lymphoma and pulmonary hypertension (PH),
but also acute bronchitis, bronchial asthma, chronic obstructive pulmonary disease
(COPD), bronchial carcinoma (BC) and pulmonary fibrosis (Table 1). COPD and lung
cancer increase with age (Staitieh 2014, Maitre 2018), whereas PCP and TB have
become less common in industrialized countries.

Table 1: Pulmonary complications in people living with HIV.

Infections Neoplasia Other
Pneumocystis jiroveci Kaposi’s sarcoma Bronchial hyperresponsiveness /
(PCP) Non-Hodgkin’s lymphoma Asthma / COPD
Bacteria Hodgkin’s lymphoma Lymphocytic interstitial pneumonia (LIP)
S. pneumoniae Bronchial carcinoma Non-specific interstitial pneumonia (NSIP)
S. aureus Cryptogenic organizing pneumonia (COP)
H. influenzae Pulmonary arterial hypertension (PAH)
B. catarrhalis
P. aeruginosa Complications under ART
Rhodococcus equi Dyspnea + cough as hypersensitivity
Nocardia asteroides reaction (ABC)
Dyspnea + tachypnea in lactic acidosis
Mycobacteria Pneumonia while on T-20
M. tuberculosis Infiltrates lymph nodes and/or fever as
Atypical mycobacteria immune reconstitution syndrome (IRIS)

Other
Cytomegalovirus
Aspergillus spp.
Cryptococcus neoformans
Histoplasma capsulatum
Toxoplasma gondii

HIV has a particular affinity for the lung. The pathogenesis is probably multifactorial
(Cribbs 2020): latent persistent virus in bronchopulmonary lymphoid tissue reduces
antimicrobial cytokines. A possible synergy exists between smoking, cytotoxic
T-cells, and activated HIV-infected alveolar macrophages. In addition, increased
senescence of lung tissue is probably pathogenetically relevant (Neri 2018).
Especially in advanced immunodeficiency, many differential diagnoses of respira-
tory symptoms must be considered. History and clinical clues often point the way.
This chapter provides an overview; further chapters are on PCP, mycobacterioses,
aspergillosis, CMV, and PH.
512 Organs · Interdisciplinary Medicine

Medical history
The most important question: What is the immune status? The CD4 T-cell count
is the most critical indicator of the patient’s risk of opportunistic infections (OI). The
current value is more essential than the nadir. Above 200 cells/µl, acute bronchitis,
and bacterial pneumonia are typical and OIs are very unlikely. Below 200 CD4
T-cells/µl, PCP is the typical complication, although bacterial pneumonia is also more
common in PLWH.
TB is the exception to this rule: while the risk increases with decreasing CD4 T-cell
counts, most TB infections are seen in patients with CD4 T-cells above 200/µl, due
to the larger numbers of these patients.
Pulmonary Kaposi’s sarcoma and Toxoplasma gondii infections are rarely seen and are
usually diagnosed below 100 CD4+ T cells/µl. Below 50 CD4 T-cells/µl, CMV infec-
tions (usually in combination with PCP), invasive pulmonary aspergilloses (usually
by hematogenous spread), atypical mycobacterioses and endemic fungal infections
(Histoplasma capsulatum, Coccidioides immitis) occur.
What are the symptoms? In PCP, dyspnea and unproductive, dry cough are typical.
Yellow or green sputum suggests a bacterial etiology, possibly a co-infection like an
OI. Bacterial pneumonia typically begins acutely, and patients present after 1–5 days,
whereas individuals with PCP are symptomatic on average 28 days before medical
attention is sought (Cilloniz 2014).
What are the pre-existing conditions? Those with PCP previously have a higher
risk of getting one again. PLWH with concurrent COPD have “normal” exacerbations.
Is the patient under prophylaxis? The use of cotrimoxazole makes PCP unlikely.
It may also reduce the risk of bacterial pneumonia. Pentamidine inhalation is likely
to cause atypical, often apically accentuated manifestations of PCP.
Has ART been started recently? Pulmonary symptoms and fever are possible in the
setting of IRIS; PCP- or TB-IRIS also occur. Hypersensitivity reaction (HSR) due to
abacavir is rare nowadays because of HLA testing. It often manifests with dyspnea
(13%), cough (27%), and pharyngitis (13%). Sometimes even pulmonary infiltrates
are found. T-20 appears to increase the risk of bacterial pneumonia, at least with
cigarette smoking.
Does the patient smoke cigarettes? PLWH are about twice as likely to smoke as
HIV-negative individuals and die significantly earlier (Helleberg 2013, Park 2016).
Smoking promotes a local immune deficit in the lungs. Bacterial pneumonia and
PCP as well as asthma, COPD, and lung cancer, are more common in HIV+ smokers.
Motivation to abstain from smoking is, therefore, an essential medical task. Study-
proven benefits can come from brief verbal interventions, motivational groups,
nicotine replacement therapy, bupropion (caveat: interactions, e.g., with ritonavir),
and varenicline (caveat: psychic disorders/suicidal tendencies). For practical help,
see the HIV Provider Smoking Cessation Handbook (VA 2012).
What is the patient’s geographical background? Histoplasmosis and coccid-
ioidomycosis are more common than PCP in some parts of the US but are rarely seen
in Europe. In Southeast Asia, cryptococci are very common. Among African migrants
and people from the former Soviet Union, (resistant) tuberculosis plays a more
significant role.
What is the route of HIV infection? People with intravenous drug use are more
likely to have bacterial pneumonia, pulmonary abscesses, endocarditis due to
Staphylococcus aureus, and TB. Pulmonary Kaposi’s sarcomas are found almost exclu-
sively in MSM.
What does the X-ray image look like? See Table 2.
HIV and cardiopulmonary disease 513

Table 2: What does the X-ray image look like?

Chest X-ray Typical differential diagnosis
Without pathological findings PCP, asthma, KS of the large airways, TB in case of low CD4 counts
Localized infiltrates Bacterial pneumonia, mycobacteriosis, lymphoma, fungi, BC
Multifocal infiltrates Bacterial pneumonia, mycobacteriosis, PCP, KS
Diffuse infiltrates Bacterial pneumonia (in low CD4+ counts) PCP (centrally
accentuated), CMV, KS, LIP, heart failure, fungal infections
Miliary pattern Bacterial pneumonia (in low CD4 count), mycobacterial and fungal
infections
Pneumothorax PCP, COPD/emphysema
Cavernous lesions Mycobacteriosis (CD4 T-cells > 200), bacterial abscess (staphylococcus,
pseudomonas), lung cancer, pulmonary embolus
Cystic lesions PCP, fungal infections
Pleural effusion Bacterial pneumonia, mycobacteriosis, KS, lymphoma, heart failure,
malignoma
(Bihilary) lymphadenopathy Mycobacteriosis, KS, sarcoidosis, lymphoma
KS = Kaposi's sarcoma, PCP = Pneumocystis jirovecii, LIP = lymphoid interstitial pneumonia,
BC = bronchial carcinoma.

Diagnostic strategy in pulmonary infiltrates

Diagnostics depend on the HIV stage and the expected pathogen spectrum. For CD4
T-cells above 200/µl, basic non-invasive diagnostics, and an empirical antibiotic
therapy are reasonable. In hospitalized patients, two blood cultures (the rate of
bacteremia is higher than in immunocompetent patients), a microscopic and cultural
sputum examination (including mycobacteria), and pneumococcal and legionella
antigen urine tests are recommended. In most immunodeficiency situations, broad
antibacterial treatment should be started immediately after obtaining blood cultures
and sputum. Multiplex PCR for several pathogens can be an additional option.
Cryptococcal and Histoplasma antigen tests have a high positive predictive value;
however, these diseases are rare in European countries.
Bronchoscopy is indicated if CD4 T-cells are below 200/µl and PCP, CMV, and TB are
suspected but must not delay therapy. Antibiotics do not alter the PCR results initially.
The sensitivity of BAL is 60–70% for bacterial pneumonia without pretreatment and
85–100% for PCP with modern PCR methods (Unnewehr 2016).
A high-resolution chest CT should be done early and with a low threshold, especially
in patients with a CD4 T-cell count lower than 200/µl. For example, PCP can be
visualized much better on CT than on usual radiography. A second bronchoscopy
with transbronchial biopsies, CT-guided biopsy, and thoracoscopic/open biopsies are
rarely necessary.

Pulmonary complications and co-morbidities

Asthma, COPD, BC, PH, pulmonary fibrosis, and pulmonary infections are more
common in PLWH (Cribbs 2020). In patients on ART, non-infectious co-morbidities
become more critical. However, it should be considered that the prevalence of
co-morbidities, especially BC, COPD, and pulmonary fibrosis is increased due to the
more intensive diagnostic efforts in PLWH and the much higher prevalence of
cigarette smoking.
514 Organs · Interdisciplinary Medicine

Bacterial pneumonias: are more common and lead to persistent limitation of lung
function and worsen the long-term prognosis due to scarring. The incidence increases
with increasing immunosuppression and age. Two or more pneumonias per year
define AIDS. In addition to the risk calculated by the CRB-65 score (confusion,
respiratory rate, blood pressure, > 65 years), SpO2 <= 90%, and co-morbidities, the
CD4 T-cell count is essential. Below 200 cells/µl, the pneumonia can be more mul-
tifocal and interstitial. Even those supposedly mildly ill with less than 100 CD4
T-cells/µl have a more than six-fold increased mortality and should be hospitalized.
As prevention, the standard vaccinations should be done (see Vaccinations).
COPD and emphysema: Next to pneumonia, COPD is the most common pulmonary
complication of an HIV infection. Patients suffer more severely from this pulmonary
co-morbidity: obstruction is more pronounced, emphysema is more common, and
quality of life is worse (Neri 2018). COPD symptoms should always be asked about,
and a pulmonary function test should be performed, especially in all smokers.
Bronchial asthma: Besides COPD, asthma is the most common (non-infectious)
pulmonary co-morbidity and probably somewhat more common than HIV-negative
individuals. Therefore, a hyperresponsive bronchial system or asthma should be
considered in case of unexplained cough, dyspnea, or recurrent bronchitis. Whether
HIV-related immunosuppression protects against or even increases the incidence of
an exaggerated immune response, like in allergy and asthma, is controversial.
Pulmonary fibrosis and lymphoid interstitial pneumonia: Lymphoid interstitial
pneumonia (LIP) is a rare chronic or subacute pneumonia in adults, clinically and
radiologically similar to PCP. It is characterized by CD8-dominant lymphocytic
alveolitis without evidence of pathogen, with CD4 T-cells above 200/µl and normal
LDH (differential diagnosis to PCP). The definitive diagnosis often requires lung
biopsy or, nowadays, bronchoscopic cryo-biopsy. LIP is considered to be steroid-
sensitive. The role of ART is unclear, mainly since LIP is also observed in the context
of immune reconstitution (Van Zyl-Smit 2015). PLWH are more likely to have
pulmonary fibrosis (Leader 2016). Various manifestations (including COP, NSIP,
IPF/UIP) have been described, including alveolar proteinosis in individuals.
Lung cancer (LC): Studies show a 2- to 8-fold increased incidence of LC in HIV infec-
tion (see Non-AIDS-defining malignancies). By now, more PLWH die from LC than
from many AIDS-defining malignancies. A low dose chest CT is reasonable in case
of suspicion or high risk (smoking > 20 pack years, age 50 to 80 years).

Rare opportunistic infections

In children, CMV pneumonia is more common than PCP, but rare in adults. However,
pulmonary CMV infections have been frequently detected in autopsy series – the
importance of the pathogen may be underestimated in the late stages. Especially in
cases of severe respiratory failure in the setting of PCP, CMV pneumonia should be
considered and treated in case of doubt, since co-infection increases mortality.
CMV pneumonia is unlikely if CMV PCR in BAL is negative. If positive, this does
not prove CMV infection because of the frequent CMV colonization of the airways.
This is why serologic markers are of little help. On the other hand, a high CMV viral
load (or antigen) in the blood and within the appropriate context is a strong indication
of a relevant infection; the probability of infection increases with the level of viremia.
Invasive pulmonary aspergillosis is also rare but occurs in the late stages, sometimes
in combination with other OIs and with additional risk factors such as neutropenia
or steroid therapy. Blood cultures, fungal cultures, galactomannan antigen tests in
BAL, and CT are helpful diagnostic tools.
HIV and cardiopulmonary disease 515

Literature
Cilloniz C, Torres A, Polverino E, et al. Community-acquired lung respiratory infections in HIV-infected patients.
Eur Respir J 2014, 43:1698-1708.
Cribbs SK, Crothers K, Morris A. Pathogenesis of HIV-related lung disease: Immunity, infection, and inflamma-
tion. Phys Rev 2020, 100:603-32.
Helleberg M, Afzal S, Kronborg G, et al. Mortality attributable to smoking among HIV-1-infected individuals: a
nationwide, population-based cohort study. Clin Infect Dis Off Publ Infect Dis Soc Am 2013, 56:727-734.
Kynyk JA, Parsons JP, Para MF et al. HIV and asthma, is there an association? Respir Med 2012, 106:493-9.
Leader JK, Crothers K, Huang L, et al. Risk factors associated with quantitative evidence of lung emphysema and
fibrosis in an HIV-infected cohort. J Acquir Immune Defic Syndr 2016, 71:420-427.
Neri S, Leung J, Besutti G, et al. Chronic Lung Disease in HIV Patients. Aids Reviews 2018, 20: 150-7
Maitre T, Cottenet J, Beltramo G, et al. Increasing burden of non-infectious lung disease in persons living with
HIV: a 7-year study using the French nationwide hospital administrative database. ERJ 2018 52 (3).
Park LS, Hernández-Ramírez RU, Silverberg MJ, et al. Prevalence of non-HIV cancer risk factors in persons living
with HIV/AIDS: a meta-analysis. AIDS Lond Engl 2016, 30:273-291.
Sigel K, Wisnivesky J, Gordon K, et al. HIV as an independent risk factor for incident lung cancer. AIDS 2012,
26:1017-25.
Staitieh B, Guidot DM. Noninfectious pulmonary complications of human immunodeficiency virus infection.
Am J Med Sci 2014, 348:502-511.
Unnewehr M, Friederichs H, Bartsch P, Schaaf B. High Diagnostic Value of a New Real-Time Pneumocystis PCR
from Bronchoalveolar Lavage in a Real-Life Clinical Setting. Respir Int Rev Thorac Dis 2016, 92:144-149.
U.S. Department of Veterans Affairs, Veterans Health Administration, Washington, DC 20420. HIV Provider
Smoking Cessation Handbook: A Resource for Providers, 2012. [Link]
tobacco/docs/IB_10-432-HIV_Provider_Smoking_Cessation_Handbook.pdf
Van Zyl-Smit RN, Naidoo J, Wainwright H, et al. HIV-associated Lymphocytic Interstitial Pneumonia: a clinical,
histological and radiographic study from an HIV endemic resource-poor setting. BMC Pulm Med 2015,15:38.
516 Organs · Interdisciplinary Medicine

Cardiovascular diseases
The prevalence of cardiovascular disease increases with age and the duration of the
HIV infection (Bloomfield 2017). Cardiovascular morbidity with HIV is higher
because of vascular and myocardial diseases (Manga 2017).

Coronary heart disease (CHD)

The prevalence of CHD and the incidence of acute coronary syndromes (ACS) are
increased, often at younger ages. Reasons or risk factors are:
1. Increased cardiovascular risk profile: Smoking is about twice as common, hyper-
tension is often not controlled, and risk factors are not always adequately treated
(Reinsch 2012).
2. Negative effects of ART: Until now, ART was considered a risk factor for ACS due
to inflammatory influences on the endothelium and concomitant dyslipidemias.
However, a beneficial effect on myocardial inflammation is also conceivable. It is
not sure whether antiretroviral agents impact cardiovascular morbidity differently
(see ART).
3. Direct consequences of HIV: progression of atherosclerosis is promoted by chronic
inflammation, possibly depending on the extent of immunodeficiency.
4. Comparatively more intense diagnostic workup in HIV+ individuals.
Due to increased cardiovascular morbidity, detection and treatment of risk factors
are essential to HIV care. Relevant guidelines, including those for secondary pre-
vention and indication for coronary angiography, also apply to HIV (Perk 2012). In
treating hyperlipoproteinemia, attention should be paid to potential interactions
between CSE inhibitors and ART (especially boosted regimens). If risk factors are
present, ECG and risk assessment using common scores (e.g., PROCAM, ESC) are rec-
ommended once a year. Symptomatic individuals require the usual further diagnostic
workup.

Cardiomyopathy
The prevalence of HIV cardiomyopathy has decreased since the pre-ART era (ranging
from 9% to 52%, Manga 2017) to 1.8%. The mortality remains slightly elevated
today (Whiteside 2015). Causes include direct myocardial injury from HIV and
autoimmune-mediated myocardial injury (Choi 2021).
Whereas some older antiretroviral drugs were previously thought to have cardiotoxic
effects, tenofovir, for example, appears to have more of a beneficial effect on heart
failure (Hsue 2017). Heart failure is diagnosed and treated the same way as
HIV-negative people, focusing on the underlying cause. People with HIV should be
asked once a year for symptoms and signs of heart failure and examined (ECG,
echocardiography, serum pro-BNP).

Pericardial effusion
Pericardial effusion is rare in Europe in PLWH, but much more common in Africa
(Lind 2011). The pathogenesis is diverse: infections (mainly TB, but also other
bacteria), neoplasms, and capillary defects due to HIV (Manga 2017). TB is by far the
most common in people from high-prevalence areas, often with chronic courses and
pericarditis constrictiva.
HIV and cardiopulmonary disease 517

Cardiac arrhythmias
HIV can lead to autonomic nervous system changes with reduced heart rate vari-
ability (Chow 2011). A structural heart disease may promote arrhythmias. Sudden
cardiac death is generally more common in PLWH (Manga 2017). Antiretroviral drugs
usually do not cause relevant arrhythmias. However, PIs, particularly ritonavir,
lopinavir, and atazanavir, can asymptomatically prolong the PR interval on ECG and
occasionally cause block images and conduction disturbances. They should there-
fore be avoided in the presence of pre-existing conditions affecting the conduction
system and co-medications affecting conduction. Ventricular arrhythmias have also
been reported in IRIS (Rogers 2008).
In clinical practice, arrhythmias caused by a combination of ART with other drugs
are far more common. Antiarrhythmic medicines such as amiodarone, quinidine,
flecainide, and propafenone can interact with NNRTIs and should, therefore, be
avoided or dosed lower. Combinations with PIs should be avoided because PIs
increase antiarrhythmic drug levels. NRTIs are less problematic. No interactions are
expected for un-boosted INSTIs.

Diseases of the heart valves

It has not been proven that people living with HIV are more likely to develop endo-
carditis. Specific risk groups, such as intravenous drug users, have a 10- to 12-fold
increased risk, especially for tricuspid valve endocarditis. The bacterial spectrum
differs in HIV: the most common pathogen (40%) is Staphylococcus aureus; other
typical pathogens are Streptococcus pneumoniae and Haemophilus influenzae. Diagnosis,
therapy, and prognosis do not differ from those of the HIV-negative population.
There is no general recommendation for endocarditis prophylaxis in HIV infection.

HIV-associated pulmonary arterial hypertension (HIV PAH)

The most common causes of high pulmonary arterial pressure (pulmonary hyper-
tension, PH) are cardiac and pulmonary diseases. Hereditary and idiopathic forms
of pulmonary hypertension, and those occurring in association with certain diseases
(“associated PH”), are sporadic and are referred to as “pulmonary arterial hyperten-
sion” (PAH). These include HIV PAH. In 2018, PAH was redefined – not without
controversies – by a mean pulmonary arterial pressure measured by right heart
catheterization of > 20 mmHg at rest (previously > 25 mmHg) in combination with
other measurements (Hon 2022).
The cause of HIV PAH is unclear; the histology is indistinguishable from other forms
of PAH. An inflammatory response of the pulmonary arterial vessel wall mediated
by the viral proteins tat, gp120, and nef with vasoconstriction and vascular remod-
eling with the proliferation of endothelial cells and smooth muscle cells (“plexiform
vasculopathy”) is discussed. PAH causes reactive hypertrophy of the right ventricu-
lar myocardium with dilatation and right heart failure. The prognosis of HIV PAH is
poor (Manga 2017, Hon 2022).
The prevalence of HIV PAH is not precisely known; it was probably at most 0.5%
before the new definition (Staitieh 2014). Thus, it is increased about 1,000-fold com-
pared to the general population. Echocardiography should therefore be performed
in cases of unclear dyspnea. Although general screening of all people with HIV is
not recommended, echocardiography is recommended for the following PAH risk
factors, regardless of symptoms: women, intravenous drug use, hepatitis C co-infec-
tion, origin from a high-prevalence country (Africa), or known nef or tat protein
expression. The further work-up is the same as for the other forms of PAH.
518 Organs · Interdisciplinary Medicine

Generally, HIV PAH is treated like the other forms of PAH, but interactions with ART
must be considered. Although no precise data exists, ART and specific PAH medica-
tions are likely beneficial for disease progression. ART does not appear to induce
PAH. PAH medication always requires individualized assessment by experts.
Literature
Bloomfield GS, Leung C. Cardiac Disease Associated with Human Immunodeficiency Virus Infection. Cardiol Clin
2017, 35:59-70.
Choi H, Dey AK, Sharma G, et al. Etiology and pathophysiology of heart failure in people with HIV. Heart Fail
Rev 2021, 26:497-505.
Chow DC, Wood R, Choi J, et al. Cardiovagal autonomic function in HIV-infected patients with unsuppressed
HIV viremia. HIV Clin Trials 2011,12:141–50
Hon SM, Alpizar-Rivas RM, Farber HW. Pulmonary Arterial Hypertension in Patients Infected with the HIV. Cardiol
Clin 2022, 40:45-54.
Hsue PY, Waters DD. Heart failure in persons living with HIV infection. Curr Op HIV AIDS 2017, 12: 534–539.
Lind A, Reinsch N, Neuhaus K, et al. Pericardial effusion of HIV-infected patients? Results of a prospective mul-
ticenter cohort study in the era of antiretroviral therapy. Eur J Med Res 2011, 16:480-483.
Manga P, MacCutcheon K, Tsabedze N, et al. HIV and ischemic heart disease. JACC 2017, 69:83-91
Perk J, De BG, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice. Eur
Heart J 2012, 33:1635-1701.
Reinsch N, Neuhaus K, Esser S, et al. Are HIV patients undertreated? Cardiovascular risk factors in HIV: results of
the HIV-HEART study. Eur J Prev Cardiolog 2012, 19:267-274.
Rogers JS, Zakaria S, Thom KA, et al. Immune reconstitution inflammatory syndrome and human immunodefi-
ciency virus-associated myocarditis. Mayo Clin Proc 2008, 83:1275-1279.
Staitieh B, Guidot DM. Noninfectious pulmonary complications of human immunodeficiency virus infection.
Am J Med Sci 2014, 348:502-11.
Whiteside YO, Selik R, An Q, et al. Comparison of rates of death having any death-certificate mention of heart,
kidney, or liver disease among persons diagnosed with HIV infection with those in the general US population,
2009-2011. Open AIDS J 2015, 9: 14–22.
519

23. HIV and nephrology

ANSGAR RIEKE

As renal function decreases with age, its preservation is a key requirement of long-
term ART. Co-morbidities in HIV are more frequent and occur earlier (Guaraldi 2011,
Bonnet 2016). Arterial hypertension, diabetes mellitus, dyslipidemia, older age, nico-
tine use, and chronic inflammation from HIV worsen renal function. Every effort
should, therefore, be made to eliminate renal risks. The START trial has shown that
early ART can prevent renal events. When selecting agents, renal-friendly ART, avoid-
ing TDF, should always be requested when additional renal risks exist: these are
present in degenerative skeletal diseases and often uncontrolled NSAID use, drug
use, chemsex practices, chemotherapy, diabetes, or hypertension, where acute renal
failure should always be expected. Proteinuria and loss of GFR regularly imply
increased cardiovascular risk, which directly correlates with the extent of protein-
uria (CKD Consortium 2010). Acute renal failure and adjusted mortality are still
significantly more common in PLWH. Cohort analyses show significantly increased
renal vulnerability compared with non-HIV-infected individuals (Schulz 2020). There
has also been no decrease in renal replacement therapy. People of African-American
descent are particularly affected, with a 10-fold higher risk of renal failure than
uninfected individuals (Lucas 2007).
In addition to the treatment of HIV infection, the most important measures to
prevent the progression of renal failure are normalization of body weight, adjustment
of blood pressure to values < 130/80 mmHg, treatment of dyslipidemia according to
cardiological guidelines, abstinence from nicotine and, in people with diabetes,
reasonable blood glucose control. Early RAAS blockade with ACE inhibitors or AT
1/2 inhibitors is recommended in proteinuria. The use of contrast media in diag-
nostics should be viewed critically.

The clinic and diagnosis of nephropathy

The clinical picture is often non-specific, with fatigue, poor concentration, loss of
appetite, hypertension, and possibly edema. Prerenal, intrarenal (glomerular, tubular,
interstitial), and postrenal damage must be differentiated. Anamnesis might provide
evidence of a renal cause (NSAIDs, infections, sepsis, contrast media?). Sonography
identifies a possible post-renal outflow obstruction (renal congestion, prostatic
hypertrophy?), and renal size (reduced with narrow parenchyma) may give clues for
chronic renal failure. The diagnosis is supplemented by a urine dipstick or sediment
and the determination of creatinine, electrolytes, and phosphate. Anemia, metabolic
acidosis (blood gas analysis), calcium-phosphate metabolism disorders, venous
thrombi, and newly diagnosed arterial hypertension help distinguish between acute
and chronic renal failure.

Creatinine, Cystatin C, GFR

Elevated serum creatinine is only to be expected from a GFR restricted by more than
50%. It is dependent on muscle mass and gender and is, therefore, not a good marker
of renal function on its own. Creatinine is predominantly glomerular filtered and
secreted in the proximal tubule via transporters. Partial blockade of tubular excre-
tion by dolutegravir, bictegravir, cobicistat, and ritonavir (see below) causes a crea-
tinine increase of approximately 0,14 mg/mL. This does not indicate a worsening of
the actual GFR (“Cobi effect”).
520 Organs · Interdisciplinary Medicine

The alternative cystatin C is constantly produced by all nucleus-bearing cells and is

not subject to the effect above at the tubule – its clinical value is questionable in
view of chronic inflammation, and the determination is more expensive. Clearance
measurements are necessary because they detect the “creatinine-blind” region of
renal insufficiency earlier, especially if the renal function is over-estimated by lower
muscle mass (in older age). The CKD-Epi formula is widely accepted among the four
methods for GFR determination, but it has only been evaluated in moderately
impaired renal insufficiency. In EuroSIDA, CKD-Epi and the Cockroft and Gault
formula indicated renal insufficiency well in more than 9000 PLWH (Mocroft 2013).
Follow-up controls should be performed using the same GFR formula in each case.

Proteinuria
The extent of proteinuria with protein loss, the imbalance of serum protein frac-
tions, and residual renal function with possible overhydration determine edema,
decreased performance, susceptibility to infection, and hyperlipidemia. As with dia-
betes mellitus, microalbuminuria (urinary micral test) is an essential indicator of
renal and cardiovascular mortality (Wyatt 2010). PLWH with confirmed microalbu-
minuria are 25 times more likely to develop proteinuria (Szczech, 2010), doubling
the mortality risk if it persists despite ART (Wyatt 2010). They should, therefore, be
screened for renal disease as carefully as people with diabetes. The extent of pro-
teinuria (UP/C = urinary protein/creatinine in urine) can be graduated using the
three ranges < 50, 50–100, and > 100. For albumin in urine (= UA/C), ranges of < 30,
30–70, and > 70 are considered graduations for the extent of glomerular proteinuria.
If the value for UP/C is greater than UA/C, the difference indicates the extent of
tubular proteinuria. The urine dipstick only detects albumin in the urine! Tubular
markers such as beta-2-microglobulin are mainly used in clinical studies.
Proteinuria and “nephritic sediment” are the leading symptoms of glomeru-
lonephritis (GN) and should be quantified. Clinical distinctions are made between
nephrotic syndrome (protein loss, edema), acute nephritic syndrome (acanthocytes
in the urine as a sign of GN), rapid-progressive GN (renal function loss within a few
days), asymptomatic proteinuria or hematuria, and chronic GN. These entities are
managed differently and require nephrology consultation. HIV-associated nephropa-
thy (HIVAN, see below) is a specific glomerulonephritis. Although mild courses are
possible, it most commonly presents as a nephrotic syndrome with edema, hypoal-
buminemia, hyperlipidemia, and proteinuria greater than 3.5 g/day.

Urine sediment and dipsticks

In addition to salts, crystals (formerly with indinavir, but also other PIs), and
epithelia, erythrocyturia (number and shape of erythrocytes?) is differential
diagnostically significant: coincidence with proteinuria is pathognomonic for GN
and usually secures the diagnosis together with nephritic sediment. Under a polar-
ized light microscope, the glomerular origin of the erythrocytes can be identified
quite reliably by glomerular deformed acanthocytes. More than five acanthocytes
per field of view is a definite indication. If there is significant erythrocyturia, bleeding
below the renal pelvis (tumors of the urinary tract?) should be excluded by
sonography and cystoscopy, especially if there is no proteinuria as a sign of GN.
Leukocyturia must be clarified microbiologically/culturally (uricult: midstream
urine); bacterial interstitial nephritis may also be present. Sterile leukocyturia may
indicate urogenital tuberculosis but may also express interstitial renal disease (e.g.,
earlier if on indinavir). Glucosuria (with normal blood glucose levels/lowering of
the normal glucose threshold)) or phosphaturia are signs of tubular dysfunction,
such as may occur with TDF.
HIV and nephrology 521

Routine tests for kidney damage

As a routine examination in PLWH, sodium, potassium, calcium, phosphate, serum
creatinine, and GFR are determined. Every 3–6 months, urinalysis should be
performed as a strip test semi-quantitatively for proteinuria, erythrocyturia, urine
sugar, and signs of urinary tract infection. If proteinuria in the urine stix is greater
than 1, it is better to measure the protein/creatinine ratio (UP/C) quantitatively in
spontaneous urine or the albumin/creatinine ratio (UA/C) for the glomerulus for the
course (see above).
If there is a significant increase in proteinuria, serum creatinine, or a drop in GFR
below 60, a nephrological consultation should be obtained (renal biopsy if necessary).
This is necessary without delay in the case of a rapid creatinine increase (rapid-pro-
gressive GN?), LDH elevation in conjunction with hyperbilirubinemia and
thrombocytopenia (hemolytic uremic syndrome in HIV?), or electrolyte imbalances
(especially hyperkalemia), or an acidosis that can no longer be controlled, as can
also occur as lactic acidosis under ART and metformin, for example.
Asymptomatic, mild proteinuria without creatinine elevation is observed in more
than 50% of patients on ART (Zeder 2016). It should be monitored every three
months. The extent of proteinuria can be estimated with the urine protein/creatinine
quotient from spontaneous urine, which should be < 1 (example: urine protein
120 mg/dl and urine creatinine 30: proteinuria of 4 g/day).
Determination of parathyroid hormone and vitamin D can detect the interaction of
kidney and bone and risks for osteoporosis.
Renal function decline is also a symptom of HIV infection and an indication for ART.
In imaging studies, contrast agents should be avoided to prevent renal failure, espe-
cially in renal function impairment, proteinuria, and all forms of intravascular fluid
deficit (including liver cirrhosis). Any change in renal function is cause for sonog-
raphy.

HIV-associated nephropathy (HIVAN)

HIVAN refers to a rapid loss of renal function that is particularly prevalent in African-
American patients. In this group of individuals, HIVAN is the third most common
reason for dialysis between the ages of 20–64. A genetic predisposition is likely due
to the interaction of the human gene MYH9 (non-muscle myosin heavy chain 9)
with HIV and an adjacent apolipoprotein L1 gene as a promoter of HIVAN. Because
mutations of the ApoL-1 gene confer an evolutionary advantage in sleeping sick-
ness, HIVAN is found almost exclusively in people of black African origin (Kao 2008,
Kopp 2008, Soleiman 2011). Despite hemodialysis, one-year mortality without ART
is about 50%; ART has reduced the risk of dialysis from HIVAN by 40%; moreover,
one-year survival on dialysis has increased from 25% to 75% with ART (Winston
2008).
There is usually a poor immune status with < 100 CD4 T-cells/µl; only in 20% does
the clinical picture occur with higher values. Isolated cases of acute retroviral
syndrome have been reported. However, there seems to be no correlation between
the level of viremia and the duration of HIV infection.
The clinical manifestation is usually nephrotic proteinuria of more than 3,5 g/day,
but less is also possible. Progression is rapid and can lead to dialysis requirement in
a few months (Szczech 2001). Blood pressure is normotensive or only moderately
elevated, and the kidneys tend to be normal in size on a sonograph.
In about 70% of patients, the histological picture corresponds to a focal segmental
sclerosing glomerulonephritis (FSGN) and cystic tubular changes and degeneration.
522 Organs · Interdisciplinary Medicine

However, other GN forms up to amyloid kidney are also possible in PLWH (Daugas
2005). Case reports proved direct infection of the glomerular basement membrane
with HIV and an impressively positive effect of ART on histological changes
(Bruggemann 1997, Winston 2001).
Only early ART – even before scarring of the glomeruli! – offers the prospect of success
(Lucas 2004). There are no recommendations for the selection – however, renal
elimination (dose adjustment from < 60 mL GFR for NRTIs) must be considered.
TDF-containing regimens are generally not suitable, but TAF is. ART should be
supplemented with ACE inhibitors or angiotensin receptor blockers for blood pres-
sure control. The use of steroids is controversial (1 mg/kg/day for 2 to 11 weeks). It
is favored in the US, especially in the lupus-like course of HIVAN (Gupta 2005, Haas
2005, Choi 2009).
Controversy surrounds the question of whether HIVAN needs to be confirmed by
renal biopsy. If ethnicity suggests the diagnosis, it is justified to start ART immedi-
ately and wait for therapy’s success over three months. During this period, the viral
load should be entirely suppressed, blood pressure should be well-controlled, diabetes
mellitus should be treated if necessary, and the therapy should be supplemented
with a lipid-lowering agent (e.g., pravastatin, analogous to the recommendations of
post-infarction cardiology) (Szczech 2009). Often, renal function improves, and
proteinuria regresses. The decision to biopsy belongs in nephrological hands.
Depending on the extent of proteinuria and limitation of GFR (< 60 mL/min/1.73 m²),
nephrologists should be consulted. Renal biopsy can clarify the multiple causes of
renal damage, prognosis, and therapy by a triple diagnosis of light and electron
microscopy and immunohistochemistry.

Other glomerulonephritides (GN) in HIV

In Caucasian patients, IgA nephropathy, membranous, and membranoproliferative
GN are particularly associated with HIV. Even without typical HIVAN, there is a
significantly higher prevalence of proteinuria in PLWH, 6–32% (Soleiman 2011). The
odds ratio for developing renal failure was increased dramatically in cohort analy-
ses at 3.85 compared with people without HIV (Islam 2012). Many other pathogens
can cause or maintain post-infectious GN or other forms of chronic GN. Viruses such
as HBV, HCV, CMV, EBV, and VZV can do so, as are influenza viruses, adenoviruses,
hantaviruses, and parvovirus B19. However, acute postinfectious GN can also occur
after malaria, syphilis, and infections with staphylococci, pneumococci, legionella,
salmonella, and other pathogens. In addition, there is a risk of circulatory renal
failure in profuse diarrhea associated with infectious bowel disease or traveler’s diar-
rhea.
In membranous glomerulonephritis, malignancy, and viral hepatitis must be
excluded as classic “secondary GN”. Chronic hepatitis C usually leads to membrano-
proliferative GN or vasculitis and renal involvement via cryoglobulinemia.
One of the most common kidney diseases is IgA nephropathy, which can also be
triggered or induced by HIV infection, respiratory infections, or hepatitis. An
imbalance of the microbiome in the axis of the intestine and kidney is discussed. In
post-infectious GN, the underlying infection is treated first. Depending on the course,
additional immunosuppression may need to be considered on an interdisciplinary
basis.
Hepatitis C-associated GN should always be treated by eliminating HCV (see below),
especially if cryoglobulin-associated vasculitis is present.
As a complication of acute infection and untreated PLWH, hemolytic uremic syn-
drome (HUS) or thrombotic thrombocytopenic microangiopathy syndrome (TTP)
HIV and nephrology 523

may occur. This is characterized by the combination of creatinine elevation,

hemolysis (LDH elevated, thrombocytopenia), and neurologic symptoms with renal
failure. The pathomechanism is probably based on the induction of procoagulant
effects of the HIV surface glycoprotein gp120 on endothelial cells with activation of
the complement system (Mikulak 2010). In these cases, plasma separation, immune
absorption, or even drug complement inhibition is necessary after nephrologic con-
sultation to halt the progression to dialysis dependency. Such forms of renal failure
can also be observed with COVID-19.

Therapeutic principles in glomerulonephritis

In post-infectious GN, the underlying disease is treated first. This also applies to
hepatitis B or C, but also to HIV infection. In the case of kidney failure caused by
hantaviruses (transmitted by mouse or rat feces), the spontaneous course can be
waited for, given the excellent prognosis in Europe but not in South America.
It is crucial to adjust blood pressure to target values below 140/80 mmHg or below
130/80 mmHg in the case of proteinuria. This is achieved primarily with ACE
inhibitors or AT-1 blockers, often in combination with diuretics. Proteinuria should
be treated independently of blood pressure with a blockade of the renin-angiotensin-
aldosterone system (RAAS), e.g., with ACE inhibitors, if necessary, also in high doses;
if proteinuria exceeds 0.5 to 1 g/day, an AT-1 blocker is recommended. Protein intake
is reduced to 0.6 to 0.8 g/kg/day; a “Mediterranean diet” with little meat is recom-
mended pragmatically. Significant proteinuria (> 3.5 g/24 h) requires anti-coagula-
tion if serum albumin concentration drops to values below 25 g/l – renal loss of clot-
ting factors causes hypercoagulability and risk of thrombosis (if so, then
phenprocoumon (Marcumar in Germany) up to INR 2–3, low molecular weight
heparins if necessary, after factor Xa determination or NOACs dosed according to
renal function). The drinking quantity is limited to 1.5–2 liters/day based on body
weight and edema tendency. Nicotine abstinence is crucial since an increased risk
of progression of GN due to nicotine is ensured “dose-dependently”.
Hyperlipidemia should be treated with medication after dietary measures have been
exhausted. HMG-CoA reductase inhibitors are suitable for this purpose, but interac-
tions must be considered (see Interactions). Fibrates or fibrate-statin combinations
should be used cautiously in patients with impaired renal function (accumulation).
Analgesics should be avoided; this applies especially to the “minor” analgesics such
as NSAIDs. When creatinine clearance is reduced below 60 mL/min/1,73 m², nephro-
logical co-care is required, especially when renal biopsy and immunosuppressive
therapy are indicated.
Table 1: Blood pressure setting.
Active ingredient Medication Dosage (examples)
class
ACE inhibitors Lisinopril, benazepril-HCL, Enalapril® 5 mg /1x morning, slowly
fosinopril sodium, enalapril, etc. increase to 20 mg/day
Beta-blocker Metoprolol, bisoprolol Beloc-Zok® (mite ) 1 x 1
AT II receptor Valsartan, candesartan, Candesartan® initially 2–4 mg/day,
telmisartan etc. increase cautiously to 32 mg/day
Diuretics Torasemide Torasemide® 5 mg 1 x 1
Ca antagonists Amlodipine Amlodipine® 5 mg 1 x 1, increase to
2 x 1 after at least 1 week if necessary
524 Organs · Interdisciplinary Medicine

Blood pressure control in PLWH

Drug-specific side effects should be considered. Caution hyperkalemia with ACE
inhibitors! Potassium-sparing diuretics should not be used above a creatinine of
1,4 mg/dl; loop diuretics such as Lasix® or torasemide should be used at a creatinine
> 1,8 mg/dl.

Renal toxicity of drugs

The spectrum of drug-allergic or autoimmune reactions in the kidney is not differ-
ent from that in the skin or other internal organs. Reactions can be humoral or T-
cell-mediated and can lead to renal failure. Even a single use of an analgesic (ibupro-
fen) can lead to renal failure. This is also conceivable with any antiretroviral therapy.
Therefore, renal function should always be monitored when changing treatment. In
case of renal abnormalities and risk factors (diabetes, hypertension, hepatitis, black
skin color, poor immune status), this should be done at short notice, especially with
TDF (even when given as PrEP). Acute renal failure or acute tubular necrosis is also
possible with acyclovir, ganciclovir, adefovir, aminoglycosides, or pentamidine.
Acute allergic interstitial nephritis may develop as part of the hypersensitivity reac-
tion under abacavir. Membranoproliferative GN has been described with atazanavir
and T-20. Ritonavir or efavirenz can also cause renal damage (Winston 2008). The
specific drug-toxic renal impairment will be presented separately.

Interstitial nephritis, crystalluria, nephrolithiasis

Various drugs such as NSAIDs, indinavir (withdrawn from the market), and atazanavir
(generics available) can cause interstitial nephritis with a decrease in eGFR and
tubular proteinuria; hematuria and leukocyturia (sterile) are indicative of such
nephritis. Antibiotics (ciprofloxacin, ampicillin), acyclovir, vitamin C, aspirin, and
also PIs such as indinavir, atazanavir, and (to a limited extent) darunavir can lead to
increased crystalluria, which, in combination with other factors (e.g., increased uric
acid), can cause nephrolithiasis. Previously common kidney stones under indinavir
are not radiopaque until combined with calcium, which can be confused with a
calcium oxalate stone. In contrast, urate stones are radiolucent. With forced fluid
administration, Buscopan®, and analgesics, the acute situation of renal colic can
usually be resolved on an outpatient basis. If urologic presentation is necessary, risks
for contrast administration must be communicated. ART history is essential because
any crystal-inducing substance can leave interstitial tubular damage over time.
Atazanavir has been associated with possible (mostly interstitial) renal changes in
cohort analyses. For example, a 21% higher risk of renal failure was seen in EuroSIDA
compared with atazanavir-free combinations, which was reversible (Mocroft 2015,
Dauchy 2011). The incidence of nephrolithiasis is also controversial, ranging from
“rare” (Calza 2012) to an FDA case analysis of 30 cases that fully recovered in renal
function after discontinuation (Chan-Tack 2007). However, if there is a known
history of nephrolithiasis, renal colic, or hematuria, atazanavir is undoubtedly not
a preferred agent (EACS 2018).

Tubular transport mechanisms and tubular-toxic damage, Fanconi syndrome

In addition to glomerular filtration of substances such as creatinine, they are also
secreted alternatively by transporters in the tubule. In the proximal tubule, the trans-
porter OCT2 leads to the uptake of creatinine from the blood into the tubule cell,
which is then secreted into the urine via MATE 1. Some integrase inhibitors inhibit
OCT 2, dolutegravir (more strongly), and bictegravir (less strongly), whereas the
pharmacoenhancer cobicistat inhibits MATE 1. Thus, these agents block the alter-
HIV and nephrology 525

native excretory pathway via the tubule cell, resulting in a mild increase in creati-
nine (approximately 0,14 mg/dl) or a decrease in estimated eGFR of approximately
15 mL. This may also be important for eliminating metformin, although clinically
relevant descriptions are still lacking. Of course, the creatinine increase does not
change the true GFR, so it does not affect glomerular filtration efficiency or renal
function. Thus, the agents above can be used to their full potential even in impaired
renal function. However, caution should be exercised when combining them with
TDF because, in this case, it may be more challenging to distinguish a true deterio-
ration in renal function, and TDF must be reduced below a GFR of 60 mL. In these
cases, TAF should always be given instead of TDF.
Tenofovir is taken up into the tubule cell via the transporter OAT 1 and glomerular
filtration. It is then actively secreted (ATP-dependent) into the urine of the proximal
tubule via the transporters MRP 2 and 4. If the true filtration in the glomerulus drops
(for example, in acute renal failure), an attempt is made to eliminate more TDF via
the tubule cell (increased activity of OAT 1). The consequence is an increased
concentration of TDF in the tubule cell, which can lead to a decrease in energy-
dependent MRP 2 and 4 transport capacity and, thus, tubule damage (Perazella 2010).
Indeed, the concentration-dependent damage of TDF to the tubule cell has been
shown people with low body weight are vulnerable (Nishijirna 2012).
Suppose the substances filtered from the glomerulus in the primary urine exceed the
transport capacity of the reabsorbing tubule cells (for example, in the case of tubule
damage). In that case, they are excreted in the urine. A prominent example is glu-
cosuria. However, transport dysfunction of the tubule system can also be caused by
drugs such as cidofovir and tenofovir. This is called secondary (drug-induced) Fanconi
syndrome. It is characterized by a dysfunction of the tubular system without impaired
GFR: phosphate, amino acids, and glucose are increased in the urine, and phosphate
is decreased in the blood. The loss of amino acids, phosphate, glucose, bicarbonate,
and other organic and inorganic substances, as well as water, may manifest clini-
cally with increased urination, thirst, fatigue, bone pain, and weakness and may lead
to secondary changes in bone metabolism and osteoporosis/reduced bone density.
But beware: not every hypophosphatemia (< 0,8 mmol/l) is immediately Fanconi
syndrome. Hypophosphatemia also occurs under the influence of alcohol, diabetes,
cachexia, diarrhea, a disorder of vitamin D metabolism, or hyperparathyroidism. In
untreated PLWH, it is found in about 10%, while on ART in 23%, and on tenofovir
in up to 31% of cases (Day 2005). The reasons may be multiple, including
inadequate phosphate intake (normal about 1,200 mg/day). Abnormal values (< 0.8 or
0.6 mmol/L) should be monitored, and start looking for other signs of Fanconi syn-
drome. Determination of intact parathyroid hormone, vitamin D, or a history of
diuretics, vomiting, or tumor disease may indicate other causes of hypophos-
phatemia. The excretion ratio of phosphate to creatinine may indicate tubular
damage if more than 10% of filtered phosphate is excreted despite hypophos-
phatemia (Jamison 1982).
Excretion Ratio: (urine phosphate mg/dl) x (serum creatinine mg/dl)
(serum phosphate mg/dl) x (urine creatinine mg/dl)
Case reports describe renal failure in pre-damaged kidneys, mainly in combinations
of boosted PIs plus TDF, but also in concomitant diseases such as liver cirrhosis or
hepatitis. From a nephrological point of view, ART should be chosen carefully in
cases of proteinuria, nephrotic syndrome, liver cirrhosis, and/or dyslipoproteinemia;
one is well advised to avoid then potentially nephrotoxic substances such as cido-
fovir, adefovir or TDF (including fixed combinations containing TDF); the use of TAF
is possible up to a GFR of 30 mL.
526 Organs · Interdisciplinary Medicine

Tenofovir-DF (TDF) and Tenofovir-AF (TAF)

Given the widespread use of TDF and its current generic availability, interest is mainly
focused on long-term renal toxicity. In cohort studies, a gradual GFR loss has been
observed in recent years with TDF regimens (Casado 2016). There is an increased
tubular risk (Dauchy 2011), which is higher than under ABC + 3TC (Moyle 2010).
Although a meta-analysis of 17 studies showed only a small decrease in GFR
(–3.92 mL/min) and a small increased risk of renal failure (+ 0.7%), TDF should not
be used uncritically and without regular testing of renal function (Cooper 2010). In
the large [Link] cohort of 22.603 patients, a drop in GFR of more than 20 mL to below
70 mL/min correlated with the use of TDF, boosted atazanavir, and lopinavir (Derek
2013). Similarly, in the EuroSIDA cohort, the incidence of renal failure was 1.05/100
person-years. Again, there was a correlation with TDF, atazanavir/r, and lopinavir/r.
In EuroSIDA, unlike the [Link] cohort, patients with renal insufficiency were not
excluded (Derek 2013). GFR under TDF falls more rapidly in combination with PIs
than with NNRTIs (Goicoechea 2008, Winston 2008, Casado 2016). In pregnancy,
TDF does not appear to cause renal injury in the newborn (Linde 2010, personal
communication). The incidence of renal events reported to the manufacturer with
TDF was 29.2 per 100,000 person-years (Nelson 2006). In the GS903E/934 prospec-
tive studies in renally healthy patients, creatinine increases to greater than 1.5 mg/dl
in 144 weeks was observed in less than 1%, and proteinuria more significant than
100 mg/dl was observed in 5% (Gallant 2008). In a meta-analysis of 11 studies, no
advantage of TAF over TDF was seen concerning renal events when boosters or PIs
were omitted (Hill 2018). Another meta-analysis with 26 studies and > 12.000 person-
years on TDF or TAF showed a benefit of TAF in initial therapy or at switch related
to more sensitive biomarkers of renal events: renal events, functional decline, or
tubule damage were significantly lower under TAF than under TDF (Gupta 2018).
The leading renal event of TDF is Fanconi syndrome (incidence 22,4/100.000 person-
years). This renal dysfunction manifests as hypophosphatemia in association with
normoglycemic glucosuria and moderate proteinuria (see above) and occurs on
average seven to nine months after the start of therapy (Izzedine 2004). Complete
regression after discontinuation may be expected in 42%, after a mean of 5 months
(Wever 2010). A rapid response with early switching is beneficial for outcomes
(Verwiys 2019). The risk of renal damage increases in combination with nephrotoxic
agents, renal disease or renal insufficiency in history, sepsis, dehydration, or severe
hypertension (Nelson 2006). In cohort analyses, this was also the case with CD4
T-cells below 50/µl, age over 45 years, diabetes mellitus, and long antiretroviral
treatment exposure (Moore 2007).
TDF is eliminated renally and must be dose-adjusted in renal insufficiency.
Combination with boosted PIs is possible, but ritonavir increases the Cmax and AUC
of tenofovir by approximately 30% (Izzedine 2005). In cohort studies, a decrease in
GFR of 7–10 mL/min per year was observed, although total GFR remained within
normal ranges. Therefore, using a boosted PI today should only be with TAF, not
TDF.
In renally healthy people on PrEP, creatinine, eGFR (calculated), serum phosphate
and glucose, and urine tix (proteinuria, glucosuria, and erythrocyturia) should be
monitored at least every three months during the first year on TDF. Check more
frequently in cases of renal dysfunction. This is especially true with additional
nephrotoxic substances or drugs that are also excreted via the renal transporter
OAT1 (aminoglycosides, amphotericin B, famciclovir, ganciclovir, pentamidine,
vancomycin, cidofovir, IL-2).
Particular caution applies to the TDF-containing fixed combination Stribild®: its use
is only considered for healthy kidney patients with a GFR > 90 mL. After the approval
HIV and nephrology 527

of Genvoya®, there is no longer any reason to accept these risks, and one is well
advised to switch.
The prodrug tenofovir-AF (TAF) achieves comparable concentrations in the target
cell. However, the dose is lower, and the plasma concentration is reduced by 90%.
As a result, the risk of accumulation in the tubule cell is reduced because signifi-
cantly less substance must be alternatively excreted. Therefore, TAF can be used up
to a GFR of 30 mL. In pivotal trials and renal insufficiency, proteinuria and tubular
protein excretion improved when switched from TDF to TAF (Gupta 2015). Renal
events such as Fanconi syndrome no longer occurred in pivotal trials. In cohorts,
patients with impaired renal function particularly benefited from switching from
TDF to TAF (Rieke 2018, Surial 2019). The effects on phosphate metabolism are lower
– there is probably also help in terms of bone density as a result. In sub-analyses,
largely stable renal function while on TAF was also observed for renally vulnerable
groups (older age or diabetes) (Gupta 2019). Patients with true Fanconi syndrome
on TDF may switch to TAF, as may those with proteinuria or renal insufficiency up
to 30 mL. From a nephrology perspective, TDF should be replaced with TAF, espe-
cially in all renally vulnerable patients. Only in pregnant women and people with
TBC (interaction) does this not apply.

Renal function and PrEP

A meta-analysis of 11 controlled trials with 3523 participants of PrEP with TDF (either
alone or combined with FTC/3TC) found only infrequent or mild impairment of
renal function during follow-up. In another cohort of 18,676 participants, GFR fell
primarily in older users and those with previously impaired renal function but not
in young, renally healthy individuals (Schäfer 2022). Nevertheless, because of renal
risks from STIs or substance use, the kidney should be regularly monitored with
creatinine, GFR, and dipstick.

Advanced renal failure, dialysis, and ART

In advanced renal failure, “renal neutral solutions” can be considered if the resist-
ance situation allows. These are, for example, combinations of boosted PIs and
dolutegravir or raltegravir, but also two boosted PIs, a combination of NNRTI/PI, or
combinations with dolutegravir or maraviroc. TDF should be avoided at a GFR
< 60 mL/min! In case of progressive renal insufficiency, dual ART should also be
considered: Dovato® (dolutegravir/3TC), 3TC is the limiting factor; from a GFR < 50,
the 3TC dose should be adjusted. If dialysis is required, all INSTIs, all PIs, and NNRTIs
are available in principle. For NRTIs, the dose must be adapted. The studies on dual
therapy with darunavir plus dolutegravir, dolutegravir plus rilpivirine, and with the
long-acting depot preparations cabotegravir plus rilpivirine or doravirine plus isla-
travir (in the future) show possibilities for use, even if there are no data on dialysis
so far. In Europe and the US, about 1,500–2,500 PLWH and on dialysis are to be
assumed. However, data on adequate ART on hemodialysis remains sparse. A single-
arm study in 26 centers in the US and Europe (Eron 2019) demonstrated safety and
efficacy for elvitegravir/c plus TAF/FTC (Genvoya®) for 48 weeks in 55 patients (Joseph
2018). Viral response and tolerability persisted after switching to Biktarvy® (Rieke
2021). TAF/FTC/darunavir/c (Symtuza®) should also be possible, but no studies or
approval exist. It is recommended that STRs be taken after hemodialysis each time.
Odefsey®, Descovy®, Genvoya®, and Biktarvy® are also approved for hemodialysis,
but EMA does not recommend use in the SmPC and remains a case-by-case consid-
eration. Because of the abundance of concomitant medications and potential inter-
actions, therapy without cobicistat is desirable. Abacavir is not appropriate because
528 Organs · Interdisciplinary Medicine

of increased cardiovascular morbidity. Careful monitoring of serum creatinine,

proteinuria, erythrocyturia, glucosuria, and serum phosphate is advised if there is
residual diuresis.

Hepatitis C and kidney

The renal parenchyma expresses CD81 and FR-B1 receptors, which allow hepatitis C
viruses to bind to the cell surface and infect the kidney’s cells through endocytosis.
Indeed, HCV RNA can be detected in mesangial cells, tubular epithelium, endothelial
cells of the glomerulus, and the tubular apparatus of the kidney. The immune
response of the body is likely triggered via Toll-like receptors (TLRS) and via the for-
mation of protein molecules, which can trigger a highly variable histopathological
picture: microdissections in the glomerular loop volume as TLR3 specificity and forms
of membranoproliferative glomerulonephritis (MPGN) are typically found in renal
biopsies in hepatitis C. If there is HCV-triggered cryoglobulinemia (circulating
proteins that precipitate in cold), this can induce ulcers as vasculitis on the skin,
especially in the extremities. The proteins are attached to the kidney, mesangial
matrix area, or glomerular capillaries and induce an immune response. Hepatitis C
and cryoglobulins can thus induce “endotheliitis” and cause renal damage through
anti-endothelial antibodies and complement activation, which can result in all forms
of glomerulonephritis: in addition to immune complex glomerulonephritis, these
include membrano-proliferative glomerulonephritis (MPGN), membranous GN,
focal segmental glomerulosclerosis (FSGS), IgA nephritis, forms of fibrillary or
immuno-tactoid glomerulonephritis, and renal involvement in the setting of pol-
yarteritis nodosa (PAN). In a compilation of renal damage (Kidder 2015), the cause
of renal impairment in HCV was seen to be chronic tubulointerstitial damage in the
majority (46%) (acute in 25%), while glomerulonephritis was distributed as mem-
brano-proliferative in 8%, minimal change GN in 4%, and membranous GN in 4%.
With today’s drugs, it is possible to treat hepatitis C even in ESRD: The combination
of glecaprevir/pibrentasvir (Maviret®) as a pan-genotypic combination and elbasvir/
grazoprevir (Zepatier®) for genotypes 1 and 4 are also available in dialysis. No agent
is renally eliminated or removed by hemodialysis; they can be dosed normally
(Kosloski 2016). Ribavirin, on the other hand, which has repeatedly led to severe
anemia, now has no place in renal failure. Sofosbuvir (such as in Epclusa®) can only be
used up to a GFR of 30 mL and may worsen renal function. The fixed pan-genotypic
salvage combination of sofosbuvir/velpatasvir/voxilaprevir (Vosevi®) is therefore only
possible up to a GFR of 30 mL. Below that; the use must be decided upon individually.

Dosage of ART in renal failure

The professional information applies. Since NNRTIs, PIs, and INSTIs (including
dolutegravir, bictegravir, cabotegravir, and islatravir) and maraviroc are almost exclu-
sively hepatically eliminated, dose adjustment is necessary only for NRTIs unless
there is concomitant hepatic insufficiency. Maraviroc should be dosed differently in
the presence of impaired renal function and in combination with a CYP3A4 inhibitor,
depending on the specific agent and GFR (see ART). The most cumulative substance
for fixed-dose combinations (FDCs) is decisive; TAF-containing FDCs can only be
used up to a GFR of 30 mL but are now approved on HD on a case-by-case decision
(see Table 2). The substances fostemsavir and ibalizumab do not need to be dose-
adapted in renal insufficiency (cf. SmPC). A good overview is also provided by the
EACS guideline: [Link]
prescribing-issues/other-prescribing-issues/arv-dosing-renal-impairment
HIV and nephrology 529

Table 2: Dosage of NRTI-containing agents adapted to renal function.

Drug Standard dose CrCl (mL/min) Dosage
AZT (Retrovir®) 2 x 250 or >50 300 mg BID
300 mg 30–10 No dose adjustment
<10 100 mg TID
HD 100 mg TID
3TC (Epivir®) 1 x 300 mg or >50 300 mg QD
2 x 150 mg 30–49 150 mg QD
10–29 100 mg QD
<10 + HD 50–25 mg QD
AZT/3TC 2 x 1 tbl >50 Standard dose
(Combivir®) <50 Not recommended
ABC 2 x 300 mg >50 300 mg BID
(Ziagen®) <30 No dose adjustment
AZT/3TC/ABC 2 x 1 tbl >50 300/150/300 mg BID
(Trizivir®) 49–<10 +HD Use single preparations
TDF (Viread®) 1 x 245 mg >50 300 mg QD
30–49 300 mg every 48 hours
10–29 Not recommended (300 mg alle
72–96 hours, if no alternative)
<10 Not recommended (300 mg every
seven days if there is no alternative)
HD 300 mg every seven days
FTC (Emtriva®) 1 x 200 mg >50 200 mg QD
30–49 200 mg every 48 hours
10–29 200 mg every 72 hours
<10 (incl. HD) 200 mg every 96 hours
ABC/3TC 1 x 1 tbl >50 600/300 mg QD
(Kivexa®) 49–<10 +HD Use single preparations
TDF/FTC 1 x 1 tbl >50 300/200 mg QD
(Truvada®) 30–49 300/200 mg every 48 hours
<30 and HD Use single preparations
RPV/DTG (Juluca®) 1 x 1 tbl >50 – HD Standard dose
TAF/FTC 1 x 1 tbl up to 30 Standard dose
(Descovy®) 29–<10 +HD Standard dose, given after HD
EVG/c/TDF/FTC 1 x 1 tbl >50 Standard dose (do not start if eGFR < 70)
(Stribild®) 49–<10+HD Do not use
EVG/c/TAF/FTC 1 x 1 tbl >50–30 Standard dose
(Genvoya®) 29–<10 +HD Standard dose, given after HD
RPV/TAF/FTC 1 x 1 tbl >50–30 Standard dose
(Odefsey®) 29–<10 +HD Standard dose, given after HD
RPV/TDF/FTC 1 x 1 tbl >50 Standard dose
(Eviplera®) 49–<10 +HD Do not use
DTG/ABC/3TC 1 x 1 tbl >50 Standard dose
(Triumeq®) 49–<10 +HD Use single preparations
530 Organs · Interdisciplinary Medicine

Table 2: Continuation
Drug Standard dose CrCl (mL/min) Dosage
BIC/TAF/FTC 1 x 1 tbl >50–30 Standard dose
(Biktarvy®) <30 + HD No dose adjustment, given after HD
(individual consideration)
DOR/TDF/3TC 1 x 1 tbl >50 Standard dose
(Delstrigo®) 49–<10 Not recommended
DTG/3TC 1 x 1 tbl >50 Standard dose
(Dovato®) 49–<10 Not recommended
DRV/c/TAF/FTC 1 x 1 tbl >30 Standard dose
(Symtuza®) 29–<10 Not recommended
Daily doses, unless otherwise stated. HD = hemodialysis

OIs and renal insufficiency

The following tables depict the treatment of the most important OIs in renal failure.

Table 3: Treatment of PCP in renal failure based on 80 kg patient.

Drug GFR GFR GFR GFR Dose adjustment for
normal >50 mL/min 10–50 mL/min <10 mL/min HD/CAPD/cont. dialysis
Cotrimoxazole 3 x 3 or 5–6 Amp of 5–6 Amp at 5–6 Amp of HD:+ as GFR <10:
4 x 2 tbl at 480 mg IV 480 mg i.v. 480 mg IV half-dose after dialysis
960 mg p.o. every 8 h all 12 h all 24 h CAPD: no adjustment
or CAVH: like GFR 10–50
3 x 5–6 Amp of CVVHD: like GFR <10***
480 mg i.v
Dapsone 100 mg 50–100% 50% avoid avoid
every 24 h
Atovaquone 750 mg 100%** 100%** 100%** HD: no adjustment
every 12 h CAPD: no adjustment*
CAVH: (GFR <10)**
Pentamidine 4 mg/kg 100% 100% 100% HD: (GFR <10)**
every 24 h all 24–36 h every 48 h CAPD: (GFR <10)**
see text! CAVH: (GFR <10)**
***For cotrimoxazole high-dose in PCP specifically: in HD 3x/week: 15–20 mg/kg before HD and
7–10 mg/kg after HD – based on the trimethoprim content in cotrimoxazole. For continuous renal
replacement therapy (CVVH): usual dosage if necessary.
A specific example for 80 kg: normal renal function 5 ampoules (400/80 mg each) every 6–8 hours.
For GFR < 30 mL/min, 5–6 ampoules (400/80 mg each) every 12 hours. In HD 3x/week, 5–8 ampoules
(400/80 mg each) every 24 hours (give at least half after dialysis on dialysis day). In CVVH(DF):
5–10 ampoules (400/80 mg each) every 12 h.
Dose-finding studies are not available, *regular dosing recommended, **dosing as it is recommended
for GFR < 10 mL/min.
HD = intermittent hemodialysis, CAPD = continuous peritoneal dialysis, CAVH = continuous arterio-
venous hemofiltration, CVVHD = continuous veno-venous hemodiafiltration.
Caution: Cotrimoxazole is nephrotoxic in high doses; its use should be critically evaluated and requires
close monitoring.
HIV and nephrology 531

Table 4: Treatment of cerebral toxoplasmosis in renal failure.

Drug GFR GFR GFR GFR Dose adjustment for
normal >50 mL/min 10–50 mL/min <10 mL/min HD/CAPD/cont. dialysis
Pyrimethamine 50 mg/12 h 100% 100% 100% HD, CAPD or CAVH:
for 2 days, no adjustment
then halve
Clindamycin 600 mg 100% 100% 100% HD: no adjustment
every 6 h CAPD: (GFR <10)*
CAVH: (GFR <10)*
CVVHD: GFR normal
Sulfadiazine 2g avoid avoid avoid avoid
every 6 h
* Dose-finding studies do not exist; dosing as recommended for GFR < 10 mL/min.
HD = intermittent hemodialysis, CAPD = continuous peritoneal dialysis, CAVH = continuous arterio-
venous hemofiltration, CVVHD = continuous veno-venous hemodiafiltration.

Table 5: Treatment of viral infections such as CMV, HSV, and VZV in renal failure.
Drug GFR GFR GFR GFR Dose adjustment for
normal >50 mL/min 10–50 mL/min <10 mL/min HD/CAPD/cont. dialysis
Acyclovir 5–10 mg/kg 5 mg/kg 5 mg/kg 2,5 mg/kg HD: Dose after dialysis
every 8 h every 8–12 h every 12-24 h every 24 h CAPD: GFR <10
CAVH: 6.5 mg/kg every 24 h
CVVHD: 6.5–15 mg/kg every 24 h
Ganciclovir 5 mg/kg 3 mg/kg 3 mg/kg 15 mg/kg HD: Dose after dialysis
every 12 h every 12 h every 24 h every 24 h CAPD: GFR <10
at GFR at GFR CAVH: 3.5 mg/kg every 24h
25-50 mL 10–25 mL CVVHD: 2.5 mg/kg every 24h
Valganciclovir 900 mg GFR 40–59 mL/min: unknown unknown
every 12 h for 450 mg every 12 h
induction (25–39: every 24 h
therapy 10–24: every 48 h)
Foscavir 90 mg/kg 50–100% 10–50% avoid HD: Dose after dialysis
every 12 h CAPD: 60 mg/kg every 48–72h
CAVH: GFR 10–50
Cidofovir 5 mg/kg 100% 0,5–2 mg/kg avoid HD: GFR 10–50
every 7 days every 7 days CAPD: GFR 10–50
CAVH: avoid
Famciclovir 250 mg every 12 h every 48 h 50% HD: Dose after dialysis
every 8 h orally every 48 h CAPD: ?
CAVH: GFR 10–50
* Dose-finding studies do not exist; dosing as recommended for GFR <10 mL/min.
HD = intermittent hemodialysis, CAPD = continuous peritoneal dialysis, CAVH = continuous arterio-venous
hemofiltration, CVVHD = continuous veno-venous hemodiafiltration.
532 Organs · Interdisciplinary Medicine

A reasonable overview of drug use in renal insufficiency can also be found in the
EACS guidelines in the chapter on dose adjustment of ARVs, as amended:
[Link]
other-prescribing-issues/arv-dosing-renal-impairment; [Link]

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535

24. Organ transplantation in HIV infection

C H R ISTIAN HOFFMAN N

Due to living longer with HIV, the number of needed transplants is growing;
especially livers (hepatitis C) and kidneys (nephropathies) are needed. According to
national guidelines, PLWH can be included on waiting lists in many countries.
However, there are still many issues and questions to consider.

Worse survival rates of PLWH?

One argument still occasionally used today against organ transplantation in PLWH
is the supposedly poorer survival rates. Large studies and meta-analyses have now
shown that success rates, if any, are barely worse than in HIV-negative individuals
(Roland 2016, Zheng 2019). In 510 HIV-positive kidney transplant recipients, neither
overall survival nor graft survival was worse in the absence of HCV co-infection
(Locke 2015). Outcomes were also good in 180 liver transplants, although HCV
co-infection did remain a risk factor (Locke 2016). This will likely continue to improve
with DAAs and the resulting significant improvement in hepatitis C therapy
(Manzardo 2018, Werbel 2019). Simultaneous kidney and liver transplants (Ballarin
2008, Di Benedetto 2011) have now been described, as have numerous re-transplants
(Agüero 2016). Individuals with hepatocellular carcinoma can also be transplanted
– their prospects are not significantly worse than for HIV-negative HCC.
Exclusion criteria for transplantation in most countries are CD4 T-cell counts below
200/µl for kidney or below 100/µl for liver and a non-controlled viral load (Trullas
2011). AIDS is usually not considered an exclusion criterion, except for PML.

Reinfection of the graft with HBV and HCV

HCV co-infection has long remained an independent factor for poorer survival after
liver transplantation (Locke 2016). This is changing with DAAs, which can be used
successfully and efficiently after transplantation – response rates are just as reason-
able, and there is a larger prospective study for glecaprevir/pibrentasvir (Reau 2018).
There is also data for co-infected individuals (Campos-Varela 2016, Manzardo 2018,
Werbel 2019).
HBV is usually treated with immunoglobulins and 3TC. As a rule, re-infection can
be prevented in this way – unlike with HCV. Any 3TC resistance can generally be
treated adequately with nucleos(t)id analogs such as tenofovir or entecavir (Tateo
2009, Coffin 2010).

Do immunosuppressants worsen the immune situation?

The rates and outcomes of surgical complications are similar to those observed in
the non-HIV setting in carefully selected HIV-infected liver and kidney transplant
recipients (Harbell 2012). However, the risks of immunosuppressive therapy are often
emphasized. Concerns are mainly directed at herpesviruses (CMV, EBV, HSV, HHV-8),
as these pathogens or their reactivations can be dangerous to HIV-positive and trans-
planted patients. This has not yet been confirmed in more recent cohorts (Teicher
2015). Moreover, laboratory studies show that immunosuppressants are well toler-
ated. In a placebo-controlled study of low-dose cyclosporin A (2 x 2 mg/kg CsA/die)
in asymptomatic PLWH, there was no adverse effect on CD4 and CD8 T-cells or
antigen-specific immune responses (Calabrese 2002). Mycophenol (Cellcept®), used
536 Organs · Interdisciplinary Medicine

in kidney, heart, or liver transplantation, is also well tolerated by people living with
HIV. If a rejection reaction occurs, thymoglobulin can be tried to suppress the reaction,
as in HIV-negative individuals. However, in one small study, prolonged CD4 T-cell
depletion occurs with thymoglobulin, leading to increased infections (Carter 2006).
CTLs are also likely reduced, which could result in reactivations of EBV infections
(Gasser 2009).

Immunosuppressants and ART – interactions?

Interactions between immunosuppressants and antiretroviral therapy are a
manageable problem. The calcineurin inhibitors cyclosporine and tacrolimus are
metabolized via the cytochrome p450 enzyme CYP 3A4, which is why significant
level changes (mainly increases) are possible, especially with PIs. Relevant
interactions are also likely with rapamycin (Krown 2012).
An INSTI-based regimen without a booster should be used; most data are available
for raltegravir (Azar 2016). ART may only be discontinued, switched, or restarted
under close monitoring of levels and in interdisciplinary cooperation!

Other organs: heart, lung, pancreas, cornea

In June 2003, an article in the New England Journal of Medicine caused a sensation
(Calabrese 2003). The list of authors was unusual: the last author was Dr. Zackin,
who, together with a team from Cleveland, US, described the world’s first success-
ful heart transplantation in an AIDS patient, namely his own. Various other successful
heart transplants have since been published, although there is still a need for edu-
cation among heart transplant professionals (Uriel 201, Agüero 2016). There are also
case reports of corneal transplantation (Vincenti 2002), lung transplantation (Bertani
2009, Kern 2014), or combined kidney-pancreas transplantation (Toso 2003,
Morabito 2016). Although data are sparse in each case, PLWH are not thought to
have worse prospects than HIV-negative individuals for organ transplantation
(Blumberg 2019).

HIV to HIV
Given the shortage of organs, an “HIV-to-HIV” approach, where PLWH receive organs
from other PLWH, has also been increasingly explored, particularly recently (Fulco
2015, Boyarsky 2019, Lushniak 2022). In a prospective, multicenter pilot study, 24
transplants were performed between 2016 and 2019. The one-year survival rate was
83%. Affected and graft survival rates were better than in previous cohorts, but some
infections and cancers were observed (Durand 2022).
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538

25. HIV-associated thrombocytopenia

H EI NZ-AUGUST HORST

Thrombocytopenia is one of the most common hematologic complications of HIV

infection. Before ART, the incidence increases markedly with the duration of infec-
tion (Heyward 1988), and cumulative incidences over ten years of up to 45% have
been described (Eyster 1993). A significant incidence of thrombocytopenia also
occurs during breaks in therapy, even with previously normal platelet counts
(Bouldouyre 2009). Thrombocytopenias in HIV are mostly mild – levels below
30,000/µl have been observed in less than 10% of all cases (Vannappagari 2011). An
initial manifestation may also occur in isolated cases during immune reconstitution
(Quach 2012). HIV-related thrombocytopenia has been generally attributed to two
different mechanisms: first, an immunologically driven destruction of the platelets,
and second, an insufficient platelet production by the megakaryocytes. While in
early HIV infection, increased platelet destruction appears to be predominant, in
advanced HIV infection, it is the combination of both mechanisms (Najean 1994,
Cines 2009).

Clinic
Usually, only mild mucosal bleeding occurs, such as petechiae, ecchymosis, gingival
hemorrhage, or epistaxis. Severe gastrointestinal or intracerebral bleeding is rare and
is only observed with platelet counts below 30,000/µl. However, platelet count and
function may play an essential role in bleeding risk (Middelburg 2016). In contrast
to patients with immune thrombocytopenia (ITP), patients with HIV-associated
thrombocytopenia often present with moderate splenomegaly and enlarged lymph
nodes. Spontaneous remissions of HIV-associated thrombocytopenia have been
described in 10–20%, mainly in mild cases (Walsh 1985, Abrams 1986).

Diagnosis
HIV-associated thrombocytopenia is a repeatedly confirmed isolated thrombocy-
topenia with platelet counts less than 100,000/µl. The platelets often show increased
variability in size. In the bone marrow, the frequency of megakaryocytes is normal
to increased. Differential diagnoses include ruling out EDTA-induced pseudothrom-
bocytopenia as well as bone marrow injury caused by drugs, narcotics, CMV, or atyp-
ical mycobacteria (MAC). For a review of drugs that can trigger associated throm-
bocytopenias, see [Link] The risk of heparin-induced
thrombocytopenia is likely increased with HIV (Thompson 2007). In isolated cases,
thrombocytopenias also occur with ART (Lebensztejn 2002, Camino 2003). Table 1
gives an overview of the leading causes of thrombocytopenia. It is essential to dis-
tinguish them from thrombotic thrombocytopenic purpura (TTP) and hemolytic
uremic syndrome (HUS), two life-threatening diseases that occur more frequently
with HIV and are associated with non-immunologically caused peripheral platelet
destruction. Platelets are also commonly reduced in liver insufficiency (hepatitis C!).
HIV-associated thrombocytopenia 539

Table 1: Causes of thrombocytopenias (except HIV, selected from Matzdorff 2021).

Pseudo-thrombocytopenia
Toxic bone marrow injury caused by drugs (e.g., TMP-SMX, rifampicin, or ethambutol), radiation.
infections such as HCV, Helicobacter pylori, CMV, MAC, COVID-19
Malignancies such as chronic lymphocytic leukemia, high-grade malignant lymphomas
Immunologic: lupus erythematosus, immune thyroiditis, Evans syndrome, heparin
Other causes: HUS, TTP, hypersplenism, vaccinations.

Therapy
First-line therapy is based on two principles: ART and, in severe forms, additional
immunosuppression with steroids. The treatment besides ART is based on recent
international consensus reports and the guidelines of the American Society of
Hematology (Neunert 2018, 2019, Matzdorff 2018, 2021). If first-line therapy fails,
thrombopoietin receptor agonists (TRAs), splenectomy, or rituximab may be indi-
cated. After successful treatment for HIV-associated thrombocytopenia, recurrences
requiring therapy are expected in more than half of cases (Ambler 2012).

Table 2: Therapy of HIV-associated thrombocytopenia.

Clinical situation Therapy
Asymptomatic and platelets ART
> 30,000/μl
Platelets < 30,000/μl or ART plus first-line therapy: corticosteroids
Platelets < 50,000/μl and Subsequent therapy(s)*: immunoglobulins,
significant mucosal bleeding splenectomy, rituximab, TRAs, azathioprine
Severe bleeding Platelet transfusions and corticosteroids
possibly additional immunoglobulins
* Subsequent therapies after failure of corticosteroids should be given according to the experience of
the treating physician since only a few prospective randomized studies are available (Vesely 2004).

ART usually leads to a recovery of the platelet count within three months (Arranz
Caso 1999). The effect is independent of the antiretrovirals used and the level of
platelets at the start of therapy (Arranz Caso 1999). It should be noted that
thrombocytopenias frequently occur during antiretroviral therapy breaks, especially
in the presence of previous thrombocytopenia (Ananworanich 2003). Therapy
beyond ART is indicated in cases of less than 30,000 platelets/µl and less than 50,000
platelets/µl with concomitant marked mucosal bleeding or risk factors such as arterial
hypertension or peptic ulcers (George 1996).
Corticosteroids: are the standard for initial therapy. A dose of 0.5–1.0 mg/kg/day
predniso(lo)ne results in a substantial platelet increase in 60–90% of patients (Abrams
1986). After a response, which can be expected within a few days, the initial dose
should be continued for 2–4 weeks and then phased out rapidly depending on the
platelet count, preferably above 60,000/µl. Therapy should not exceed six weeks
(Provan 2019, Matzdorff 2021). In cases of life-threatening bleeding, we recommend
higher doses (1 g methylprednisolone/day for three days, then gradual dose reduc-
tion). An alternative, especially in poor immune status, is the short-term adminis-
tration of high-dose dexamethasone. After four days of 40 mg dexamethasone/day,
a response is achieved in 85% of non-HIV-infected patients with thrombocytopenia.
Only 50% had a relapse within six months (Cheng 2003). After four cycles of this
540 Organs · Interdisciplinary Medicine

dexamethasone therapy given at 14-day intervals, a response was achieved in 74%

for at least eight months (Mazzucconi 2007). Retrospective studies of HIV-negative
patients with ITP indicate an increased rate of fatal infections with prolonged steroid
administration (Godeau 2007).
Intravenous immunoglobulins: used at a dose of 1 g/kg/day for 1–2 days without
response or contraindications to corticosteroids or in the presence of threatening
bleeding. The response rate is approximately 60%. However, without maintenance
therapy, platelets usually drop again after a few weeks and reach baseline levels after
about one month (Godeau 2007).
Splenectomy: is effective, even after failure of corticosteroid and immunoglobulin
therapy. Platelet count usually increases within the first postoperative week, often
to normal values (Ravikumar 1989). The feared additional weakening of the immune
system leading to an acceleration of the HIV infection was not observed in long-
term follow-up (Oksenhendler 1993). However, long-term complication risks are well
documented and may be one of the reasons for the overall low acceptance of this
procedure (Lambert 2017). For prophylaxis of life-threatening bacterial infections,
vaccination against pneumococcus, Haemophilus influenzae, and meningococcus is
recommended at least two weeks before splenectomy (George 1996). However,
vaccine response is uncertain with CD4 T-cell counts below 400/µl (Greub 1996).
Splenectomy should therefore be performed only in individual cases of therapy-resis-
tant severe thrombocytopenia and after an observation period of preferably not less
than 12 months (Provan 2019).
Rituximab: The CD20 antibody rituximab has also been used successfully in HIV-
associated thrombocytopenia (Ahmad 2004) and is an alternative to splenectomy.
Especially in cases of low CD4 T-cell count (< 100/µl), its use should be carefully con-
sidered because rituximab may increase susceptibility to infection. Fatal progressive
multifocal leukoencephalopathies have been observed in HIV-negative patients
(Carson 2009). A literature review of clinical efficacy in HIV-negative patients (age
over 15 years) with ITP revealed a response rate (platelets > 50,000/µl) of over 60%.
The platelet increases usually occurred after 3–8 weeks and lasted 2–48 months (Arnold
2007). However, a long-term effect is questioned in other studies (Ghanima 2015).
Platelet substitution: Since increased platelet destruction is an essential mechanism
in HIV-associated thrombocytopenia, platelet transfusions are only useful in rare sit-
uations with life-threatening bleeding. Platelet transfusions are combined with cor-
ticosteroids and/or immunoglobulins in this situation. Platelet transfusions are also
recommended before splenectomy if the platelet count is below 10,000/µl despite
adequate therapy.
Thrombopoietin receptor agonists (TRAs): TRAs offer an essential treatment option
in the event of failure or inadequate response to steroids and are characterized by a
relatively favorable safety profile with a lack of immunosuppressive effect (Neunert
2018). They show efficacy even after splenectomy. When on TRAs, a platelet count
of 50–150/µl is targeted (Matzdorff 2021). Subcutaneous administration of the peptide
romiplostim has been shown to increase platelet counts in 88% (non-splenec-
tomized) and 79% (splenectomized) in Phase III trials in HIV-negative patients.
A permanent increase was observed in 56% and 38%, respectively (Kuter 2008).
Dosage is initially 1 µg/kg SC once weekly, then 1–10 µg/kg SC once weekly, adjusted
for platelet count. An increment can be expected after 7–10 days. A response rate of
over 80% has also been seen with the small molecule eltrombopag, which has the
advantage of oral administration (Bussel 2007). However, intake restrictions should
be considered with antacids, dairy products, and polyvalent cations (Fe, Ca, Mg).
The recommended starting dose is 50 mg once daily PO (while for ITP associated
HIV-associated thrombocytopenia 541

with hepatitis C and for Asian ancestry, 25 mg once daily). It needs to be adjusted
up to 75 mg daily according to the platelet count. A platelet response can be expected
after 7–10 days. After the failure of other therapies, both molecules have been shown
to positively affect HIV-associated thrombocytopenias (Quach 2012, Vishnu 2015).
In the case of concomitant administration of protease inhibitors, it should be noted
that a 17% decrease in plasma AUC has been described for eltrombopag (Wire 2012).
Systematic studies in HIV-associated thrombocytopenias are pending. Side effects
reported for eltrombopag include an increased risk of thromboembolism and possi-
ble liver damage in chronic liver disease (Vishnu 2015). An increase in bone marrow
reticulin has also been observed with TRAs (Lambert 2017). Sustained responses of
the platelet count after discontinuation of TRAs have been reported. After an ade-
quate treatment response (e.g., platelet count > 50,000/µl) has been achieved for
several months, discontinuation of TRAs was suggested in a stepwise fashion
(abruptly stopping treatment can lead to a rebound of thrombocytopenia). Platelet
counts should be monitored during tapering and thereafter (Cooper 2021, Matzdorff
2021).
Avatrombopag, another TRA, has been approved for treating chronic ITP by the FDA
(2019) and the EMA (2021). However, there is insufficient data on its efficacy in HIV-
associated thrombocytopenia.
SYK inhibitors: Fostamatinib is the first approved SYK (spleen tyrosine kinase)
inhibitor. It was approved for treating chronic ITP in adults refractory to other treat-
ment modalities. Adequate data on HIV-associated thrombocytopenias are lacking
to date.
Interferon-α: Efficacy over placebo (dose 3 million IU 3x/week) was demonstrated
in a small, double-blind, randomized trial in 15 patients with HIV-associated throm-
bocytopenia (Marroni 1994). A significant platelet response was observed after three
weeks. However, platelet levels dropped back to baseline after the end of therapy.
Side effects include flu-like symptoms and, less frequently, cytopenias.
Other options: Various other treatment options for ITP, such as danazol and
mycophenolate, have been reported (review in Matzdorff 2021). However, the case
numbers are mostly small, and the effect is not proven.

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543

26. HIV-associated skin diseases

ST E FA N E S S E R

Compared to the general population, PLWH develop dermatoses more frequently

(Tan 2018). Skin and mucosal findings are directional in the initial diagnosis of HIV
infection and determination of clinical stage and manifest as a function of immun-
odeficiency (Schöfer 1991, Esser 2021). Diseases with skin or mucosal involvement
can often be diagnosed by simple inspection. Typical marker diseases of skin and
mucous membranes appear: during acute HIV infection, exanthema is often
observed. In clinical CDC stage B, oral and vulvovaginal candidiasis, herpes zoster,
oral hairy leukoplakia, carcinoma in situ of the cervix, and bacillary angiomatosis
are diagnosed. Many AIDS-defining diseases also develop manifestations on the skin
and mucous membranes. In untreated PLWH, Kaposi’s sarcoma is the most common
AIDS-defining neoplasm. Approximately 10% of initial HIV diagnoses are due to
changes in the skin or mucous membranes (Itin 2008).
The HIV Indicator Diseases Across Europe Study (HIDES) showed a high prevalence
of HIV in people with STDs (see STD) and certain skin diseases such as seborrheic
dermatitis and mononucleosis-like exanthema (Chatzikokkinou 2008, Sullivan
2013). HIV testing should, therefore be offered for indicator diseases.
The spectrum has changed considerably with antiretroviral therapy: Kaposi’s sarcoma
and opportunistic infections such as Candida infections (Friedman-Kien 1981,
Gottlieb 1981) have become rarer, whereas drug side effects, epithelial tumors, and
STDs have increased (Hartmann 2019, Esser 2021). Especially in advanced immun-
odeficiency, immune reconstitution syndrome may occur after ART initiation. In
this context, opportunistic infections of the skin and mucous membranes may
unmask, but also dermatoses may exacerbate.
Skin and mucous membranes have an independent immune system. Immuno-
deficiency allows even harmless saprophytes to penetrate deeper tissue layers, causing
e.g. folliculitis. Dry skin, chronic itching, exacerbation of atopic dermatitis, and
prurigo nodularis are prevalent in up to 38% of people living with HIV infection
(Rudikoff 2002, Coates 2019). Wound and soft tissue infections, pyoderma, and
methicillin-resistant Staphylococcus aureus infections are frequently observed (Burkey
2008, Imaz 2010). In addition to common dermatoses (oral candidiasis, herpes zoster,
seborrheic eczema), diseases that are otherwise rare are diagnosed in immuno-
deficiency, including cutaneous cryptococcosis, bacillary angiomatosis, oral hairy
leukoplakia, or infections with Talaromyces marneffei (Esser 2021).
A functional cellular immune system can protect against the development of neo-
plasms. The longer cellular immune deficiency persists, the more likely malignant
tumors will develop on the skin and mucous membranes. Cancers are more common
in PLWH, even at younger ages (Yarchoan 2018). Several cohorts worldwide observe
an increased risk of both basal cell carcinoma and cutaneous squamous cell carcinoma
(Silverberg 2013, Omland 2018, Coates 2019), while recent data on the incidence of
melanoma are conflicting (Coates 2019, Facciola 2020). Low CD4 T-cell counts
increase risk. Oncogenic viruses and immunodeficiency increase the risk for Kaposi’s
sarcoma (HHV-8), non-Hodgkin’s lymphoma (EBV, HHV-6, and HHV-8), and cervi-
cal and anal carcinomas (high-risk HPV types) (Esser 1998, Hartmann 2019, Clifford
2021). Despite ART, HPV-associated diseases continue to increase. In addition to the
already established colposcopic screening of cervical carcinomas, regular proctolog-
ical screening examinations are also indicated due to the increasing incidence of
anal carcinomas in PLWH (Esser 2015, Clifford 2021). Pre-cancerous lesions should
be removed early. Screening and early treatment of HPV-associated lesions reduce
544 Organs · Interdisciplinary Medicine

the incidence of anal carcinoma (Revollo 2020, Palefsky 2022). Merkel cell carcinomas
caused by polyomaviruses are sporadic but may also be more common (Wieland 2011).
Attention should be paid to regular skin cancer screening by reflected light
microscopy (Burgi 2005).

Dermatological examination and treatment

Regular inspections of the entire skin surface, the mucous membranes of the mouth,
genitals and anal region, and palpations of the lymph nodes are easy to perform.
Diseases of the skin and mucous membranes are often more severe, rapid, and
refractory to treatment in PLWH (Ameen 2010); the germ spectrum is also unusual
(Imaz 2010). Therefore, material for pathogen diagnostics should be obtained even
before treatments. In the case of unclear findings and ulcerative dermatoses, a punch
biopsy should always be taken.
Because standard treatments often fail due to advanced immunodeficiency and resist-
ance, higher and longer doses must be given (note side effects!), or alternative drugs
must be used (Osborne 2003). Interactions with ART must be considered. Systemic
immunosuppressive therapies and biologics should be used with caution. For
example, significant decreases in CD4 T-cells are observed with fumaric acid, increas-
ing the risk of opportunistic disease even without HIV infection (Philipp 2013).
Progressive multifocal leukoencephalopathies have been reported with TNF-alpha
inhibitors, and they should be avoided in PLWH if possible (Kumar 2010). IL-17
blockers are associated with increased fungal infections (Siegel 2019). Viral infec-
tions can be provoked, and tumors can be induced during UV treatments (Popivanova
2010).
Diagnosis and therapy may require the entire repertoire of an infectious disease-ori-
ented specialty clinic and the interdisciplinary cooperation of various specialist
groups. Brief descriptions of selected HIV-associated dermatoses and tumors can be
found in the alphabetical appendix.
ART-associated adverse reactions frequently affect the skin and mucous membranes
(Esser 2007). In the case of exanthema, it is often challenging to distinguish drug
reactions from immune reconstitution syndrome, syphilis, or viral exanthema
(Beatty 2010). Also, the causative agent often cannot be identified with certainty.
A switch of ART should be considered before symptomatic treatment of adverse
events. The resistance situation, co-morbidities, and interactions must be considered
(see Side Effects).

Drug reactions and allergies

The risk of cutaneous drug reactions in AIDS is approximately 9-fold (Hernandez-
Salazar 2006), and the risk of severe drug reactions is even more than 500-fold greater
than in the general population (Ward 2002). In 86% of PLWH, these reactions occur
within the first four weeks of the start of therapy (Rotunda 2003). Exanthems (rashes)
(Pirmohamed 2001, Shibuyama 2006) range clinically from macular to toxic epi-
dermal necrolysis. In principle, all drugs can be considered as triggers (Esser 2007).
The type of exanthema does not usually allow conclusions to be drawn about the
triggering allergen, but rather the temporal relationship with the initial ingestion
(latency on average, 9 ± 2 days). Drug exanthema is particularly frequent with nevi-
rapine and efavirenz (Van Leth 2005, Hartmann 2005), abacavir (Clay 2000), and
cotrimoxazole. Prophylaxis with glucocorticoids or antihistamines is ineffective
(Montaner 2003, Launay 2004). Pharmacogenetic HLA-B*57:01 testing is mandatory
before abacavir administration (see ART; Mallal 2008). Pharmacogenetic predictors
have also been studied for other drugs (Littera 2006, Wyen 2011). ART can often be
HIV-associated skin diseases 545

continued for mild or moderate drug reactions. Patients are monitored closely and
receive glucocorticosteroids locally or systemically (up to 1 mg/kg body weight) for
a short time if needed, as well as antihistamines for pruritus. Drug reactions often
regress despite the continuation of therapy.
Severe drug exanthema is often accompanied by general symptoms such as fatigue,
fever, and gastrointestinal complaints. Alarm signs include extensive skin
detachment (TEN: Toxic epidermal necrolysis), blistering (vesicles, bullae, SJS –
Stevens-Johnson Syndrome) and hemorrhage (petechiae, purpura, vasculitis) without
previous trauma, generalized seeding of sterile pustules and pustules (AGEP, Acute
Generalized Exanthemetous Pustulosis), dead, scabbed areas of skin (necrosis), and
sudden onset and disappearance of wheals and fluid retention in tissues (edema).
Mucosal involvement (eye, oral cavity, pubic region) is also classified as dangerous.
Blood eosinophilia indicates a DRESS syndrome (Drug Rash with Eosinophilia and
Systemic Symptoms). In the case of such symptoms, the affected person must be
monitored as an inpatient and treated systemically; the previously taken medica-
tions, including ART, may have to be discontinued permanently.
If general symptoms co-occur with exanthema, life-threatening and even lethal
courses are possible. In severe cases such as toxic epidermal necrolysis, immediate
intensive medical care is necessary. After severe reactions, the responsible substance
should not be used again. Different half-lives must be considered when discontinu-
ing ART, as resistance can develop rapidly under functional monotherapy. Some
patients take medications, drugs, herbal and other preparations, and dietary
supplements, often without informing their healthcare provider. Many “alternative
medicine” preparations have a relevant potential for allergic or toxic reactions
(Witkowski 2003).
The trigger often remains open if several medications have been restarted simulta-
neously. In such cases, “allergological” test methods are available. In type I reactions,
e.g., for penicillin, specific IgE antibodies can be detected in the blood. Lymphocyte
transformation tests are not yet methodologically mature. Cutaneous prick and
scratch and intracutaneous tests primarily evaluate immediate type I reactions.
Epicutaneous and patch tests are used to confirm a type IV reaction and other late-
type reactions. They must be read over several days. All skin tests are not able to
detect reactions against possible metabolites.
If all skin tests are negative, graded systemic provocation testing under inpatient
conditions (readiness for resuscitation, strict indication) can definitively clarify
whether a drug reaction to a specific substance is present (Shear 2008). A diagnosed
reaction or allergy should be recorded in an allergy passport, to be carried by the
person at all times.

Specific dermatological side effects of antiretroviral drugs

The intragluteal administrations of modern “long-acting injectables” such as
cabotegravir and rilpivirine (Landovitz 2016) cause local irritation and granulomas
at the injection sites that may persist over time. Laugier-Hunziker-Baran syndrome
with melanonychia striata medicamentosa (streaky brownish nail pigmentation) and
endobuccal mucosal lentiginosis (pigmentation of buccal mucosa, DD melanoma!)
is rarely observed with AZT (Greenberg 1990). Nearly 2% of (dark-skinned) patients
experience mostly mild palmoplantar hyperpigmentation with FTC (Nelson 2004).
However, there are case reports of PLWH who develop hyperpigmentation of the
nails, skin, and mucous membranes even without ART (Granel 1997).
Fat distribution disorders, lipodystrophy syndrome (Potthoff 2010), and weight gain
under certain substances are discussed elsewhere.
546 Organs · Interdisciplinary Medicine

Alphabetical overview of selected HIV-associated dermatoses and

their therapy
Folliculitides: Follicular bound pustular, papular efflorescences, emphasized on the
upper trunk and proximal extremities. Causes include staphylococci, Malassezia
furfur, Acinetobacter baumanii (Bachmeyer 2005), Demodex folliculorum, scabies mites
(Sarcoptes scabiei var. hominis), drugs, or atopic dermatitis (Rudikoff 2002) (Budavari
2007). Treatment depends on the cause with staphylococcal-active antibiotics, anti-
fungals, DADPS, isotretinoin, and ivermectin. Local therapy with topical gluco-
corticosteroids, calcineurin inhibitors such as pimecrolimus or tacrolimus (Toutous-
Trellu 2005), low-dose UV-311nm irradiation (Holmes 2001), and discontinuation
of triggering drugs. ART renders these dermatoses associated with cellular immuno-
deficiency less frequent; in particular, the eosinophilic variant improves on ART
(Hayes 2004).
Mollusca contagiosa (“dell warts”): Benign viral dermatosis caused by poxvirus
mollusci. Especially children with neurodermatitis contract the disease. In adults, it
is usually an STD. Extragenital molluscs in adults are a marker of advanced HIV infec-
tion (CD4 T-cells usually below 100/µl). In addition to the characteristic “dell wart”
with central expressible crumbly pulp, there are also large nodular conglomerates or
endophytic growth—differential diagnoses: cutaneous cryptococcosis, penicillinosis,
and histoplasmosis. Gentle procedures, as well as spontaneous healing, are possible
after initiation of ART. Surgical ablation with a curette or egg skin forceps (van der
Wouden 2005); topical: 5% KOH solution (Infectodell® solution). In individual cases,
an attempt at treatment with imiquimod can be made in cases of high suffering pres-
sure (Liota 2000).
Papular dermatoses: Diffuse appearance of monomorphic, skin-colored to reddish
papules (2–5 mm) or the combined eruption of papules and pustules (sterile
eosinophilic pustulosis, Ofuji’s disease [Kanaki 2021]): Upper trunk, extremities with
larger plaques that heal centrally with hyperpigmentation. Heterogeneous etiology
(Ramos 2006): an autoimmune reaction against follicular antigens as eosinophilic
folliculitis (See folliculitides), a variant of adult pruriginous type atopic dermatitis,
hypersensitivity reaction to drugs or by microbial agents, parasites, or saprophytes.
Diagnosis: drug history, histological special stains (PAS and others), mite search with
dermatoscopy (mite ducts?). Therapy: pathogen-specific or sanitation of focal infec-
tions. Otherwise, symptomatic antihistamines, itraconazole (200 mg/d for two
weeks), isotretinoin, dapsone, mild PUVA or UVB (311 nm) irradiation (most effec-
tive), 5% permethrin cream or topically glucocorticosteroids, calcineurin inhibitors
such as pimecrolimus or tacrolimus (Ellis 2004, Kanaki 2021).
Pityriasis versicolor: One of the most common superficial skin mycoses is caused
by lipophilic yeasts of the genus Malassezia and is favored by immunodeficiency, a
strong tendency to sweat, and a warm, humid climate. In areas rich in sebaceous
glands, white to dark brown, sometimes erythematous macules with fine, bran-like
scaling, which tend to confluence like a map, appear, depending on the UV expo-
sure. Even after successful therapy, it may take months for “repigmentation” to occur.
Detection is usually made directly by clear adhesive strip tear-off preparations or by
taking scale material from the marginal area of the lesion, making a potassium alkali
preparation (15% KOH) while staining with methylene blue and subsequent
microscopy at 400× magnification, or a calcofluorine or black phosphorous prepa-
ration for fluorescence microscopy. Wood light examinations (UV light of 365 nm
wavelength) show a yellowish-green fluorescence of the affected skin areas. It is
usually not necessary to perform a culture. Topically effective are azoles. Systemic
therapy is indicated for frequent recurrences.
HIV-associated skin diseases 547

Prurigo nodularis: Cutaneous manifestation of HIV infection (Liautaud 1989, Coates

2019). Chronic persistent, massively pruritic, usually excoriated papules and nodules
(0.5–3cm) mainly on the extensor sides of the extremities. Itch-scratch cycles with
lesional proliferation of cutaneous nerves maintain the disease for years. Severe
scratching enlarges the nodules. Hemorrhagic crusts, dark discoloration, keratotic or
verrucous dirty gray overgrowth, scars, depigmentation after healing. Frequent
psychiatric comorbidity and psychosocial disorders. Therapy: topical – potent
corticosteroids if possible occlusive, polidocanol, calcipotriol, capsaicin; photother-
apy (UVB, UVA1) or PUVA therapy. Treatment of persistent single-cell lesions:
injection with triamcinolone crystal suspension, cryotherapy, excision, dermabra-
sion, electrocaustic or laser surgical ablation. Systemic: sedating antihistamines (caveat:
interactions), psychotropic drugs (neuroleptics, antidepressants), corticosteroids,
retinoids. Good results are obtained with thalidomide up to 400 mg/day (caveat:
neurotoxicity, teratogenicity) (Matthews 1998). Adjunctive psychosomatic therapy.
Dressings to prevent mechanical irritation.
Pruritus: Chronic, often distressing pruritus is a common clinical symptom in PLWH
(Tarikci 2015, Coates 2019). Etiological clarification and therapy are complex (Singh
2003). In addition to infectious causes (follicular and non-follicular infections caused
by bacteria, viruses, fungi, and parasites such as Sarcoptes scabiei and crabs), dryness
of the skin (xeroderma, exsiccation eczema), erythrosquamous dermatoses, systemic
diseases such as lymphoma, renal insufficiency, hepatitides, and hepatoses, as well
as drug reactions, can also cause pruritus. Diagnosis includes exclusion of skin and
systemic diseases, especially scabies. The diagnosis of “idiopathic HIV-associated
pruritus” is a diagnosis of exclusion. Some authors suspect a direct connection with
HIV viral load (Zancanoro 2006).
Therapeutically, there are various phototherapies (UVA, PUVA, UVB-311nm) in addition
to antihistamines (cave interactions) and (primarily topical) glucocorticosteroids
(Tarikci 2015) (Singh 2003). For longer-term topical treatments, calcineurin inhibitor-
containing topicals are available for glucocorticosteroid sparing. Care should be taken
to ensure an appropriate base for all topical therapies. In severe, refractory individ-
ual cases with pruritus, especially on the extremities, costly local treatment with
capsaicin may also provide relief (Tarikci 2015). Gabapentin or neuroleptics such as
promethazine are also used systemically in extreme and chronic courses, as are
biologics such as dupilumab (Avallone 2021) and tralokinumab or JAK inhibitors in
individual cases, especially in atopic dermatitis.
Psoriasis vulgaris is an inherited, chronic autoimmune disease (0.2–2.8% of the
population) provoked by physical stimuli (including friction, lack of UV light), and
endogenous factors (infections, alcohol abuse, drugs such as beta-blockers or
“stress”). Psoriasis is now considered a systemic disease, as cardiovascular events, for
example, are also observed more frequently due to chronic inflammation. Psoriasis
occurs for the first time or as an exacerbation triggered by HIV infection in about
5.4% of PLWH (Tan 2018). The more severe the immunodeficiency, the more severe
and refractory the course (Ceccarelli 2019). Clinically, psoriasis can manifest eruptive-
exanthematous, chronic stationary, or atypical with an inverse pattern of involve-
ment (involvement of groin, axillae, palms, soles, face) as erythrosquamous plaques
or exudative, pustular, or erythrodermic. Involvement of the scalp and nails (spotted
or crumbled nails), joint involvement, and pustular forms are possible.
First, triggering factors should be eliminated and ART initiated. Local therapy with
dithranol, glucocorticosteroids, calcipotriol, tacalcitol, or a topical retinoid
tazarotene is sufficient in case of circumscribed affection. For localizations on the
capillitium and nails, corticosteroids can be combined, and for intertriginous areas,
548 Organs · Interdisciplinary Medicine

calcineurin inhibitors such as pimecrolimus can be used (Gisondi 2005). In case of

generalized or exudative involvement, systemic treatment is required, e.g., with
acitretin = neotigason 25–75 mg/d (von Zander 2005) or fumarates with gradual
dosage, in severe cases also with immunosuppressants such as methotrexate,
cyclosporine or hydroxyurea (Kumar 2001). When fumaric acid esters are
administered, CD4 and CD8 T-cells drop off – Kaposi’s sarcomas have been observed
with long-term administration even in people without HIV (Philipp 2013).
Alternatives: Photo- and photochemotherapy (UVB 311, UVB, PUVA: local or sys-
temic) are effective and have few adverse effects on HIV infection (Schoppelrey 1999).
Clinical experience is now increasingly available for people with HIV with biologics
that specifically inhibit factors of the inflammatory cascade (e.g., TNF-alpha, IL-12,
IL-23, IL-17A, and JAK) but may also increase the overall risk of infection. In a sys-
tematic review of 25 cases published between 1985 and 2015, serious infections
occurred almost exclusively in cases of ineffective ART (Nakamura 2018). Therefore,
the current German psoriasis guidelines recommend systemic treatment only in
severe, refractory psoriasis when HIV infection is successfully treated with anti-
retroviral therapy. Systemic biologics are indicated especially in cases of joint involve-
ment but also in cases of poor response. The selection is individual, based on the
dynamically changing guidelines (AWMF Psoriasis 2021). Before using biologics,
co-infections with tuberculosis, hepatitis B, and other opportunistic infections
should be excluded. Among some biologics, the increased incidence of PML (rare
overall) should be pointed out (Kumar 2010, Bharat 2012).
Scabies: Extremely pruritic dermatosis, especially at night. Predilection sites: finger
interdigitates, wrists, nipples, anterior axillary line, umbilicus, penile shaft: fine tor-
tuous red lines a few millimeters long (scabies ducts) and generalized eczema with
scratch marks (head free, exception: scabies norvegica and infants), especially inner
thighs and buttocks region. Typical are additionally inguinal and genital (penis shaft,
scrotum) red-brown, itchy nodules (= scabies granulomas), which can persist for
months even after successful therapy. Diagnostically difficult: “well-groomed”
scabies with severe pruritus but hardly detectable mites. In case of severe immun-
odeficiency special form: scabies crustosa (norvegica): marker disease of HIV infec-
tion. Over months, large eczematous foci develop with an asbestos-like shimmering
or bark-like scaling and head involvement (caution: confusion with psoriasis). These
foci may be asymptomatic but are highly infectious (up to 10,000 mites/g of skin
scales). Indicative: cases of ordinary scabies in the area. Complications: secondary
impetiginization, post-scabies eczema, protozoan mania. Diagnosis: dermoscopic
detection of mites, eggs, or mite feces (skybala) from mite duct by careful opening
with a cannula or lancet on a microscope slide under a magnifying glass. Treatment:
topical – 5% permethrin cream (Infectoscab®, day 1 + day 8 if necessary); other alter-
natives are benzoyl benzoate, pyrethrum extract, or allethrin/piperonyl butoxide. If
necessary, keratolysis as well as antiseptic and antieczematous treatment. In case of
scabies crustosa scale detachment, treat locally for several days and then anti-scabies
for at least 3–4 days (permethrin 5% cream, including capillitium and under distal
edges of fingernails). Systemic: if skin involvement exceeds 50%, scabies crustosa,
repeated unmanageable outbreaks in community settings, polymorbid, immobile
patients, or multiple recurrences: a combination of local keratolytic/antiscabiother-
apy plus systemic ivermectin, e.g., 200 µg/kg bw Scarbioral® (Alberici 2000). Since
ivermectin is not ovocidal: repeat administration after 1–2 weeks. Antipruritic
adjunctive therapy, e.g., with antihistamines (desloratadine, clemastine) at night
(caveat: interactions with ART). In addition, change of clothing and bedding (wash
at 90° Celsius or place in an airtight plastic bag for 3–5 days); sanitation of the
environment; examination and co-treatment of contacts. Aftercare: topical gluco-
HIV-associated skin diseases 549

corticoid-containing externals; antiseptic local treatment. Hygienic measures and

simultaneous treatment of all contacts are essential. Even after successful therapy,
the eczema must still be treated with local glucocorticoids, depending on the clinic
(Paasch 2001, AWMF Skabies 2016).
Seborrheic dermatitis: Incidence in untreated PLWH is between 30 and 83%,
depending on immune status (Chatzikokkinou 2008). The lipophilic yeast Malassezia
furfur is thought to have pathogenetic relevance, although subtype rather than
density of colonization appears to be important. Seborrheic dermatitis may be a
marker of progression of HIV infection and often improves with ART. Clinical: seba-
ceous follicle-rich areas (eyebrows, nasolabial folds, forehead, capillitium, external
auditory canal, anterior sweat groove, genitals); greasy yellow fine- to coarse-lamel-
lar scaling on usually sharply demarcated erythema. Treatment with topical anti-
fungal agents, such as ketoconazole, ciclopirox, or terbinafine cream, alternatively
selenium disulfide, metronidazole, low-dose dithranol, or lithium succinate- and zinc
sulfate-containing cream, or calcineurin inhibitors (Rigopoulos 2004). For treatment
of the hairy head, antifungal shampoos are appropriate. In severe cases, systemic
itraconazole 1 x 100 mg/d or terbinafine 250 mg/d (Gupta 2004, Kose 2005).
Warts: Human papillomaviruses (HPV) cause verrucae vulgares, verrucae plantares
(plantar warts), verrucae planae juveniles, epidermodysplasia verruciformis, condy-
lomata acuminata (genital warts), condylomata gigantea (Buschke-Löwenstein),
bowenoid papulosis and mucinous papillomas (Heck’s disease), in situ carcinomas,
squamous cell carcinomas (see STD). More than 150 types have been identified,
divided into “low risk” and “high risk” according to their oncogenic potential. HPV
exclusively infects epithelial cells of the skin and mucous membranes mostly via
micro-injuries. Infection from person to person, but also via vectors. Symptomatic
HPV infection leads after an undetermined latency period to a reactive, tumor-like,
keratinizing, mostly skin-colored epithelial hyperplasia with black stipples often
visible in reflected light microscopy (thrombosed vessels in papillomatosis). As a
result of a cellular immune response with lasting immunity to the respective subtype,
spontaneous remissions are observed in about 60%. Viral persistence is considered
the leading cause for the generally high recurrence rates after therapeutic interven-
tions and can lead to malignant transformation in high-risk HPV types. In addition
to other predisposing factors (atopy, UV light exposure, smoking), immune status is
a major contributor to further progression. In PLWH, HPV infections persist more
frequently, become symptomatic more often, tend to recur, and spread over large
areas due to autoinoculation, develop into carcinomas more quickly, and prove to
be particularly refractory to treatment.
There are a plethora of treatment options: topically, patients can use keratolysis with,
for example, salicylic acid-containing topicals or cyto- or virostatically active agents
such as acetic saltpeter lactic acid, trichloroacetic acid, podophyllin, and 5-fluo-
rouracil or immunomodulators such as imiquimod (Esser 2015). Dry extract of green
tea leaves is available as another effective local therapy. Surgical options include
scissor beating and excision, cryo-therapeutic, laser surgical, or electrocaustic
ablation. Malignancy and invasive growth should be excluded histologically if clin-
ical findings are abnormal. Often, the repeated combined use of different procedures
is necessary. In individual cases, systemic therapy with interferon-alpha can be
helpful, although health insurance does not usually cover this.
Xeroderma/dry skin: a frequent accompanying symptom of immunodeficiency.
About one-third of all HIV patients complain of excessively dry, itchy, scaly skin
and hypersensitivity to exogenous stimuli. Skin-care emulsions (containing lactic
acid, urea), dexpanthenol, and oil baths. In highly inflammatory forms, 3–5 days of
external corticosteroids (class 3–4) can help (Rudikoff 2002).
550 Organs · Interdisciplinary Medicine

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552

27. HIV-1-associated neurocognitive disorder

(HAND) and HIV-associated myelopathy
C H R ISTIAN EGGERS AN D THORSTEN ROSEN KRANZ

HAND
HIV-1-associated neurocognitive disorder (HAND) is caused by infection of cerebral
macrophages and microglial cells with HIV. Neurons are not infected, but functional
and structural disturbance of these cells occurs via immunopathological mechanisms.
The CNS is a partially independent compartment from the hematolymphatic system
concerning viral replication and quasispecies (Eggers 2003). On autopsy, PLWH with
advanced HIV infection show aspects of AD pathology, nonspecific histologic
changes, and “classic” histopathology (Everall 2009). The HAND classification
(Antinori 2007) distinguishes the stages or severities of “asymptomatic neurocognitive
impairment (impairment)” (ANI), “mild neurocognitive disorder (disorder)” (MND),
and “HIV-associated dementia” (HAD).

Table 1: The categories of HAND ("Frascati criteria", Antinori 2007).

HIV-1-associated Cognitive-psychological testing (age- and education-normed
asymptomatic assessment) with deterioration by ≥ 1 standard deviation (SD) in
neurocognitive ≥ 2 functional domains (language, attention/working memory,
impairment (ANI) abstraction/executive, verbal memory, processing speed,
perceptual/motor)
Disorder is not relevant to daily living (e.g., cognitive accuracy, lower
work effectiveness, household management, social activities)
HIV-1-associated Cognitive-psychological testing like ANI
mild neurocognitive At least minor disturbance of activities of daily living, according
disorder (MND) to self-report or external history
HIV-1-associated Cognitive-psychological testing as ANI, but deterioration by 2 standard
dementia (HAD) deviations.
Pronounced disturbance of activities of daily living

With ART, the prevalence of severe cases has decreased significantly, but that of mild
cases has increased (Heaton 2010). Worldwide, the prevalence of impaired
neurocognition in PLWH was 39%, although this includes asymptomatic cases and
is subject to the method to ascertain cognitive impairment (Keng 2023). The preva-
lence is higher in comorbid and elderly PLWH (Goodkin 2017). After the age of 50,
even with suppressed plasma viral load, there is a higher risk of dementia overall,
not just HIV-associated forms (Lam 2021). The CDC stage A now carries a higher
incidence of mild to moderate neurocognitive impairment. However, the “Frascati”-
classification, particularly its concept of “ANI” has received criticism. Due to method-
ological issues with normative values, it may assign people to pathological states,
not often reflective of daily experience (Gisslen 2011, Nightingale 2023). HAND is
associated with shortened survival and poorer treatment adherence (Albert 1999,
Vivithanaporn 2010). People with stage ANI are at greater risk for conversion to
symptomatic HAND (Grant 2014).
In untreated individuals, ART improves cognitive performance and functional con-
nectivity (Zhuang 2017). In treatment-experienced patients, the effect is less clear or
debatable. Despite suppressed plasma viremia, chronic progressive and sometimes
HIV-1-associated neurocognitive disorder and HIV-associated myelopathy 553

fluctuating cognitive impairment is possible (Brew 2004, Antinori 2007, Simioni

2010, Grant 2014). Early initiation of therapy mitigates the incidence of HAND
(Crum-Cianflone 2013). Over the years, improvements have become as common as
deteriorations or stability in cognitive performance (Sacktor 2016). Neurocognitive
impairment relevant to employment also occurs despite good viral suppression and
good immune status (Dore 2003).
In untreated infection, CSF and plasma viral load are significant predictors of the
development of HAND. However, this is less true when the viral load is suppressed
more successfully. Rather, recent cross-sectional and longitudinal studies identified
the following risk factors for cognitive impairment: low CD4 T-cell nadir, preexist-
ing severe immunosuppression or AIDS, longer duration of HIV infection, lower edu-
cational attainment, older age, obesity, diabetes, and elevated plasma concentrations
of TNF-alpha and MCP-1 (Sevigny 2004, Robertson 2007, Tozzi 2007, Bhaskaran
2008, Heaton 2010, Ellis 2011, Mind Exchange Working 2013, Grant 2014, Goodkin
2017, Rubin 2019a). The development and persistence of HAND despite ART may
be explainable by chronic immune activation in the CNS (Eden 2007, Lackner 2010,
Vera 2016), suggesting a “disconnection” of the brain from the systemic compart-
ment. Intact and replication-competent proviral DNA in the brain parenchyma can
still be detected after more than two years of plasma viral suppression in SIV-infected
mice and PLWH (Tang 2023). A few months before death, some patients diagnosed
with HAND showed no active viral replication in the brain parenchyma postmortem,
but strong signs of immune activation and neurodegeneration (Desplats 2013,
Gelman 2013). Whether concomitant HCV infection per se induces neurocognitive
impairment is unclear (Clifford 2015).
A so-called CSF viral escape occurs in about 10% of individuals with well-controlled
plasma viral load (Mastrangelo 2019, Pérez-Valero 2019). This is defined by a higher
viral load in CSF than in plasma; the plasma virus is often below the detection limit.
Clinically, there is usually headache and cognitive or focal neurological signs, but
some cases are asymptomatic (Chan 2021). In symptomatic cases MRI most times
shows white matter hyperintensities. The CSF is usually moderately inflammatory;
the CSF virus may show resistance discordant to plasma.
More recently, a new type of encephalitis with prominent brain infiltration of CD8+
T-lymphocytes was described in PLWH with mostly apparently well-working ART
(Lucas 2022). This disease manifests as a sometimes severe and life-threatening dis-
order with encephalopathic signs up to cerebral coma which can be explained by
marked cerebral inflammation and swelling. Pathogenetically, it has been implicated
with alterations in the virus-immune system interplay such as ART interruption,
immune reconstitution inflammatory syndrome (IRIS) after starting ART, and CSF
viral escape. On MRI prominent findings are bilateral, confluent, and symmetrical
high signal intensities, localized throughout the white matter. Treatment with cor-
ticosteroids has resulted in improvement.

Clinical manifestation
HAND is classified as a subcortical dementia. With the widespread use of ART, the
clinical picture has shifted to more cortical signs such as mnestic disturbances
(Heaton 2011). Motor and autonomic phenomena have become less common, occur-
ring only at advanced stages.
HAND develops over weeks and months. If it develops more quickly, other causes
should be considered. If the affected person is in a reduced general or conscious state
due to fever, fatigue, sedation, or an acute illness, the diagnosis may only be made
after a repeat examination under improved conditions.
554 Organs · Interdisciplinary Medicine

The fact that people complain about cognitive impairment does not mean that they
are objectively cognitively impaired. The correlation between subjective complaints
and neuropsychologically objectifiable disorders is low (Simioni 2010). In the case
of actual disturbances, patients tend to estimate the extent as low, whereas in the
case of existing depression, they tend to overestimate their degree of cognitive
disturbance (Thames 2011). Symptoms are sometimes more likely to be noticed by
relatives than by the affected persons themselves (external history!). Typical
complaints include slowing, disturbance of memory and concentration, loss of drive,
mild depressive symptoms, and affective flattening. For symptoms and findings, see
Tables 2 and 3.

Table 2:. Symptoms of HAND (self-reported and external history).

Cognition Concentration and memory disorders, slowing down of all mental
performances (perception, processing)
Emotional Loss of energy and initiative, social withdrawal, loss of social competence
(dealing with money, contact with authorities), depressiveness, and reduced
emotional vibrancy
Motor skills Slowing down and disturbance of fine motor skills (e.g., typing on a computer
keyboard, closing buttons), gait disturbance
Vegetative Micturition dysfunction (urge incontinence), decreased libido, erectile
impotence

Table 3: Findings for HAND.

Psychopatho- In early stages, decreased emotional vibrancy, personality flattening,
logical aspontaneity, and distractibility
findings In the advanced stage, additional time grid disturbance, and finally,
disorientation to time, place, and situation. In the final stage mutism
Neuropsycho- Decrease in memorization (remembering named items, digit span) and mental
logical findings flexibility (spelling backwards), impaired executive functions (trail-making test),
psychomotor slowing (e.g., reciting months backwards)
Neurological Early stage (ANI) is often unremarkable. Middle and late stages (MND, HAD):
findings gait unsteadiness, slowing of rapid alternating movements, hypomimia,
sometimes small-stepped gait, and tremor
Later increase in muscle reflexes with positive Babinski, slowing of gaze
saccades, positive palmomental, grasping, glabellar reflexes, and sphincter
disturbance. Occasional accompanying polyneuropathy
In the final stage spastic tetraplegia and incontinence

Definite attention disorder, focal or lateralizing signs (e.g., hemiparesis, aphasia), or

neck stiffness are not part of the picture, nor are psychotic symptoms without accom-
panying cognitive-motor disturbance. The coincidence of HAND and psychosis is
low. Focal and generalized epileptic seizures are also rare.

Diagnostics
The diagnosis of HAND is based on a synopsis of clinical, neuropsychological, and
technical findings and always requires the exclusion of other diseases (Table 3). No
technical finding alone proves the diagnosis of HAND.
HIV-1-associated neurocognitive disorder and HIV-associated myelopathy 555

Clinically, the cognitive disturbance is in the foreground. Psychopathological and,

even more so, motor disturbances may be absent or discrete initially but are virtu-
ally always present in full-blown dementia (stage HAD) (Table 2). Simple screening
tests for cognitive impairment include the HIV Dementia Scale (Morgan 2008,
Zipursky 2013) and the somewhat more comprehensive MOCA test, which also works
well in Alzheimer’s disease (AD) (Overton 2013).

Table 4: Differential diagnoses of (more pronounced) HAND and diagnostic measures.

Disease Appropriate diagnostic measure (comment)
Primary and degenerative Medical history (disturbance patterns typical for the disease,
dementias: microangiopathic family history, arterial hypertension with end organ damage)
leukoencephalopathy detailed neurological findings
(cerebral small vessel neuropsychological-cognitive profile
disease), Alzheimer's disease, MRI, PET, etc., with typical findings
Lewy body dementia, CSF pressure measurement and probatory drainage of CSF,
frontotemporal dementia, if necessary
normal pressure hydro- CSF with "dementia markers" such as Aß42, tau, phospho-tau,
cephalus, Parkinson's disease neurofilament light chain
Creutzfeldt-Jakob disease 14-3-3 protein and tau in CSF, EEG, MRI
Depression with psychiatric examination
pseudodementia
Intoxication Drug level/drug screening
Progressive multifocal MRI with single or multiple white sub-stance lesions (without
leukoencephalopathy (PML), KM enhancement, edema, or space-occupying lesions)
classic form CSF: No signs of inflammation, but positive PCR for JC virus (JCV)

PML in the setting of MRI with KM enhancement, edema, and possibly space-occupying
immune reconstitution lesion. CSF: If necessary, signs of inflammation, PCR detection of
syndrome (IRIS). JCV DNA
Metabolic encephalopathy Laboratory (electrolyte, kidney, liver, thyroid, and cortisol if
and poor general condition necessary, blood count)
Vit B12 deficiency (methylmalonic acid and homocysteine in serum)
Hypoxemia? (Blood gas analysis)
severe AZ reduction? (bedriddenness in cachexia, fever).
Neurosyphilis Antibody diagnostics and CSF analysis (pleocytosis ≥ 15/μl)
(Typical antibody findings as in florid syphilis may be absent).
Primary CNS lymphoma CT/MRI/PET or SPECT (uni- or multifocal, mainly ventricular lesions;
decreased diffusion in DWI).
CSF cytology (immunocytology if necessary)
EBV PCR (PCNSL are almost always EBV-induced).
Toxoplasmosis CT/MRI (uni- or multifocal contrast-enhancing lesions; in DWI,
increased diffusion in the abscess core)
Antibodies in serum and CSF (seronegativity rare in toxoplasmosis)
CMV encephalitis CSF with CMV PCR and pp65 antigen in EDTA blood; CMV serology;
MRI (subependymal contrast enhancement); ophthalmologist
Cryptococcosis CSF (opening pressure often elevated, cell count and protein
sometimes normal), ink stain, fungal culture, cryptococcus antigen
VZV encephalitis CSF with VZV PCR and serology in blood
556 Organs · Interdisciplinary Medicine

The gold standard, however, is comprehensive neuropsychological testing of at least

five cognitive domains (language, attention/working memory, abstraction/executive
function, learning/recall, information processing speed, and fine motor skills). As
the HIV population ages, the differential diagnosis to age-related forms of demen-
tia, such as Alzheimer’s disease, vascular dementia, Lewy body disease, or depressive
pseudodementia, becomes increasingly important.
The task of additional diagnostics is to exclude differential diagnoses. In stages ANI
and MND, routine MRI may show diffuse and relatively symmetric white matter
hyperintensities (WML) with ill-defined margins. Still, these do not necessarily cor-
relate with neurocognitive dysfunction (Mina 2021). In the stage of dementia (HAD),
these abnormalities are more frequent and more pronounced and are often accom-
panied by global brain atrophy. These findings may also indicate microangiopathic
leukoencephalopathy (small vessel disease, SAE) in elderly and additionally hyper-
tensive individuals (Mina 2021). In contrast to PML, the so-called U-fibers are usually
not involved, i.e., the subcortical changes do not extend to the cortical band. Findings
of marked asymmetric hyperintensities, multiple infarcts, edema, space-occupying
lesions, and contrast enhancement should raise suspicion of conditions other than
HAND.
In fully developed HIV dementia (HAD) and stage AIDS (without active CNS disease
such as cryptococcosis), the CSF cell count is usually normal to rather low. It may
be normal or slightly elevated in stages CDC A and B. In immune reconstitution
syndrome or only partially effective ART, it may also be moderately elevated,
suggesting an inflammatory character of HAND. Total protein and albumin quotient
may be slightly elevated (disturbance of blood-brain-barrier, BBB). Oligoclonal bands
and an elevated CSF-to-plasma IgG ratio as an expression of autochthonous IgG
production in the CNS are found early after infection in almost all PLWH and are
thus not specific for HAND.
In untreated HAND patients, viral load in CSF is elevated compared with non-
demented individuals, but this is not true for patients on ART (McArthur 2004).
However, using an ultrasensitive assay (detection limit 1 copy/mL), there was a
correlation between viral load in CSF and cognitive impairment (Anderson 2021).
In differentiating Alzheimer’s dementia and Creutzfeldt-Jacob disease, determining
the proteins Aß42, τ (tau), phosphorylated-τ and protein 14-3-3 in the CSF may be
useful. Isolated changes in Aß42 (pathologic if levels are decreased) have also been
found in HAND (Fields 2020).
The electroencephalogram (EEG) is normal, or there is a slight general slowing of
the basic rhythm in the sense of a slight general change. Moderate or severe general
slowing or clear and continuously occurring focal findings point to other diseases.
In common depressive pseudodementia (Pence 2012), the high level of complaints
of cognitive impairment contrasts with objectively nonpathological performance on
neuropsychological testing (Thames 2011).

Screening and therapy

Screening for HAND is recommended for all PLWH regardless of immune and treat-
ment status (Mind Exchange Working 2013, [Link]/guide-lines). This
should be done before ART initiation so that baseline data are available. Depending
on risk, screening should be done every 6 to 24 months. Appropriate screening instru-
ments include the HIV Dementia Scale, the MoCA test, and the “NEU screen” instru-
ment (Morgan 2008, Munoz-Moreno 2013, Brouillette 2015). With abnormal results,
HIV-1-associated neurocognitive disorder and HIV-associated myelopathy 557

the patients should be comprehensively examined neurologically and cognitively.

The aim of a causal therapy of HAND is the suppression of viral replication in the
CNS. Even though the CNS is an independent compartment of viral replication, ART
usually leads to a rapid decrease of viral load in the CSF (Eggers 1999+2003) with
clinical improvement within the first 3–9 months (Price 1999, Cysique 2009, Zhuang
2017). However, the clinical effect is highly variable, ranging from massive improve-
ment in therapy-naïve, severely demented individuals to small or equivocal effects,
especially in therapy-experienced individuals with minor disturbance. Leuko-
encephalopathy on MRI may be progressive initially but is usually regressive after
one to two years. Certification of permanent inability to work based on mild HAND
or suspicion may be premature.
Treatment: In general, the choice of antiviral substances should follow the principles
laid out by, e.g., the European AIDS Clinical Society (EACS) ([Link]
org/media/guidelines-11.1_final_09-[Link]; accessed August 2023). With regard to the
specific treatment of HAND, it remains unclear which antiretroviral agents are most
suitable and in which combination. Reports of inadequate suppression of CSF viral
load with monotherapy with a moderately CNS-penetrating PI (Gutmann 2010)
provide evidence that penetration into the CSF or parenchyma plays a role. Letendre
and colleagues introduced a “CNS penetration score” (CPE), which has since been
modified several times, with the fourth category (the highest, and thus best for CSF
penetration) including the following agents: AZT, nevirapine, indinavir/r,
dolutegravir. In category 3 are: Abacavir, FTC, etravirine, efavirenz, darunavir/r,
fosamprenavir/r, lopinavir/r, maraviroc, and raltegravir (Letendre 2011). Most studies
showed a better effect of ART with higher CPE scores on suppression of CSF viral
load (Letendre 2008, Cysique 2011, Cusini 2013). Regarding neurocognition, some
found improvement; fewer found no effect (Letendre 2023). These inconsistent
results are likely due to methodological differences. Human CSF penetration, for
instance, was exclusively examined using lumbar CSF. Ventricular CSF, however, is
much different from lumbar CSF and harbors much higher concentrations of some
antivirals, as shown for AZT and 3TC (Eggers 2020).
The importance of viral suppression in the CNS is supported by the phenomenon
of CSF viral escape, which occurs in roughly one-tenth of PLWH with well-suppressed
plasma virus (see above). Risk factors identified so far are longer ART duration, lower
nadir CD4 T-cell count, PI-containing ART (particularly atazanavir), and a combi-
nation of the CPE score with resistance mutations (Mukerji 2018, Trunfio 2023).
Most cases improved clinically and virologically after switching to resistance-adapted
ART with a higher CPE score (Mastrangelo 2019).
One paper suggested a preventive effect of early ART initiation (Ellis 2011). In several
cross-sectional studies, virologically stable and completely suppressed PLWH per-
formed worse than comparable HIV-negative individuals regarding cognition and
brain volume (Sanford 2018). In contrast, longitudinal studies with observation over
a few years yielded inconsistent results. Some found more rapid cognitive decline
despite viral load suppression (Gott 2017), whereas others found the same trajectory
of cognitive performance as in HIV-negative controls (Sanford 2018). One explana-
tion could be that fresh or early untreated HIV infection sets irreversible structural
damage that effectively sets the individual back functionally, the so-called legacy
effect.
In a recent prospective study, 191 PLWH with cognitive impairment despite sup-
pressed plasma viral load were randomized to add dolutegravir, dolutegravir plus
maraviroc, or placebo to their ART. Cognitive performance and depression scores
improved in all three arms without significant difference, thus not supporting the
idea of intensified ART in viral suppression without evidence of “CSF viral escape”
558 Organs · Interdisciplinary Medicine

(Letendre 2022). A small randomized trial of the antidepressant paroxetine found

evidence for improved cognition (Sacktor 2018). Other (non-antiviral) therapies
targeting the modulation of cerebral inflammation, neurotransmission, and struc-
tural neuronal integrity have been without clinically relevant effects (Sacktor 2011,
Simioni 2013).
As in general neurology, complaints of cognitive deficits are not infrequently an
expression of depression (“pseudodementia”), which is why this should always be
considered in the differential diagnosis. On the other hand, depression can also be
associated with a genuine and objectified cognitive disorder, especially in women
(Rubin 2019b). Therefore, the diagnosis of depression does not absolve the physician
from the need for HAND diagnostics.
Not to be neglected is the treatment of concomitant diseases such as hepatitis and
drug abuse, vascular risk factors, and adherence improvement (Mind Exchange
Working 2013). Neurotoxicity of antiretroviral agents must also be considered in
the presence of neurological, cognitive, and psychiatric complaints, and this is best
documented for efavirenz (Hakkers 2019). There have been reports of toxic effects
of otherwise suppressive ART, although some have questioned this (Munoz-Moreno
2010, Grund 2013). In suspected cases, modification of ART can be considered.
Therapy interruptions are not recommended (Mind Exchange Working 2013).

HIV myelopathy
Epidemiology and pathology
HIV myelopathy (HIVM) is very rare with ART. Because it can occur without the
neuropsychological disturbances of HAD, it is considered a separate clinical entity.
The histomorphologic correlate is the spinal cord’s vacuolization with the lateral
cords’ accentuation and lipid-laden macrophages’ appearance (Petito 1985). The
histopathology resembles that seen in funicular myelosis associated with vitamin
B12 deficiency. Because the detection of viral products in the lesions is not always
successful, the relevance of HIV infection of the spinal cord to HIVM is not certain.
Pathogenetically, a disturbance of cobalamin-dependent transmethylation is dis-
cussed. HIVM occurs in the late stages of HIV. Only some of the affected patients
with autoptic findings of HIVM have a corresponding clinical symptomatology (Dal
Pan 1994).

Clinic and diagnostics

The diagnosis is based on the clinical evidence of spastic syndrome most pronounced
in the legs with spastic-ataxic gait, hyperreflexia, and positive Babinski, disturbance
of sphincter control, potential erectile dysfunction, as well as minor glove- and sock-
shaped sensory disturbances. An independent HIVM can only be diagnosed if a pos-
sible concurrent dementia disorder is secondary to the myelopathic one. Exclusion
of differential diagnoses is crucial (Table 5).

Therapy
HIVM can improve significantly even with ART (Oksenhendler 1990). A controlled
study on L-methionine showed an electrophysiological but no clinical improvement.
HIV-1-associated neurocognitive disorder and HIV-associated myelopathy 559

Table 5: Differential diagnoses of HIV myelopathy and diagnostic measures.

Disease Appropriate diagnostic measure (comment)
Mechanical myelon Degenerative cervical spine changes
compression (cervical MRI evidence of depleted CSF space and hyperintensities
myelopathy, disc prolapse) in the medulla
Neurosyphilis Antibody and CSF diagnostics (pleocytosis) – typical antibody
findings, as in florid syphilis, may be lacking
CMV myelopathy CSF (inflammatory signs), PCR for CMV in CSF
Antibodies in serum and CSF (possibly elevated IgG, antibody
index)
Toxoplasmosis Contrast-enhancing focus on MRI
VZV myelitis CSF (clear signs of inflammation)
Antibodies in serum and CSF, PCR for VZV in CSF
Usually preceding or accompanying cutaneous zoster
manifestations and concomitant radiculitis.
HSV-1 myelitis CSF (inflammation may be absent), PCR for HSV
HTLV-1 Travel history (Caribbean, West Africa, and East Asia),
(Tropical Spastic Paraparesis) mostly chronic evolution, sphincter disturbance,
inflammatory CSF, antibodies against HTLV-1
Funicular myelosis Vitamin B12 level, macrocytosis
Hereditary diseases (familial Appropriate examinations of general neurology
spastic spinal paralysis,
adrenoleukodystrophy,
Friedreich's ataxia, etc.)

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562

28. Neuromuscular diseases

THORSTEN ROSEN KRANZ AN D C H R ISTIAN EGGERS

Polyneuropathies and polyradiculitis

Peripheral nerve disorders are the most common neurological complication of HIV
infection. They affect approximately 30–50% of patients in the era of modern
antiretroviral therapies (Kaku 2014). At the same time, primary HIV-associated
neuropathies have taken a back seat to drug-toxicity-related neuropathies (Gonzalez-
Duarte 2008).

Clinic
Acute inflammatory demyelinating polyneuroradiculitis
(AIDP, acute Guillain-Barré syndrome, acute GBS)
AIDP characteristically occurs during seroconversion and early stages of HIV infec-
tion, rarely in the context of an immune reconstitution syndrome. Within days to
a maximum of four weeks, symmetric paresis of the legs and arms typically develops,
often ascending distally, and may lead to respiratory insufficiency and dysphagia if
the trunk muscles and cranial nerves are affected. Sensory disturbances often present
initially as irritant symptoms in the form of pain and paresthesias; sensory deficits
are usually not clinically leading. When autonomic fibers are involved, life-threat-
ening cardiac arrhythmias or blood pressure derangements are possible. Muscle
reflexes are extinguished.
The CSF examination typically reveals a disturbance of the blood CSF barrier with
markedly elevated total protein and, at most, mild pleocytosis of a maximum of
50 cells/µl. With and without treatment, the disease enters a plateau phase lasting
several weeks, followed by a gradual remission. This can last a few weeks to two years,
and disability remains in about 30% of cases.

Chronic inflammatory demyelinating polyneuroradiculitis

(CIDP, chronic Guillain-Barré syndrome)
In contrast to AIDP, CIDP is a chronic progressive or relapsing disease. Paresis and
sensory disturbances often develop over many months. Areflexia also usually occurs.
In addition to steadily progressive courses, there are also those characterized by
relapses, partial remissions, and stable phases of varying length. In contrast to HIV-
negative persons, the protein elevation in the CSF is not always accompanied by a
normocytosis but often by a moderate pleocytosis of up to 50 cells/µl. CIDP occurs
preferentially in the early stages of infection.

Neuropathy in vasculitis
Rarely, necrotizing vasculitis occurs in the course of HIV infection. In the course,
involvement of other organs such as kidneys, heart, or skeletal muscles is possible,
determining the prognosis. Sometimes, there is an association of vasculitis with cryo-
globulinemia and hepatitis C.

Neuropathy in diffuse infiltrative lymphocytosis syndrome (DILS)

In DILS, a rare clinical picture similar to Sjögren’s syndrome, a mostly distal-symmet-
ric PNP may occur in addition to a sicca syndrome (Ghrenassia 2015). In addition
to the sicca syndrome, a pronounced infiltration by CD8 T-cells also leads to pneu-
monitis, lymphadenitis, gastritis, nephritis, or splenomegaly (see Rheumatic Diseases).
Neuromuscular diseases 563

Table 1: Forms of polyneuropathy and polyradiculitis in HIV infection.

Form HIV infection Clinic Special findings
Primary HIV-associated polyneuropathies
Acute inflammatory Seroconversion, Symmetrical paresis Demyelination in ENG,
demyelinating asymptomatic, > sensory disturbances, marked disruption of the
polyneuroradiculitis without or with mostly areflexia blood-liquor barrier, and
(acute Guillain-Barré incipient moderate CSF pleocytosis
syndrome, GBS). immunodeficiency. (up to 50 cells/μl)
Chronic inflammatory Asymptomatic, Distal and proximal Demyelination in ENG,
demyelinating possibly with paresis > Sensory marked disruption of the
polyneuroradiculitis incipient disturbances, often blood-liquor barrier, and
(CIDP, chronic GBS) immunodeficiency, areflexia in progression moderate CSF pleocytosis
rarely AIDS (up to 50 cells/μl)
Neuropathy in Asymptomatic with Mostly multiple, Elevation of ANA,
vasculitis or without incipient asymmetric deficits circulating immune
immunodeficiency, of single nerves, complexes,
rarely AIDS rarely distal cryoglobulinemia, often
symmetric sensorimotor concomitant hepatitis C
deficits infection; vasculitis in nerve
biopsy, also in muscle,
kidney, and other organs
Neuropathy in diffuse Incipient Mostly distal- Sjögren's syndrome-like
infiltrative immunodeficiency symmetric, rarely clinical picture,
lymphocytosis multifocal CD8 lymphocytes
syndrome (DILS) sensorimotor deficits > 1200/μl.
Distal symmetric, Usually prolonged Distal symmetrical, Axonal changes of
predominantly infection, high viral predominantly preferentially sensitive leg
sensory, axonal load sensory disorders of nerves in
polyneuropathy the legs, often painful electroneurography
Secondary polyneuropathies
Drug toxic Incipient or Distal symmetrical, Under therapy with d4T,
polyneuropathy advanced predominantly ddI, ddC, dapsone,
immunodeficiency sensory disorders of vincristine
the legs, often painful
Acute neuromuscular Incipient or Rapidly progressive Lactic acidosis usually
weakness syndrome advanced tetraparesis, usually occurs with NRTI therapy,
immunodeficiency only minor sensory mostly axonal lesions,
disturbances. possibly additional
myopathy
Mononeuritis AIDS Asymmetric CMV infection of other
multiplex with sensorimotor deficits organs, CMV DNA in
CMV infection plasma, history of
or lymphoma lymphoma
Polyradiculitis in AIDS Flaccid paraparesis CMV infection of other
infection with CMV, of the legs, sensibility organs (CMV DNA!),
M. tuberculosis, and bladder disorders acid-fast rods or lymphoma
or in meningeosis cells in CSF
lymphomatosa
564 Organs · Interdisciplinary Medicine

Distal symmetric sensory polyneuropathy (DSSP)

DSSP is by far the most common form of HIV-associated neuropathy. Predictors
include low CD4 nadir and persistent HIV replication (Octaviana 2018). For the
clinic, see Table 2. Other HIV-independent risk factors include older age, drug use,
HTLV-1 coinfection, diabetes mellitus, statin use, and hypertriglyceridemia (Banerjee
2011, Robinson-Papp 2012, Silva 2012).

Table 2: Clinical features of HIV-associated distal symmetric sensory polyneuropathy.

Numbness, pain, dys- and paraesthesia in the feet and lower legs
Decreased or absent Achilles’ tendon reflex
Decreased or absent vibratory senses of the toes and ankles
No or only minor motor dysfunction
No or only minimal involvement of hands and arms
Slowly progressive course
In EMG/ENG, signs of axonal damage to predominantly sensory leg nerves
Vegetative disorders: orthostatic dysregulation, erectile dysfunction, trophic disorders of the skin

Drug toxic polyneuropathy

The nucleoside analogs ddI and d4T (formerly also ddC) cause distal symmetric,
sensory, and axonal polyneuropathy in 10–30% of cases, which cannot be distin-
guished from HIV-associated DSSP either clinically or electroneurographically. Since
these agents have been discontinued, the incidence of drug-induced polyneuro-
pathies in people with HIV has decreased significantly. PNP is a possible side effect
in the labeling information for many new antiretroviral drugs because it occurred
more frequently in the verum groups of pivotal trials than in the control groups.
Based on clinical experience, the risk of PNP from therapy with NNRTIs, PIs, or inte-
grase inhibitors appears to be very low. Isolated cases of demyelinating neuropathy
have been described with darunavir, although the causal relationship has remained
questionable (Lorber 2013). A recent African study described the occurrence of sen-
sitive PNP in 11% of 120 ART-naïve patients without neuropathy six months after
starting tenofovir-containing treatment (Pillay 2019).

Table 3: Major neurotoxic drugs in HIV medicine.

Virustatics ddI, d4T, ddC (now off the market)
Antibiotics Dapsone, metronidazole, isoniazid
Cytostatics Vincristine, etoposide, vincristine

Acute neuromuscular weakness syndrome associated with lactic acidosis

In the context of lactic acidosis, usually induced by NRTI, a rapidly progressive life-
threatening tetraparesis can occur, which mimics the picture of AIDP. In most cases,
axonal nerve damage is the underlying cause, although demyelinating changes have
also been detected in isolated cases. In a small proportion of cases, a muscle biopsy
also revealed findings of myositis or mitochondrial myopathy (Simpson 2004).

Amyotrophic lateral sclerosis

Motor neuron disease occurs with an incidence of 3.5/100,000 in PLWH, compared
to 1–2/100,000 in the general population (Bogoch 2015). The disease is similar to
that in HIV-negative patients, but the age of onset is younger, and the course is even
more rapid. In individual cases, ART has been described to halt and improve the
disease (Bowen 2016).
Neuromuscular diseases 565

Polyneuropathies and -radiculitis in other diseases

PNP of the mononeuritis multiplex type, as occurs in the context of vasculitis (see
above), may rarely also be caused by CMV infection or by non-Hodgkin’s lymphoma.
Acute or sub-acute polyradiculitis predominantly of the cauda equina with rapidly
progressive flaccid proximal and distal paresis of the legs and bladder-, defecation-
and sensory disturbances may occur with opportunistic infections (CMV, tubercu-
losis) or in the setting of meningeosis lymphomatosa. Other causes include alcohol
abuse, diabetes mellitus, malnutrition in prolonged gastrointestinal disorders, con-
sumptive diseases, or cachexia.

Diagnostics
In most cases, disease history and clinical findings allow the assignment to one of
the above-listed PNP forms. The additional diagnostic procedures primarily serve to
confirm the presence of a PNP and to differentiate it from a myelopathy, for example.
Only if the stage of HIV infection does not match the recognized form of polyneu-
ropathy – e.g., painful DSSP with good immune status, low viral load, and without
neurotoxic medication – are invasive measures indicated, up to and including nerve
biopsy. For practical purposes, the procedures described in Table 4 have proven useful.

Table 4: Diagnostics of polyneuropathies and polyradiculitis.

Investigation Findings Suspected diagnosis
Generally recommended examinations for suspected polyneuropathy
Medical history Medication Drug toxic PNP
Opportunistic diseases Neuropathy or radiculitis in CMV,
lymphoma, etc.
Alcohol consumption Ethyltoxic polyneuropathy
Neurological Detection of PNP syndrome e.g., no myo- or myelopathy
examination
Electromyography Neuropathy safeguarding e.g., no myo- or myelopathy
Electroneurography Demyelination AIDP, CIDP
Axonal neuropathy DSSP, multiplex neuropathy, DILS
Blood tests HbA1c, glucose profile Diabetic polyneuropathy
Vit B12, B1, B6, iron, ferritin Neuropathy in malnutrition,
malassimilation
ANA, cryoglobulins, Neuropathy in vasculitides
HCV serology, circulating
immune complexes, ANCA
Treponema serology Neurosyphilis
CD8 T-cells > 1,200/μl Neuropathy in diffuse infiltrative
lymphocytosis
Lactate NRTI neuropathy
CMV DNA (only if CD4 Multiplex neuropathy, radiculitis
cells < 100/μl) in CMV infection
566 Organs · Interdisciplinary Medicine

Table 4: Continuation
Investigation Findings Suspected diagnosis
Necessary additional examinations only for specific suspected clinical diagnoses
CSF Blood Liquor Barrier AIDP, CIDP
Disorder
Granulocytic pleocytosis, CMV polyradiculitis
CMV DNA
Malignant cells, EBV DNA Meningeosis lymphomatosa
Mixed-cell pleocytosis, Tuberculous polyradiculitis
acid-fast rods,
mycobacterial DNA
Vegetative function Involvement of sympathetic Concomitant autonomic neuropathy with,
tests (e.g., Schellong, and/or parasympathetic e.g., orthostatic dysregulation,
sympathetic skin nerves in neuropathy erectile dysfunction
response, heart
rate variance)
MRI of the lumbar Spatial growth in the Spinal lymphoma
spine cauda equina Spinal toxoplasmosis
Nerve and Necrotizing vasculitis Neuropathy in vasculitis
muscle biopsy Perivascular infiltration Neuropathy in diffuse infiltrative
of CD8+ lymphocytes lymphocytosis
without vascular necrosis

Occasionally, affected persons complain of considerable pain and paresthesia, sug-

gesting polyneuropathy without clinically pathological findings. In these cases, there
is usually isolated damage to the small, unmyelinated nerve fibers (small fiber
neuropathy). This small fiber neuropathy cannot be detected in normal electro-
neurographic examinations. The diagnosis is usually made with a skin biopsy
demonstrating the reduction of intradermal nerve fibers. Additionally, measuring
the pain-related evoked potentials can be useful (Obermann 2007).

Treatment
For therapy, see Table 5. CIDP responds significantly better to corticosteroids in PLWH
than in HIV-negative patients. In DSSP, no causal treatment is known; in some cases,
neuropathic symptoms improve with effective ART. Treatment is usually limited to
symptomatic measures such as pain therapy. The approach is similar to painful
polyneuropathies in patients without HIV (Finnerup 2015). The drugs listed in Table 6
have a low interaction potential with ART. Lamotrigine is effective in a larger
controlled trial in DSSP on continued neurotoxic ART (Simpson 2003). Dosing up
slowly and reducing or discontinuing early if skin reactions occur is crucial.
The tricyclic antidepressants amitriptyline and nortriptyline have marked anti-
cholinergic effects. Therefore, the higher dose necessary for a sufficient analgesic
effect is often not reached. Lower doses are ineffective in DSSP (Dinat 2015). Because
of its severe interferences with other drugs, including ART, carbamazepine, widely
used in neuropathy pain management, must be avoided.
Local treatment with a highly concentrated (8%) capsaicin patch is also effective for
DSSP in PLWH; it is approved for this group (Thomas 2020). Smoking cannabis was
effective for neurotoxic PNP symptoms in two controlled trials, but only for a short
period (Abrams 2007, Ellis 2009). Following the release of cannabis flowers for
Neuromuscular diseases 567

medical use, they are increasingly prescribed to PLWH with painful neuropathies as
an extract from flowers or via a vaporizer. However, there is insufficient data to eval-
uate the benefits and risks of long-term, regular use.

Table 5: Causal treatment of polyneuropathies and polyradiculitis.

Polyneuropathy diagnosis Treatment (bw = body weight)
AIDP (acute Guillain-Barré Immunoglobulins IV 0.4 g/kg bw daily for 5 days
syndrome) Alternative: Plasmapheresis (5 x in 7–10 days)
CIDP (chronic Guillain-Barré Immunoglobulins IV 0,4 g/kg bw daily for 5 days
syndrome) Plasmapheresis (5 x in 7–10 days)
Prednisone 1–1.5 mg/kg bw daily for 3–4 weeks orally or IV,
then decreasing doses over 12–16 weeks until below Cushing's
threshold
All three methods are equivalent in terms of effectiveness.
Neuropathy in vasculitis Prednisone 1–1.5 mg/kg bw daily for 3–4 weeks orally or IV,
then decreasing the dose over 12–16 weeks until below
Cushing's threshold
Neuropathy in diffuse Start or optimize ART
infiltrative lymphocytosis plus prednisone 1–1.5 mg/kg bw daily for 3–4 weeks,
syndrome (DILS) then decrease doses over 12–16 weeks until below Cushing's
threshold
Distal symmetric, No causal therapy is known; improvement with ART in some
predominantly sensory, cases
axonal polyneuropathy For symptomatic therapy, see Table 6
Drug toxic polyneuropathy If possible, discontinue or change the use of neurotoxic drugs
Recovery is somewhat delayed
Mononeuritis multiplex or Foscarnet IV 2 x 90 mg/kg bw daily in combination with
polyradiculitis in CMV infection ganciclovir IV 2 x 5 mg/kg bw daily
Polyradiculitis in meningeosis Initiation or optimization of ART plus methotrexate
lymphomatosa intraventricularly via meningeosis lymphomatosa or lumbar
intrathecally 12–15 mg 2x/week until CSF is sanitized,
then 1x/week for 4 weeks, then 1x/month plus 15 mg each
of folinic acid orally with each injection plus systemic therapy
for lymphoma (see chapter Malignant Lymphoma)
Polyradiculitis in infection 4-fold tuberculostatic therapy (see Opportunistic
with M. tuberculosis Infections/Tuberculosis Treatments)
568 Organs · Interdisciplinary Medicine

Table 6: Symptomatic therapy of painful polyneuropathies.

Therapy Side effect
1st stage: Physical therapy (alternating baths, etc.), Rarely allergy
general measures (wide shoes),
Lidocaine gel 5% or patch
2nd stage: Trial with 3–4 x 1,000 mg paracetamol or Nausea, vomiting, allergy (rare)
2–3 x 50 mg diclofenac or 4 x 40 trp.
Novaminsulfone limited over 10–14 days
or 8% capsaicin patch Temporary skin redness or irritation
3rd stage: Gabapentin 300 mg at night, Sleepiness, fatigue, nausea, dizziness,
increase by 300 mg every 3 days rarely pancreatitis
to a maximum of 3 x 1200 mg
or
Pregabalin 2 x 75 mg, increase to Nausea, vomiting, diarrhea,
2 x 150 mg after 1 week, further allergic exanthema
increase to 2 x 300 mg possible
after another week
or
Lamotrigine 25 mg in the evening, Allergic exanthema, cephalgia, nausea
increase by 25 mg every 14 days
to a maximum of 2 x 200–300 mg daily
or
Amitriptyline 25 mg at night, Fatigue, sleepiness, hypotension,
increase by 10–25 mg constipation, dizziness, dry mouth,
every 2–3 days arrhythmia, urinary retention,
until 3 x 50 mg cave: glaucoma
or
Nortriptyline 25 mg in the morning, Hypotension, constipation, dizziness,
increase by 25 mg every 2–3 days until dry mouth, dysrhythmia, urinary
2–3 x 50 mg retention, cave: glaucoma
or
Duloxetine 1 x 60 mg in the morning Nausea, diarrhea, restlessness
4th stage: Opioids or Sedation, constipation, nausea
Gradually increase sustained-release
morphine 2 x 10 mg to a maximum Sedation, nausea, constipation
of 2 x 100 mg.
General Change to the next stage in each case if the complaints persist.
Combinations of stage 3 or stage 3 and 4 preparations are useful.
If a rapid effect is desired, start with level 4 and slowly add a substance from
level 3.
The slower the up-dosing, often the greater the achievable dose and the greater
the chance of effect.
Close contact with patients is crucial for compliance and finding the best
individual treatment.
Neuromuscular diseases 569

Myopathies
The incidence of myopathies, which can occur at any stage of infection, is 1–2%.
Cytotoxic T-cell-mediated HIV-associated polymyositis is the most common primary
HIV-associated myopathy. Even with low-dosage NRTIs, there are occasional exer-
cise-induced myalgias. On muscle biopsy, patients show isolated evidence of mito-
chondrial dysfunction (Landon-Cardinal 2019).

Table 7: Overview of the most important myopathies. Except for polymyositis of drug-induced
disorders, these are very rare diseases.
Primarily HIV-associated Secondary
Polymyositis Drug-induced mitochondrial dysfunction
Nemaline myopathy Myopathy in vasculitis
Vacuolar myopathy Infiltration by non-Hodgkin's lymphoma
Inclusion body myositis Pathogen-induced myositis
Acute rhabdomyolysis (with seroconversion). Drug toxic rhabdomyolysis

During seroconversion, rapidly progressive rhabdomyolysis with acute renal failure

may occur as part of a mononucleosis-like clinical picture (Ranabhat 2021). Also,
some drugs (ddI, cotrimoxazole, pentamidine, sulfadiazine, lipid-lowering agents)
and the integrase inhibitors raltegravir and dolutegravir (Zembower 2008, Saad 2018)
can rarely cause acute rhabdomyolysis with tetraparesis and massive increase in
serum CK activity. Note that serum concentrations of many statins are increased
with PIs, increasing the risk of rhabdomyolysis (Hare 2002). Raltegravir may also
cause less acute proximal myopathies with muscle pain without increased serum cre-
atine kinase activity (Lee 2012). Serum CK activity is often increased with tenofovir,
especially with HBV or HCV coinfection. This is not due to muscular dysfunction
but to type II macro-CK and is not correlated with any disease. In these cases, the
clearance of this liver-derived CK-isoenzyme appears to be reduced by tenofovir
(Schmid 2006).

Clinic
Regardless of etiology and entity, myopathy often begins with muscle soreness-like
myalgias induced by physical stress, primarily affecting proximal muscle groups.
Over weeks to months, muscle atrophy and paresis develop. Limb-girdle muscles are
usually affected, but involvement of trunk, neck, pharyngeal, facial, or distal limb
muscles is also possible.

Diagnostics
Myalgias and increased serum CK activity are common in HIV infection. Many anti-
retroviral drugs, especially NRTIs, NNRTIs, maraviroc, and integrase inhibitors, can
trigger myalgias. The careful documentation of drug history is critical, and the
improvement of myalgias after stopping the drug supports the causal relationship.
However, myopathy diagnosis requires the presence of muscle atrophy, paresis, or
evidence of myopathic findings on electromyogram. In these cases, muscle biopsy
is indicated (Table 7).
570 Organs · Interdisciplinary Medicine

Treatment
Mild myalgias can be treated symptomatically with non-steroidal anti-inflammatory
drugs. Prednisolone (100 mg daily for 3–4 weeks, then slowly tapering off) or intra-
venous immunoglobulin (0.4 g/kg over 5 days) were effective as therapy for
polymyositis in small studies (Johnson 2003, Viard 1992).
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571

29. HIV and psychiatric diseases

C H R ISTIAN PER RO

Depression and anxiety disorders are the most common psychiatric disorders among
people living with HIV (Capaldini 2000, Gallego 2011, Lopes 2011, Mascolini 2016).
With HIV infection, the risk of mental illness is twice as high. Conversely, mental
illness increases the risk of becoming infected with HIV and is also considered a
negative predictor of the further course of infection (Nel 2011). Mental illnesses can
express reactive disorders, be primarily related to HIV infection or its treatment, or
occur independently of HIV (pre-existing). They affect quality of life and are often
characterized by profound disruption of social and occupational participation. Rarely
do they impair the capacity for insight and consent to such an extent that there are
legal consequences, such as the initiation of legal guardianship.
Although treatment is generally no different from HIV-negative individuals, some
unique features should be considered. Symptoms should be treated consistently,
psychotherapeutically, and/or medicinally. Constantly, current ART should also be
reviewed. For example, neuropsychiatric side effects have been repeatedly described
in recent years for antiretroviral agents such as efavirenz and second-generation
INSTIs (Hoffmann 2016+2019). Sometimes, it may then make sense to switch ART.
From experience, individuals are often reluctant to report psychological symptoms.
Therefore, patients should always be asked about psychological problems in every-
day life.

Depression and other affective disorders

Depression – with or without anxiety/panic disorder – is still considered the most
common affective disorder (Eshun-Wilson 2018). Depending on the stage of
infection, lifetime prevalence is sometimes significantly higher than in the general
population, which is thought to be 16–20% (Tegger 2008, Mascolini 2016, Eshun-
Wilson 2018). Depression can be a one-time occurrence or recurrent. Depression is
underdiagnosed. Even when it is diagnosed, only a fraction of patients receive
adequate treatment (Mascolini 2016).
In clinical practice, the question often arises: Is the patient “just sad and in a bad
mood” or are the criteria of a depressive episode already met? The diagnosis of HIV
infection alone is usually not the cause of depression. The diagnosis leads to
psychological distress and psychopathological symptoms, but these often do not
fulfill the criteria of a diagnosis of depression according to ICD-10/11. A recom-
mendable depression screening is PRIME-MD PHQ2 with two quick-to-answer
questions (Kroenke 2003). Treatment of depression is essential in PLWH because it
can improve virologic response to ART and adherence (Pence 2007, Gonzalez 2011,
Ngum 2017). Psychiatric screening with targeted questions is recommended at least
every 1–2 years. The exact cause of depression remains unknown, but a genetic
predisposition has been established. Currently, the vulnerability-stress model applies,
and neurotransmitter imbalances are assumed. Depression is characterized by main
symptoms such as depressed, depressive mood, loss of interest and joylessness and/or
lack of energy, and increased fatigue. Moreover, there may be additional symptoms
such as feelings of guilt and worthlessness, sleep and appetite disturbances,
concentration disorders, suicidal thoughts, and others.
These features should be present for at least two weeks and not describe a general
personality trait. The severity depends on the number of symptoms present. Not all
features need to be present at the same time. Between single and recurrent episodes,
572 Organs · Interdisciplinary Medicine

longer-lasting depressive symptomatology (over two years = dysthymia), adjustment

disorder, and mixed anxiety and depression disorders.
In addition to the psychiatric interview, the diagnostic workup should include
cerebral imaging (ideally a cranial MRI) if possible, and a cerebrospinal fluid (CSF)
puncture if necessary to rule out opportunistic CNS disease or incipient HIV-associated
dementia (HAND) and its precursors. Third-party or self-assessment scales (HAM-D
or BDI) are recommended and are often easy to perform. Immunologic and virologic
values should be available. Careful medication history is also essential to identify
affective disorders as possible side effects (e.g., efavirenz and some INSTIs) or inter-
actions between psychiatric medication and ART.
After depression, the second most common disorder is anxiety and panic disorder;
the less common affective disorders include the very rare primary mania, the more
common bipolar affective disorder, and cyclothymia (frequent mild depressive
and hypomanic swings around a balanced mood). Bipolar disorder and manias, in
particular, should be treated only by psychiatrists or neurologists. In this case, a pre-
existing disposition should be assumed. Every depressive should, therefore, also be
asked about day-long phases with an unusually low need for sleep, high energy, and
an extraordinarily good mood since these episodes are often not reported sponta-
neously, and bipolar disorder entails other therapeutic consequences.

Treatment
Treatment need not differ from HIV-negative people. A multimodal treatment
concept consisting of psychoeducation, mindfulness training, psychotherapy, and
medication is favored. The latter is indicated if the affected person desires, but
especially in severe and/or prolonged courses. It depends on previous experience,
physical illnesses, comedication, potential side effects, previous adherence,
individual preference, and ultimately the costs or availability.
No antidepressant class is better (efficacy, onset of action) than any other. There are,
of course, differences in the side effect profile, interactions, and the possibility of
overdose. Treatment usually consists of the so-called serotonin reuptake inhibitors
(SSRI or SSNRI). Tricyclic antidepressants play a lesser role because they potentially
cause more interactions and autonomic side effects such as dry mouth, urinary
retention, or cardiac arrhythmias (Watkins 2011). Table 1 shows dosages and inter-
actions of common antidepressants ([Link]). The only approved
herbal antidepressant, St. John’s wort, should be used cautiously because of possible
interactions with ART. Newly added in recent years are studies on rapid-acting
antidepressants (RAADs); ketamine and esketamine were approved last year.
However, both are so far only available under inpatient conditions. The principle of
“start low and go slow” applies to the start of pharmacological treatment.
Regarding symptoms, all depressed people should be asked about suicidal thoughts.
This is usually perceived as relieving rather than embarrassing. In the case of man-
ifest suicidal thoughts, they should be asked about plans or previous suicide attempts.
If true, the individual should be moved to an emergency psychiatric presentation.
Recognized risk factors for suicidality are a known mental illness (> 90% of all suicide
victims), suicide attempts in self and/or family history, male gender, and high age
(prevalence increases at retirement age).
While mild and reactive depressive syndromes can undoubtedly be treated by general
practitioners, treatment-resistant and recurrent depressive disorders should always
be managed by specialists, as highly effective alternatives exist, for example, with
awake and light therapy, irreversible MAO inhibitors, electroconvulsive therapy
(ECT), or, more recently, ketamine (Berger 2012, Westring 2022).
HIV and psychiatric diseases 573

Table 1: Commonly used antidepressants in PLWH.

Drug Metabolism, Interactions (IA) Dosage
Sertraline CYP2B6, CYP2C9, CYP2C19, CYP2D6; 50–100 mg QD, starting with 25 mg,
(SSRI) no relevant IA with cytochromes known always in the morning.
Escitalopram Mainly CYP2C19; no relevant IA with 10–20 mg QD, start with 5–10 mg,
(SSRI) cytochromes known always in the morning, QTc
prolongation dose-dependent
Mirtazapine CYP3A4, CYP1A2, CYP2D6; 15–45 (60) mg QD, always at night,
(NaSSA) no relevant IA with cytochromes known good sleep induction, not in diabetes
Bupropion CYP2B6; in vitro inhibitor of CYP2D6 150–300 mg QD; start with 150 mg
(NDRI) (metabolite) for at least four weeks, a very good
increase in energy
Duloxetine CYP1A2, CYP2D6; inhibitor of CYP2D6 30–60 (120) mg QD, start with 30 mg,
(SNRI) always in the morning, good for
chronic pain
Venlafaxine CYP2D6, CYP3A4, CYP2C19, CYP2C9; 75–375 mg QD, start with 37.5 mg,
(SNRI) no relevant IA with cytochromes known always in the morning, a good increase
in energy usually with higher doses
Amitriptyline CYP2C19, CYP2C8, CYP2C9, CYP3A4, 25–(150) mg, multiple daily dosing,
(Tricyclic) CYP2D6; no relevant IA with moderate sedation, and level
cytochromes known monitoring are useful.
Trimipramine CYP2C19, CYP2D6, CYP2C9; 25–150 mg, evening, dose-dependent
(Tricyclic) no relevant IA with cytochromes known strong sedation
Trazodone CYP3A4, CYP2D6; no relevant IA with 25–100 mg at night for resistant sleep
(dual cytochromes known disorders, high interaction potential,
serotonergic) and vegetative side effects
MILNA (SSNRI) 25–100 mg, similar to other SSNRIs.
Trazodone is recommended for resistant sleep disorders, not in primary antidepressant therapy. SSRI:
serotonin reuptake inhibitor, NaSSA: noradrenergic-specific serotonergic antidepressant, NDRI:
noradrenergic-dopaminergic reuptake inhibitor, SNRI: serotonergic-noradrenergic reuptake inhibitor,
MAOH: monoamine oxidase inhibitor. QD: once daily, BID: twice daily.

Psychotherapy is generally recommended as an alternative to medication for mild

depressive disorders and coping with the illness. In particular, cognitive behavioral
therapy (CBT) and short-term psychodynamic methods achieve high recommenda-
tion levels in the guidelines.

Psychotic disorders
In HIV infection, psychotic symptoms are usually independent of HIV, except for
delirium and intoxication or in the context of depression. The best-known psychotic
disorder is schizophrenia. Its features usually exist before infection (Cournos 2005).
Whether schizophrenia increases the likelihood of HIV infection is not known with
certainty. Primary diagnoses after age 40 are a rarity and require intensive diagnos-
tic testing. The hallmarks of schizophrenia are hearing voices, delusions, or a sense
of being made (“the world has been changed because of me; everything has meaning
to me”). In addition, there are often other symptoms such as body hallucinations
(“animals crawling under my skin”, “implanted chip in my head”), observational
574 Organs · Interdisciplinary Medicine

experience, disturbances of affect, disturbance of thought structure (incoherence,

disjointedness), and posture (stereotypies, catatonia). All symptoms should be
present for over a month and not related to intoxicants.
It is essential to know that a psychotic person usually does not question his
perceptions. For the affected person, these are inherently logical and true; correction
is not possible. Counterarguments should be made only cautiously, if at all. They
have no therapeutic benefit and serve as diagnostic reassurance.

Therapy
Rapid drug therapy is essential and, for the time being, independent of the etiolog-
ical classification since the increasing duration of untreated psychosis is infectiously
and psychiatrically unfavorable in terms of prognosis (Nurutdinova 2012). In the
acute situation, benzodiazepines are appropriate. However, if possible, treating psy-
chotic disorders should be reserved for specialists. So-called atypical antipsychotics
(AAP, formerly atypical neuroleptics) are most suitable, as they have a less severe
antidopaminergic effect. HIV-infected patients are more likely to have extrapyrami-
dal motor movement disorders when taking conventional antipsychotics (AP); the
cause is still unclear. The dose should always be chosen carefully. The classic atypi-
cal antipsychotic clozapine should be used cautiously and only by a specialist in HIV
infection because of the increased risk of neutropenia.
Psychotic illnesses that manifest themselves only after HIV diagnosis should always
give cause for intensive diagnostics. Often, they are the first signs of opportunistic
infections or the preliminary stages of HIV-associated dementia; they should then
be classified as organic psychotic disorders. In addition to the underlying disease,
these disorders should be treated symptomatically with antipsychotics. Injectables
(now up to 3 months) seem to have advantages with regard to compliance and main-
tenance of remission but should be reserved for specialists.
Table 2: Antipsychotics frequently used in Germany.
Drug Metabolism Dose range
Aripiprazole (AAP) CYP3A4 (CYP2D6) 5–15 mg, QD
Amisulpride (AAP) Renal elimination 50–800 mg, BID
Risperidone (AAP) CYP2D6, CYP3A4 1–3 mg, QD
Quetiapine (AAP) CYP3A4 25–800 mg,
QD (sustained-release tablets if necessary)
Olanzapine (AAP) CYP1A2, CYP2D6, 5–20 mg, QD
hepatic conjugation
Haloperidol (AP) CYP3A4, CYP2D6 0.5–10 mg QD (emergency drug!)
Flupentixol (AP) CYP2D6 Frequently as depot 20–40 mg/14 days IM
Cariprazine CYP3A4 1.5–6 mg
Note: Depot preparations of haloperidol, risperidone, aripiprazole, olanzapine, and flupentixol are avai-
lable. QD: once daily, BID: twice daily. AAP atypical antipsychotics (formerly atypical neuroleptics), AP
conventional antipsychotics

Psychotherapeutic approaches play only a minor role in psychotic disorders,

although they have proven effective. Psychotic disorders lead in about 85% to only
incomplete recovery and thus usually to considerable, permanent participation
restrictions. In severe psychotic crises, however, there are often few alternatives to
psychiatric hospitalization (Berger 2012).
HIV and psychiatric diseases 575

Addictive disorders
Addictions are common in the general population and at least as common in PLWH;
it is assumed that 80–90% practice “inconspicuous” use, and only 10–20% develop
long-term problems (addiction). It often takes 5–8 years before help systems are
contacted. In general, the awareness of problems regarding the use of harmful
substances or even a possible addiction is relatively low. In particular, ChemSex, i.e.,
sex in connection with new psychoactive substances (NSP) and resulting complica-
tions, is a highly topical issue. At least half of MSM report substance use during sex
(ASTRA study 2014). These are primarily young users; the use goals are defined
differently, and identification runs through sex, not the drug itself (see Sexual
Dysfunction). Intravenous drug use remains a significant risk factor for HIV and
hepatitis C co-infection (Lucas 2011).
Addiction is also a significant cause of social, occupational, and health decline in
PLWH -particularly alcohol dependence (Gruber 2010, Lopes 2011, Watkins 2011);
ethanol-triggered neurodegeneration is thought to be synergistic with neurodegen-
eration triggered by HIV itself (Hahn 2010). Dependent alcohol use is also a factor
that significantly increases mortality in HIV (Obel 2011). The CAGE questions were
developed for evaluation in practice:
• Have you ever thought about drinking less? (Cut down drinking)
• Have you ever been annoyed because someone criticized your drinking behavior?
(Annoyed)
• Have you ever felt guilty about drinking? (Guilt)
• Have you ever had to consume alcohol in the morning to get through the day or
get rid of a hangover? (Eye-opener)
If more than two questions are answered positively, there is an urgent suspicion of
alcohol dependence.
Benzodiazepines are likely to exacerbate cognitive deficits in prolonged use. Still,
they invariably disrupt memory functions and sleep architecture, making them
useless for prolonged therapy despite their excellent short-term effects. HIV treat-
ment providers are often a great confidante. Suspected or known addictions should
be addressed, and various outpatient, in-patient, and rehabilitative services should
be offered. In a French HIV cohort, persistent benzodiazepine use was present in up
to 29% (Roux 2011). However, whether this influences the course of the disease is
not precisely known. In general, benzodiazepines with a short half-life (e.g., triazo-
lam, midazolam) should be avoided during concurrent ART, as respiratory depres-
sion, among other effects, has been observed.
Less well known and often insufficiently considered are addictions in the field of
non-substance-related addictions (e.g., internet addiction, chat, and gaming addic-
tion) or addictions to substances of synthetic or herbal origin, so-called “legal highs”
(e.g., “bath salts”). More traditional addictive substances such as khat or cannabis
are not well known in connection with HIV infection in terms of infection risk and
course. Adequate care structures are mostly lacking, as these issues are significantly
behind alcohol and opiate addiction care in psychiatric addiction care. Overall,
awareness of these addictions does not seem to be high among the general popula-
tion, physicians, and other therapeutic disciplines.
Since ongoing addictive drug use can lead to changes in metabolism, and ART can
affect substitution treatments for opiate addicts, drug interactions should be partic-
ularly monitored in this group (see ART).
576 Organs · Interdisciplinary Medicine

Treatment
Addiction-related conversations should follow the principles of “motivational inter-
viewing” (Miller and Rollnick 1991). A non-confrontational approach and an
empathic basic attitude are crucial. Often, there is little awareness of the problem
and a high degree of defense mechanisms (rationalization). The first step is to create
awareness and to approach the topic in a non-judgmental way. Often, it is neces-
sary to clarify the contradiction, “Actually, I don’t want to, but...” (desire vs. func-
tional). Confrontational interviewing techniques have proven ineffective because
they usually only encourage shame and associated repressive behavior. Unlike
alcohol or benzodiazepine dependence, attention to HIV infection plays a vital role
in opiate addiction therapies. Addicts should urgently be referred to specialized coun-
seling and therapy services. Drug therapy, on the other hand, plays only a minor
role, apart from substitution therapy. Alcohol addicts are temporarily treated with
the glutamatergic modulator acamprosate and the opiate antagonist naltrexone. A
novel therapeutic option exists with the opiate antagonist nalmefene. Nalmefene is
indicated for treating alcohol-addicted individuals for whom complete abstinence is
not an option; it is intended to reduce excessive drinking, which should reduce the
somatic and social late effects of alcohol dependence. Aversive therapy with disulfi-
ram should be reserved for specialized centers because of its potential risk. Opiate
addicts can also be treated with naltrexone at their request to ensure abstinence.

Personality disorders
The best-known personality disorder is narcissism; the most common is emotion-
ally unstable or borderline personality disorder. As a rule, a personality disorder can
be explained by the fact that the person concerned repeatedly exhibits/applies behav-
ioral patterns even though they are fraught with negative consequences. One study
(Newville 2012) has shown that antisocial (“dissocial”), depressive, and borderline
personality disorders, in particular, increase HIV risk and continued risk behaviors.
The latter appears to lead to an increased risk of HIV infection, particularly in con-
junction with addictive disorders (Chen 2007). A borderline personality disorder is
manifested by feelings of emptiness and a severe fear of abandonment; most notable,
however, are frequent self-injury of all kinds, severe, unpredictable mood swings,
and the expression of frequent suicidal ideation. Dissocial personalities are conspic-
uous by a severe disregard for social norms and persistent denial of one’s guilt with
generally high emotional coldness. This should be considered in HIV therapy since
a person with such accentuated personality traits will not change his behavior. Should
such personality disorders become apparent in everyday practice, a psychiatric and/or
psychotherapeutic presentation is advisable. Positive effects are most likely achieved
through psychotherapy (Berger 2012).

Legal aspects and psychiatric emergencies

During HIV diagnostics and therapy, there may be doubts about the person’s capacity
to consent and/or act. There may also be actions with a high potential of endan-
gering oneself or others, especially in the case of neurocognitive diseases or in
advanced stages of HIV. In case of doubt, the capacity to consent should be assessed
by a psychiatrist. According to psychiatric doctrine, a person is capable of giving
consent if his or her ability to absorb and understand information for a specific per-
sonal decision-making situation is not significantly limited by a current mental state.
The capacity to consent also exists only in cases where decisions can be made without
HIV and psychiatric diseases 577

coercion. Incapacity is different; it only includes permanent conditions. Should it

be necessary, legal guardianship can be appointed for individual areas of responsi-
bility. Any person can apply for such guardianship to the competent guardianship
courts, and a psychiatric report is only mandatory if the person concerned does not
agree to it. In the case of acute danger to oneself or others, people can be accom-
modated based on state laws; the procedures are always somewhat different accord-
ing to the jurisdiction, but what they all have in common is that ultimately, a judge
must decide, based on personal conviction, whether the person concerned should
remain in a psychiatric hospital (Berger 2012).
Primarily, psychiatric emergencies are delirium, characterized by a disturbance of ori-
entation and consciousness, psychotic/manic exacerbation with agitation, severe
intoxication, and acute suicidal crisis.
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on the initiation of highly active antiretroviral therapy among HIV-infected individuals. AIDS Patient Care STDS
2008, 22:233-43.
Watkins CC, Pieper AA, Treisman GJ. Safety considerations in drug treatment of depression in HIV-positive patients:
an updated review. Drug Saf 2011, 34:623-39.
578

30. HIV and rheumatology

GUIDO SCHÄFER

Rheumatologic diseases are common both in the general population and among
PLWH. They encompass various clinical manifestations within the spectrum of
autoimmune and autoinflammatory conditions. Among the frequently encountered
conditions are rheumatoid arthritis and multiple types of spondyloarthritides. Other
examples of rarer diseases are subgroups of collagenoses and vasculitides. Given the
extensive nature of these diseases, it is impractical to delve into each of them in great
detail within this context. Moreover, the available data concerning PLWH is often
limited. Consequently, this chapter aims to present conceptual frameworks and
assistive measures for managing PLWH with co-morbid rheumatologic diseases.

Prevalence
A cohort analysis conducted in France (Lebrun, 2017) examined the prevalence of
(auto-) immunological diseases among more than 33,000 PLWH, revealing a preva-
lence rate of approximately 4%. This finding was substantiated in a separate analysis
(Schäfer, 2019). Interestingly, two conditions, namely psoriasis and inflammatory
bowel disease, exhibited the highest prevalence rates despite not being primarily
diagnosed or treated by rheumatologists. However, there is a significant overlap,
particularly with psoriatic arthritis, which is likely underdiagnosed, and associations
with spondyloarthritides in inflammatory bowel disease. Furthermore, some of the
same immunomodulatory therapies are employed for these conditions. The research
also demonstrated associations between HIV infection and chronic viral hepatitides
(hepatitis B and C), which, in turn, contribute to the development of autoimmuno-
logical phenomena (Lebrun, 2017). In laboratory diagnostics, it is essential to con-
sider that HIV infection, like other viral infections, can trigger autoimmune
responses. Consequently, various autoantibodies are often detected in clusters among
PLWH, although they frequently lack clinical significance (Iordache, 2017). Notably,
these include antinuclear antibodies (ANA), rheumatoid factor (RF), cyclic citrulli-
nated antibodies (CCP-AK), and antiphospholipid antibodies. Several rheumatologic
diseases are strongly associated with the T cell-associated immune system, as demon-
strated in studies focusing on rheumatoid arthritis, sarcoidosis, and systemic lupus
erythematosus (Virot, 2017). Importantly, when CD4 T-cell count increases due to
successful antiretroviral therapy (ART), there is a risk of immune reconstitution
syndrome (IRIS), which may trigger disease relapse or initial manifestation of these
rheumatologic conditions, which must be distinguished from treatment failure.

Special features
In most rheumatological studies, PLWH are excluded, resulting in a lack of system-
atic data on the use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) in PLWH.
As a result, case reports, or case series are often relied upon in these situations.
However, caution is warranted when interpreting such reports due to potential
selection or publication biases. Likely, cases with positive outcomes and successful
therapeutic responses without complications are more frequently reported. A
commonly shared opinion suggests that because of a greater experience with
conventional therapies (csDMARDs), such as methotrexate, these should be
prioritized in PLWH. However, conventional and “more modern” DMARD options
lack systematic randomized controlled trials for PLWH. Consequently, it does not
HIV and rheumatology 579

appear rational to withhold the latter options from PLWH and deprive them of treat-
ment that aligns with established guidelines.
• Most DMARDs are associated with frequent, generally harmless bacterial infections
(such as bronchitis, skin infections, and cystitis) and viral infections (especially
gastroenteritis, nasopharyngitis, and bronchitis). These infections can typically be
managed on an outpatient basis. However, caution is advised in individuals with
a poor immune status.
• The evaluation of (latent) tuberculosis status should always be conducted.
Generally, this assessment is done during the initial HIV diagnosis. However, when
a rheumatological disease is diagnosed, and before the initiation of immunosup-
pression, treatment for latent tuberculosis should be considered (using standard
regimens), preferably in consultation with rheumatologists (see Tuberculosis).
• The selection of rheumatologic therapy should also consider the presence of
chronic active or previous hepatitis B (see Co-infection). For instance, rituximab
significantly increases the risk of hepatitis B reactivation, necessitating appropriate
prophylaxis.
• Vaccination status should be carefully considered (see Vaccinations). Some
immunomodulatory therapies heighten the risk of herpes zoster outbreaks or
hepatitis B reactivation. Additionally, immune responses to vaccines are often
diminished, and live vaccines may be contraindicated under specific immuno-
suppressive therapies. Ideally, vaccines should be administered before initiating
immunosuppression. Still, this may be challenging in practice due to disease relapse
or high disease activity and the initiation of treatments such as high-dose pred-
nisolone. As a rule of thumb, a stable phase of the rheumatic disease is the optimal
time for vaccination.
• Interactions between medications must be considered. While antibody therapies
(biologics) generally have few issues in this regard (as the liver or kidneys do not
metabolize them), Janus kinase inhibitors (a relatively new class of drugs) and
specific cortisone preparations can pose significant problems when used
concomitantly with specific antiretroviral substances. Even with intra-articular
triamcinolone administration, systemic interactions with drugs like ritonavir or
cobicistat can occur.
• In individuals with a compromised immune status or inadequate viral suppression,
challenges may arise in managing concurrent rheumatologic diseases and
immunomodulatory therapy. Atypical opportunistic infections and oncological
diseases, which can be exacerbated by DMARD therapy, are potential concerns.
Therefore, prophylaxis against Pneumocystis jirovecii pneumonia (PCP) should be
considered, especially in combined or prolonged immunosuppression (Salzer, 2018).

Selected features of important rheumatologic therapies

Corticosteroids: Steroids play a vital role in acute therapy due to their rapid efficacy
and controllable dosing. Other DMARDs require weeks to months to achieve full
immunomodulatory effects (though side effects may occur early). Systemic cortisone
treatment (usually prednisolone) leads to immunosuppression that depends on the
dosage and duration of therapy. Vaccinations should be postponed during higher
doses (> 20 mg/d). Interactions with other medications should also be kept in mind.
Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs):
Many csDMARDs have been used for decades.
Methotrexate (MTX) remains the standard treatment for rheumatoid arthritis and
other conditions. It is administered weekly subcutaneously or orally, with folic acid
taken the following day. Severe side effects are rare unless there is accidental misuse
580 Organs · Interdisciplinary Medicine

(e.g., daily instead of weekly intake). Nausea, which often occurs, may necessitate
discontinuation. MTX pneumonitis is less common than previously believed, while
pneumologic involvement of the underlying rheumatologic disease is more frequent.
Hydroxychloroquine (HCQ), a standard therapy in systemic lupus erythematosus,
has minimal immunosuppressive effects and allows for the administration of live
vaccines. Regular eye examinations are necessary to detect rare retinopathy.
Other agents in this group (including azathioprine, leflunomide, and sulfasalazine)
are used much less frequently or in special indications.
Biological DMARDs (bDMARDs):
TNF-alpha Inhibitors: TNF-alpha inhibitors (adalimumab, infliximab, certolizumab-
pegol, etanercept, golimumab) are the biologics with the most extended experience
in rheumatology. Numerous case reports exist regarding their use in PLWH (Kaur
2007, Cepeda 2008, Gaylis 2012, Liang 2017, Marco 2019, Rafael 2019). Latent tuber-
culosis should be excluded and treated before initiating therapy if necessary, as
TNF-alpha inhibitors carry the highest risk of tuberculosis reactivation among
DMARDs. These inhibitors are primarily used in rheumatoid arthritis, various forms
of spondylarthritis, inflammatory bowel disease (IBD), and psoriasis.
Anti-B-cell-directed therapies: The CD20 antibody rituximab is approved for use
in rheumatology, particularly in ANCA-associated vasculitides and rheumatoid
arthritis. It causes immunoglobulin deficiency lasting approximately six months.
Vaccinations should be completed before starting rituximab therapy or timed for
optimal efficacy in the interval between doses. Reactivation of hepatitis B is a poten-
tial risk. Belimumab, an antibody against soluble human B lymphocyte stimulator
protein (BLyS), is approved for systemic lupus erythematosus, but there is not much
experience in PLWH.
T-Lymphocyte Co-stimulation Inhibitor: Abatacept is approved for rheumatoid
arthritis but lacks published literature regarding its use in PLWH. Particular caution
should be exercised due to its impact on T-cell interaction in patients with low CD4
counts.
Interleukin-1 Inhibitors: Anakinra and canakinumab are primarily used in various
autoinflammatory syndromes (“fever syndromes”). Despite being expensive,
Canakinumab offers the advantage of less frequent dosing compared to daily doses
of anakinra.
Interleukin-6 Inhibitors: Tocilizumab and sarilumab are used in large vessel vas-
culitis/giant cell arteritis (tocilizumab) and rheumatoid arthritis. A relevant feature
is the almost obligatory ‘negative’ CRP (caveat: masked infections, e.g., cases of unrec-
ognized diverticulitis with intestinal perforation).
Interleukin-12/23 Inhibitors: Ustekinumab (inhibiting IL12/23) and guselkumab
(inhibiting IL23) are used for psoriasis (-arthritis) and have shown positive case
reports in PLWH (Paparizos 2011, Bartos 2018, Wang 2019).
Interleukin-17A Inhibitors: Secukinumab and ixekizumab are approved for pso-
riasis (-arthritis) and spondylarthritides. Thrush is a common side effect during
therapy (Di Lernia 2019). Bimekizumab is a newer antibody that uniquely neutral-
izes both IL-17A and IL-17F, but there is no experience in PLWH.
Targeted synthetic DMARDs (tsDMARDs):
Janus kinase inhibitors (JAKi): This class of drugs with several approved agents
shows a short half-life with daily oral intake as a characteristic. This ensures good
controllability in the event of side effects. Noteworthy is a significantly increased
risk of herpes zoster, so a zoster vaccination – even in those < 50 years – before using
HIV and rheumatology 581

JAKi seems particularly useful. Indications and the number of agents (e.g., tofacitinib,
baricitinib, upadacitinib, and filgotinib) are increasing. Some papers report the effects
of JAKi on the viral reservoir (e.g., Gavegnano 2017). However, the relevance for
practice remains unclear. Related to the Janus kinase inhibitors are the tyrosine kinase
inhibitors, which may play an increasing role in the future (assuming successful
further developments). JAK inhibitors should be used with caution in patients aged
65 years or above, those at increased risk of major cardiovascular problems (such as
heart attack or stroke), those who smoke or who did so for a long time in the past,
those at increased risk of cancer and those with risk factors for blood clots in the
lungs and in deep veins (EMA 2023).

Conclusions
Rheumatological diseases and their therapy in the context of HIV infection form one
of the most interesting clinical and scientific interfaces between rheumatology and
infectious diseases. In decisive points, there are parallels:
• Review vaccination status and immunizations, if applicable.
• Evaluation (and treatment) of cardiovascular risk profile and relevant aspects of
lifestyle (obesity, blood lipids, hypertension, etc.).
• Consideration of increased risk of oncologic disease (regular screenings should be
performed).
• Knowledge of opportunistic infections is essential with the use of immunosup-
pressants.
By acknowledging and addressing these factors, healthcare professionals can effec-
tively navigate the complexities of managing rheumatological diseases in PLWH,
ultimately providing optimal care within this unique clinical and scientific inter-
face.
Literature
Bartos G, Cline A, Beroukhim K, et al. Current biological therapies for use in HIV-positive patients with psoria-
sis: case report of guselkumab used and review. Dermatology 2018, 24:13030/qt3db748cg.
Cepeda EJ, Williams FM, Ishimori [Link] use of anti-tumour necrosis factor therapy in HIV-positive individuals
with rheumatic disease. Ann Rheum Dis 2008;67:710–712
Di Lernia V, Casanova DM, Garlassi E. Secukinumab in an HIV-positive patient with psoriasis. J Dtsch Dermatol
Ges. 2019 Jun;17(6):646-648.
EMA (European Medicines Agency 2023): [Link]
kinase-inhibitors-jaki#overview-section (accessed 11 July 2023).
Gavegnano C, Brehm JH, Dupuy FP, et al. Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.
PLoS Pathog 2017, 13:e1006740.
Gaylis NB. Long-term follow-up of an HIV-infected patient with reactive arthritis treated with infliximab. J Clin
Rheumatol 2012, 18:153-4.
Iordache L, Bengoufa D, Taulera O, et al. Nonorgan-specific autoantibodies in HIV-infected patients in the HAART
era. Medicine (Baltimore). 2017, 96:e6230.
Kaur PP, Chan VC, Berney SN. Successful etanercept use in an HIV-positive patient with rheumatoid arthritis. J
Clin Rheumatol 2007, 13:79-80.
Lebrun D, Hentzien M, Cuzin L, et al. Epidemiology of autoimmune and inflammatory diseases in a French nation-
wide HIV cohort. AIDS 2017, 31:2159-66.
Liang SJ, Zheng QY, Yang YL, Yang Y, Liu CY. Use of etanercept to treat rheumatoid arthritis in an HIV-positive
patient: a case-based review. Rheumatol Int 2017, 37:1207-1212.
Marco J, Bays A. Anti-TNF Therapy in Patients with HIV Infection [abstract]. Arthritis Rheumatol 2019; 71 (suppl
10). [Link]
Nakamura M, Abrouk M, Farahnik B, et al. Psoriasis Treatment in HIV-Positive Patients: A Systematic Review of
Systemic Immunosuppressive Therapies. Cutis 2018, 101, 38-42
Paparizos V, Rallis E, Kirsten L, Kyriakis K. Ustekinumab for treating HIV psoriasis. J Dermatolog Treat 2012, 23:398-9.
Peluso MJ, Chen J, Munter S, et al. Outcomes of immunomodulatory and biologic therapy in people living with
HIV. AIDS 2020, 34:1171-1179.
Rafael MA, Lourenço LC, Oliveira AM, et al. Successful treatment of severe perianal Crohn’s disease with inflix-
imab in an HIV-positive patient. Clin J Gastroenterol 2019, 12:583-587.
582 Organs · Interdisciplinary Medicine

Salzer HJF, Schäfer G, Hoenigl M, et al. Clinical, Diagnostic, and Treatment Disparities between HIV-Infected and
Non-HIV-Infected Immunocompromised Patients with Pneumocystis jirovecii Pneumonia. Respiration 2018,
96:52-65.
Schäfer G, et al. HIV-positive Menschen mit rheumatologischen Systemerkrankungen – eine Kohortenanalyse zu
einem kooperativen deutschen Pilotprojekt. PW 140, DÖAK 2019.
Virot E, Duclos A, Adelaide L, et al. Autoimmune diseases and HIV infection: A cross-sectional study. Medicine
(Baltimore) 2017, 96:e5769.
Wang DM, Fernandez AP, Calabrese CM, Calabrese LH. Treatment of psoriasis with ustekinumab in a patient with
HIV-related Kaposi sarcoma. Clin Exp Dermatol 2019, 44:113-115.
583

31. Sexuality
Male sexual dysfunction
SEBASTIAN NOE
(earlier versions edited by Christoph Mayr)

Male sexual dysfunction (SD) usually refers to changes that disrupt “normal” sexual function.
These are essentially
• Erectile Dysfunction (ED)
• Decrease or loss of libido
• Disorders of ejaculation
Sexual dysfunction in male PLWH is common: between 30% and 50% appear to be
affected (Collazos 2007, De Ryck 2012, Tindall 1994, Goggin 1998). In a recent obser-
vational study of 501 male PLWH, the prevalence of ED was 58.5% (Fumaz 2017).
Of the men surveyed, 19% reported regular use of PDE5 inhibitors.
Data from the German 50/2010 study of men aged 50 years and older showed that
among participants with HIV infection, 7.7% suffered from hypogonadism,
compared to 3.5% of men without HIV. Interestingly, the frequency of pure testos-
terone deficiency in the two groups did not differ significantly; the differences were
due to a higher burden of symptoms of SD in men living with HIV (Postel 2021).

Etiology
Both psychological and somatic factors can play a role in developing sexual
dysfunction, whereby an organic (co-)cause can be identified in up to 80% of all
affected persons (NIH 1993).
Age is the most critical biological influencing factor (Feldman 1994). The reason lies
in multiple age-related and degenerative changes of the organs and structures
involved, including endocrine, neuronal, micro- and macrovascular changes.
However, accumulating risk factors and co-morbidities will likely play a role (see
below). In Germany, the prevalence of erectile dysfunction in men between 30 and
80 years of age is estimated at 19% (Braun 2000). In the 50/2010 study, 50% of par-
ticipating men aged 50 years and older reported moderate to significant loss of sexual
function. HIV was the only significantly associated parameter (Mueck 2010).
Risk factors/co-morbidity: In men living with HIV, common risk factors of ED are
excessive alcohol or drug use or smoking. Metabolic disorders (hyperlipidemia, dia-
betes mellitus, obesity) and cardiovascular disease (especially arterial hypertension)
are significant promoters. Pathophysiologically, ED is based on neuronal (neuropa-
thy) and vascular (micro- and macroangiopathy) changes. Therefore, it can be an
early sign of a general (poly-)neuropathy and/or angiopathy (e.g., coronary heart
disease). Hormonal disorders, neurological diseases (e.g., herniated discs), and infec-
tious diseases are also considered risk factors. A common cause in younger men is
chronic kidney and liver dysfunction (hepatitis, cirrhosis). Psychosocial problems,
relationship conflicts, and psychiatric disorders often accompany sexual dysfunc-
tion. Sleep apnea may also be a cause – mask breathing at night significantly improves
ED (Taskin 2009). Cycling over three hours/week is also considered an independent
risk factor for moderate to severe ED. Special bicycle saddles can prevent this (Huang
2005, Schrader 2008).
Medications: Many medications negatively affect libido and erectile function (Table 1).
In the MACS cohort, these were mainly antidepressants and antihypertensives (Hart
2012). Decreased spontaneous erections and libido have been described with 5-alpha
reductase inhibitors for treating LUTS (lower urinary tract symptoms) (Corona 2012).
584 Organs · Interdisciplinary Medicine

Table 1: Substances/substance classes that can cause erectile dysfunction.

Alcohol Nicotine
Antihypertensives Antidepressants
Diuretics Antirheumatic drugs (NSAIDs)
Lipid-lowering agents H2 antagonists, proton pump inhibitors
Antiepileptic drugs Tranquilizer
Opiates Progestins/estrogens
Chemotherapeutics, ART Amphetamines, hallucinogens

An association with sexual dysfunction has been described with the use of older anti-
retroviral agents (e.g., Cove 2004). In contrast, few consistent results are available
on today’s drugs.

Diagnosis
In addition to clinical examination, basic diagnostics include sexual, social, and
family history and a complete history of medication and drug use. The testicular
function cannot be reliably assessed by total testosterone in men living with HIV
because of increased sex hormone binding globulin (SHBG); therefore, free testos-
terone should be measured or estimated (Bhasin 2018). To also detect pre-clinical
changes or further classify the genesis of a testosterone deficit, LH (Luteinizing
Hormone) should also be determined; determination of FSH (follicle-stimulating
hormone) is dispensable outside of fertility diagnostics. Due to circadian rhythms,
only early-morning measurements are usable (ideally by 8 a.m.), and results should
always be confirmed by repeated measurements (at least twice). If characteristic symp-
toms of testosterone deficiency are present, repeated low-normal free testosterone
concentrations are also sufficient for the diagnosis.
In a large cross-sectional study of 1,317 men living with HIV (often with lipodys-
trophy), 16% had testosterone deficiency; visceral fat and high BMI were predictive
(Rochira 2011). De Ryck (2013) found signs of erectile dysfunction in 62%. In total,
37% of men living with HIV and sexual dysfunction also had a testosterone deficit.
The critical question is that of nocturnal, morning, and spontaneous erections. A
low invasive diagnostic tool is the nocturne penile tumescence (NPT) measurement;
3–6 erections/night of at least 10 minutes duration and at least 70% rigidity are con-
sidered average values.
Depending on the suspected genesis of a testosterone deficit, sonography of the testes
(in the case of a suspected primary component of hypogonadism) or MRI of the
skull, including fine-slice MRI of the pituitary gland (in the case of a suspected sec-
ondary component of hypogonadism) may be necessary additional examinations.
Vascular diagnostics (Doppler sonography of the penis, pharmacocavernosography)
and neurophysiological procedures (e.g., sphincter and pudendal nerve EMG) are
reserved for urological specialists.

Table 2: Laboratory diagnostics for erectile dysfunction.

Special hormone diagnostics Environmental diagnostics
Free testosterone Blood count
LH Glucose, HbA1c
(FSH) Cholesterol (incl. HDL, LDL)
Prolactin Triglycerides
TSH Urine status
Sexuality 585

Treatment of sexual dysfunction

Knowing the risk factors and changing lifestyle habits is a priority. Studies show the
positive effect of physical training, weight reduction, and abstinence from nicotine
on erectile function (Hannan 2009, Reis 2009). In addition, attention must be paid
to medication selection when treating co-morbidities. For example, nebivolol appears
to have an advantage over metoprolol in preventing ED (Brixius 2007, Cordero 2010).
Phosphodiesterase-5 inhibitors (PDE-5 inhibitors) have significantly improved
erectile dysfunction therapy. They are easy to take, effective, and well-tolerated
(Waldkirch 2005, Nehra 2009, Alwaal 2011). Intracavernosal corpus cavernosum
auto-injection or intraurethral application of vasoactive prostaglandins (alprostadil)
plays a role today only for a few men who do not respond adequately to PDE-5
inhibitors. A complete andrologic diagnosis should always precede their use, and
men should be trained. The vacuum erection device (VED) is a good non-drug alter-
native with 80–95% response rates.
It is essential to be aware of possible interactions of PDE-5 inhibitors. Their active
levels are significantly increased via inhibition of the cytochrome P450 enzyme
system. Especially with boosted PIs, start with a low dose! Specifically, we recom-
mend a small test dose (e.g., a 1/4 tablet of sildenafil 50 mg). This is usually suffi-
cient and can be increased if there are no side effects. If effects do not occur (long-
lasting HIV infection, multimorbidity, psychological overlay), the approved
maximum dose should not be exceeded. Simultaneous use of nitrate- or nitrite-con-
taining substances (molsidomine; “poppers”) is contraindicated, as therapy-resistant
hypotension may result. In case of doubt, it is advisable to exclude severe cardio-
vascular diseases.
In case of psychosocial problems, relationship conflicts, or depressive development,
psychotherapeutic or sexual medical counseling is advised. A review of psychosocial
interventions showed that group therapy – with and without sildenafil – signifi-
cantly and long-lasting improved the signs of ED (Melnik 2007).

PDE-5 inhibitors
Sildenafil (Viagra®) was the first PDE-5 inhibitor approved; generic versions have
been available since 2013. It is sold in dosages of 25, 50 and 100 mg. The effect occurs
after 12–40 minutes, but can be delayed by a high-fat meal or alcohol consumption.
The maximum concentration is reached after about one hour, and the duration of
action is about 8–12 hours. The response rate depends on the etiology of the ED and
varies from 43% to 83%. Cephalgia (11%), facial flushing (11%), dyspepsia (3%),
dizziness (3%), rhinitis (2%), and color vision disturbances (1%) are common.
Previous studies showed no increased risk of myocardial infarction or death.
Vardenafil (Levitra®) was approved in 2003 and inhibits phosphodiesterase-5 or
hydrolysis of cGMP tenfold more than sildenafil, but bioavailability is low at 15%.
The effect with 10 and 20 mg occurs after 15–30 minutes and can last up to 12 hours;
the maximum plasma concentration is 60 min. Vardenafil is also effective and tol-
erable with concomitant antihypertensive therapy. Side effects, as with sildenafil,
include cephalgia (10–21%), skin redness (5–13%), dyspepsia (1–6%), and rhinitis
(9–17%). A double-blind, placebo-controlled study showed slight superiority to silde-
nafil (Rubio-Aurioles 2007) with reasonable safety.
Tadalafil (Cialis®) was also approved in 2003. There are doses of 5, 10 and
20 mg. The maximum plasma concentration is 2 hours; the effect occurs after 15–
20 minutes. Since the plasma half-life is approximately 17.5 hours, response times
of up to 36 hours are possible. This fact, in particular, promotes the popularity of
tadalafil (“weekend pill”). The most common side effects include cephalgia (7–21%),
586 Organs · Interdisciplinary Medicine

dyspepsia and heartburn (1–17%), myalgias (3–7%), back pain (4–9%), rhinitis (5%),
and facial flushing (1–5%). Clinical effects on the cardiovascular system were not
observed, and the incidence of myocardial infarction was not increased in any study.
Since the end of 2017, significantly cheaper generics have been available.
Avanafil (Spedra®) is a fast-onset and selective PDE-5 inhibitor (onset of action after
30–40 minutes, half-life approximately 75 minutes). It has been approved in Europe
since 2014 (50, 100, 200 mg) and has also shown satisfactory response in people
with diabetes. Potential side effects are similar to those of the other PDE-5 inhibitors.
Recently, studies in MSM point to the correlation between drug use and PDE-5
inhibitors and risky sexual behavior (Purcell 2005, Swearingen 2005, Spindler 2006,
Dirks 2012).
Due to a relative NO deficiency, the success of PDE5 inhibitors is limited in some
diseases, such as diabetes mellitus or CHD. Alternative therapeutic concepts with
sGC stimulators, Rho kinase inhibitors, and new NO donors are emerging (Lasker
2010). Topical therapy with alprostadil (1%-containing gel) is being investigated, as
is gene transfer therapy to be applied locally (Alwaal 2011).

Testosterone
In case of confirmed testosterone deficiency and clinical symptoms, intramuscular
injections (testosterone enanthate 250 mg IM every 14 to 21 days or testosterone
undecanoate 1000 mg every three months after saturation dose after six weeks) or
application of gel as a transdermal system (e.g., Testogel 25 mg/50 mg daily) can be
considered. Peroral substitution is obsolete and associated with an increased risk of
liver toxicity. Relevant side effects are hair loss, skin irritation (with gel!), liver value
and lipid elevations in serum, polyglobulia, and water retention in the tissue.

Therapy of ejaculatio praecox

Various options are available for prolonging the time until ejaculation; for example,
learning techniques for delaying orgasm and psychotherapeutic support can be
helpful. Prolongation can be achieved with SSRIs, although only dapoxetine
(Prilegy®) is approved for this indication.
Sexuality 587

Chemsex
MARTI N VI EHWEGER

In the last decade, a new phenomenon – predominantly among men who have sex
with men (MSM) – has become established: chemsex. The term, used in English-
speaking countries since around 2004 (in Germany since 2009), describes the use of
certain chemical psychoactive substances to reduce inhibitions and to amplify one’s
own sexual experience. This happened through online networks and dating forums
(Stuart 2016). Chemsex is the result of a change in the use of technology (dating
apps, media), easier availability of sex on the one hand and substances on the other.
Since chemsex primarily refers to a phenomenon of sexual culture between men* in
the strictest sense (according to David Stuart), masculine pronouns will be used here.
Chemsex practices are not solely due to gender or identity but take place
independently of them. For this purpose, the term “sexualized substance use” is
introduced to clarify specific vulnerabilities, needs, and, if necessary, therapeutic
consequences.
Most of the available data come from the US and the UK. The experience of German
NGOs, especially AIDS help centers, confirms a comparably frequent use of drugs
during sex here. Depending on the effect, the substances are called “uppers” (acti-
vating intoxication) or “downers” (relaxing intoxication). Joint consumption takes
place at sex parties in clubs but mostly at private (after-)parties at homes, with
substances often being consumed together over the entire weekend and in different
combinations as well as applications. The most common substance classes are 3- or
4-methyl methcathinone (mephedrone, metaphedrone), gamma-Butyrolactones
(precursor of gamma-hydroxybutyrates; GBL, GHB), ketamines, methamphetamines
(crystal meth, “T”) and cocaine (see glossary at the end of the chapter). They are
often combined with poppers (amyl nitrite) as well as PDE5 inhibitors (sildenafil,
tadalafil, and others) (Bracchi 2015, Stuart 2016). Substance use occurs inhalational
(smoking), intranasally (sniffing), intravenously (slamming), orally (swallowing
“gobs”), and rectally (suppositories). “Slamming”, often injecting unknown quanti-
ties of unknown mixtures of many drugs mentioned above, plays a unique role. Half
of the users have used substances within the last three months, and a quarter of
them have at least three different ones in combination. HIV-positive men are more
likely to use other substances simultaneously and more frequently (Bracchi 2015,
Hegazi 2017).
Substance use is most common among MSM (Deimel 2016) and most likely to occur
in major cities with higher tourist traffic (Hockenhull 2017): London (13%),
Amsterdam (11%), Barcelona (8%), Zurich (7%), Berlin (5%). A survey conducted at
STD clinics in London between January 2015 and June 2016 revealed high levels of
prevalence, with 655 of 818 clients using substances during sex. 30% of respondents
described themselves as open to various substances, of whom more than half (57%)
were open to the above-mentioned chemsex substances. 13.5% had already injected
drugs at least once.
Many users avoid interviews out of fear or shame and to protect the “chemsex
community” (Stuart 2016). A high number of unreported cases may, therefore, be
assumed. Validated surveys are scarce. Many MSM have already had experience with
at least one of the substances mentioned above at parties; new users are also
confronted with the substances through sexual partners.
Substance use carries an enormously increased risk of infection with classic sexually
transmitted infections (syphilis, gonorrhea, chlamydia), viral hepatitis (A–C), and
HIV. Chemsex mainly occurs with changing sex partners, during group sex, and in
the context of high-risk sexual practices (fisting, urethral sounding). Shared use of
588 Organs · Interdisciplinary Medicine

sex toys, shared needles, and, most importantly, unprotected (raw) sexual intercourse
(barebacking) are additional significant risk factors. Chemsex users are more likely
to use post-exposure prophylaxis or to be HIV-positive (Bracchi 2015, Deimel 2016).
Substance use also weakens adherence to ART, with the risk of possible development
of resistance. In addition, the interactions between antiretroviral substances and the
substances used in chemsex are underestimated (Bracchi 2015). The interactions
between the so-called “boosters” (ritonavir or cobicistat) and the chemsex substances
GHB/GBL, alcohol, or amyl nitrite (poppers) should be highlighted. Hazards include
overdoses and dose level reductions (Pebody 2015) (see [Link]).
Fatal accidents after consumption with GHB or GBL are no longer rare. GHB/ GBL
are discredited for being used as so-called “knockout drops” (Hockenhull 2017),
where someone can be stealthily put to sleep. Many substances are not well-known
to the public, experience in dosage and in combination(s) is low, and access to infor-
mation is difficult. There is a rapid risk of psychological dependence and associated
substance abuse. Mephedrone or methamphetamine should be emphasized here.
Under the influence of drugs, interpersonal communication regarding consensual
sexual practices is more complex (Bourne 2015).
Substance use is primarily intended to reduce the sexual inhibition threshold of the
“user”, increase the sensation of pleasure, and prolong the sexual act. Euphoria
(intense excitement or happiness) often contrasts with pseudo-intimacy: intimate
acts are accepted under the influence of drugs that would otherwise not be permit-
ted. Reasons for using sexually stimulating substances may include testing limits,
escapism, defense against social pressure to perform and optimize life experiences,
competition, compensation for social or personal conflicts, and defense toward dead-
ening monotony or everyday normativity. Substance use before sex reduces the sense
of shame, lowers the threshold of contact (entactogenic), increases sexual appetite
(sex drive), and prolongs pleasure (Stuart 2016). It empowers specific sexual practices
(kinks). These effects may be desirable in the context of coming out or sexual identity
exploration. In discussion groups, there were also indications of internalized homo-
phobia, supposed pressure of subcultural affiliation in case of negative self-image,
and guilty experience of otherness. MSM can quickly become vulnerable to health
risks (Deimel 2016, Villarreal 2017).
In another group discussion, illicit substances are perceived as particularly harmful.
At the same time, the physical and health-economic damage – viewed in terms of
society as a whole – still mainly occurs in the abuse of alcohol and cigarettes (Bourne
2014). Lack of access to information, prejudice, and stigma pose additional risks
(Villarreal 2017). Most users may go through a phase in their lives with substance
use without incident, but many experience severe physical and psychological trauma,
some of which can be life-threatening (Hudson 2017). Stuart (2017) concludes,
“... chemsex will be a lifelong phenomenon that defines an important period in the
history of homosexuals.”

Therapeutic concepts
The fundamental question is when use becomes overuse/abuse. Currently, opportu-
nities for education and counseling for “users” exist primarily in low-threshold
services offered by the gay community or self-help. These services are particularly
valuable in conjunction with access to free STD testing and anonymous substance
checks. In the case of indications of substance use, a complete medical history, includ-
ing sexual and drug history, as well as an initiating counseling interview are required
from a medical perspective: appreciative, unprejudiced communication with an
evaluation of restricted or limited interests, social deprivation, focusing of leisure
activities on the next chemsex session, financial restrictions due to substance
Sexuality 589

procurement, changing patterns of drug use and forms of application, more frequent
sick leave, depression, and concentration issues.
Overall, out-patient and/or in-patient somatic withdrawal is very complex.
Specialized outpatient facilities and withdrawal clinics for long-term withdrawal and
rehabilitation are rare. Especially in the withdrawal of GBL (inpatient possible, e.g.,
with Xyrem®), there is little experience: internal medicine clinics are overburdened
with the alternating between hyper- and hypokinetic delirium during withdrawal.
In contrast, psychiatric clinics often have no possibilities for somatic monitoring of
circulatory functions (necessary in the withdrawal of GBL). Medical and psycho-
therapeutic staff are rarely sensitized and not adequately trained. With few excep-
tions, no well-established, adapted aftercare (post-withdrawal) concepts exist. High
relapse rates have been the rule up to now.
For the needs of chemsex users, new integrative, therapeutic concepts are needed:
bodywork – letting people experience closeness and intimacy anew, reoccupying
sexual fantasies, finding, fostering, and practicing social skills: practicing occupa-
tional therapy-guided craft exercises and transforming them into practical skills
suitable for everyday life. Create alternative opportunities, e.g., invitations to game
nights, readings on topics such as, among many others, masculinity, drag workshops,
or open mics. Enduring shame – not taking “no” as a devaluation, listening and
understanding each other in the age of anonymous dating apps. Education and train-
ing in sexuality and intimacy for those affected, and training for medical staff and
psychotherapists to give clients adequate conversation and therapy options during
withdrawal. Offer workshops for saunas/bars/clubs on safer clubbing and partying
for professional staff.
To identify and understand these needs, the ChemSexNetwork Berlin met for the
first time in 2018 and proposed relevant services to interested individuals working
in the field. The network tries to promote synergies, create a common understand-
ing of different sexual cultures, improve social/sexual skills, develop treatment
pathways and guidelines, and represent common political interests. It sees itself as
a skills-building forum. The support of controlled consumption by a network of
NGOs and self-help, sports, and leisure groups is being discussed. There are promis-
ing approaches in “mindfulness-based” complementary psychosocial interventions
(Gonzales-Baeza 2017).
To evaluate existing services and create new ones, BISS, the Federal Initiative on
Sexualized Substance Use, was constituted in 2022. BISS deals with the topic of sex-
ualized substance use, including chemsex and the interplay between sexuality and
patterns of use, such as substance use, media use, and the effects associated with them.

Skin and soft tissue infections

Skin and soft tissue infections (SSTI) are common in injecting substance use. They
usually heal without medical intervention or are treated with simple incision and
drainage (Review: Bamberger, year?). Rare complications can result in sepsis, necrotic
fasciitis, endocarditis, septic embolism, amputation, and death. Injecting with a
needle that has been used previously and the length of time injected increases the
likelihood of developing an SSTI. Some drugs, such as amphetamines or cocaine, are
lipophobic and are not readily absorbed intramuscularly or subcutaneously. These
substances immediately induce a burning sensation and initiate an inflammatory
response caused by the immediate chemical reaction itself, and usually resolve
without treatment in a few days. Symptoms include redness, heat, pain, and functio
laesa. An abscess filled with pus usually develops three to ten days after injection
and slowly increases in size and discomfort the following week. The traditional single
590 Organs · Interdisciplinary Medicine

incision is recommended for small abscesses (less than 4 cm in diameter). Despite

the lack of proven efficacy of antibiotics, it is recommended to use Staphylococcus-
covering antibiotics (e.g., cephalexin or dicloxacillin – narrow-spectrum Beta-lactam
antibiotic of the penicillin class) after successful incision. The so-called cellulitic
abscesses (areas of erythema extending beyond the borders of the abscess itself) must
be closely monitored and treated with antibiotics to prevent rapid progression and
cellulitis. Here, ceftriaxone (1 gram given every 24 hours until erythema resolves,
followed by oral antibiotics as above) may be effective. Patients who experience ery-
thema that increases daily beyond the limits of an abscess often require hospital-
ization. Affected patients with a pus-filled wound who refuse incision should not be
offered antibiotics. There would be a risk of selecting antibiotic-resistant bacteria
because antibiotics do not adequately penetrate pus-filled spaces.

Glossary of common substances in chemsex

Mephedrone (Meow Meow, MCAT, plant food): Tablets or powder (intravascular,
intranasal, or rectal administration).
Effects: euphoria, more intense music experience, improved mood, decreased
hostility, improved mental function, and sexual stimulation.
Side effects: anxiety and paranoia, overstimulation of the heart, circulation, and
nervous system, and risk of epileptic seizures.
GHB/GBL (G, Gina, liquid ecstasy): liquid or powder added to an alcohol-free
beverage, occasionally intravascular.
Effects: euphoria, decreased inhibitions, increased sex drive. Enhancement of the
effects of other drugs. Relaxant effects may make receptive anal intercourse easier or
more pleasurable.
Side effects: memory lapses, clumsiness, drowsiness, tremors, agitation. Very risky in
combination with alcohol and/or amphetamines. Overdose may cause “G-sleep” –
unconsciousness requiring medical intervention.
Crystal methamphetamine (Crystal, tina, meth, ice, T): Inhalation (glass tube);
intranasal; intravascular; rectal.
Effects: euphoria, increased energy during sex or dancing, increased self-confidence,
feelings of invincibility and impulsivity, decreased experience of pain, intense sexual
stimulation, and decreased inhibitions.
Side effects: sleep disturbances, loss of appetite, tremors or convulsions, irregular
heartbeat, depression, fatigue, and paranoia.
Ketamine (K, special K, vitamin K): tablets; as intranasal or intravascular adminis-
tration powder.
Effects: In subanesthetic doses, ketamine produces a dissociative state characterized
by detachment from one’s physical body and the external world. A so-called
“K-hole” can occur at sufficiently high doses, a form of extreme dissociation with
visual and auditory hallucinations.
Side effects: confusion, agitation, panic attacks, impaired short-term and long-term
memory, and depression (with long-term use). Hardening of the bladder walls and
problems with urination (ketamine bladder).
Cocaine (coke, Charlie, snow, blow): powder for intranasal or inhalation use (“crack
cocaine”).
Effects: increased energy, confidence, and exhilaration. People who use cocaine often
describe more sociable and physically stronger behavior.
Side effects: increased body temperature and heart rate; risk of heart attack. Long-
term damage to the cartilage of the nose.
Sexuality 591

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Sexuality 593

Trans*Medicine
MARTI N VI EHWEGER

Transmedicine is the general healthcare profile for people who do not identify with
the gender they were assigned at birth. Transition describes the process of social,
legal, and/or medical alignment with an individual’s gender identity, such as through
coming out, name change, hormone treatment, and/or surgery. The self-knowledge
of being trans* is not freely chosen, and the feelings associated with it cannot simply
be turned off or discarded.
The number of consultations on transition processes is increasing (Kost 2022). The
extent to which this is a phenomenon of raising awareness or whether the incidence
of people in transition is growing cannot yet be ascertained. People in transition
who do not have access to medical facilities use the offers of the illegal market in
self-experimentation (Viehweger 2022). Although these people gather an astonish-
ing amount of information in their research, uncertainties often remain due to
different, sometimes one-sided, and even adversarial views from the community.
Medical education, accompaniment, and empowerment can lead to risk reduction,
psychological stabilization, and happiness in an otherwise dysphoric setting among
a vulnerable, often traumatized group.

Epidemiology
Sexual orientation can be divided into several dimensions:
• gender identity (“how do I feel?”, e.g., female, male, other),
• sexual identity/desire or attraction (“sexually attracted to” for example, hetero-
sexual, homosexual, or bisexual),
• gender expression (“how do I present myself to the outside world?”, e.g., feminine,
masculine, other),
• sex assigned at birth (male/female).
The dimensions do not have to correspond and can change (Cerwenka 2018). Some
transgender persons apply to change their civil status and first name. Between 2008
and 2016, these applications increased from 903 to 1,868 per year (Bundesamt für
Justiz 2017). The frequency of transgendering is 4.6 per 100,000 people in an inter-
national meta-analysis (Arcelus 2015). Regarding intersexuality, about 150 children
with “variants/disorders of sex development (DSD)” are born each year in Germany
(Bundesärztekammer 2015). According to the German Ethics Council estimate,
80,000 intersex people live in Germany (Höhne 2008).
The heteronormative orientation of society can be a health risk for LGBTI+ persons.
Heteronormativity describes the notion that there are exclusively two biologically
and socially overlapping genders (women and men) related to each other in their
sexual orientation (Wagenknecht 2007). This manifests in normative social expec-
tations that intersex, transsex, and non-heterosexual people do not conform to.
Heteronormativity can manifest socially in the non-recognition of innate variations
in gender characteristics, gender identity, gender self-representation, or sexual ori-
entation. This lack of recognition can range from prejudice and discrimination to
physical and sexual assault (Beigang 2017). It also includes legal regulations that
exclude LGBTI+ persons from certain rights. Such experiences can affect physical
and mental health and negatively influence health behaviors (Meyer 2003,
Hatzenbuehler 2009). For example, the sometimes-pejorative labels of “gay” or
“lesbian” can lead to negative internalized attitudes toward homosexuality (Berg
2015), which can foster lower self-acceptance, self-deprecation, or a sense of loneliness
594 Organs · Interdisciplinary Medicine

in lesbian, gay, and bisexual people and have a negative impact on mental health
(Krell 2015). An essential resource in coping with discriminatory experiences and
forming a positive self-image is provided by LGBTI communities and their civil
society organizations, which provide important contact, networking, and counsel-
ing services. Contact with people with similar life experiences and interests, as well
as joint activities, can positively influence psychological well-being (Ceatha 2019).
The lifeworld experience of the trans* persons concerned always has priority. It is
about improving the subjective quality of life to feeling comfortable in one’s body
and the environment. The medical art lies not only in the prescription of hormones
but also in the accompaniment. The responsibility is not to take away from the
clients – they decide which changes and steps they want to take.
The prevalence of HIV is likely to be significantly higher in transgender people.
According to a survey of transgender people in the US, 1.4% lived with HIV, compared
to 0.3% in the general population (James 2016). In addition, 46% did not know their
HIV status. A review of 88 studies (Becasen 2018) estimated HIV prevalence among
transgender women in the United States at 14.1% (95% confidence interval 8.7–22.2)
and among transgender men at 3.2% (1.4–7.1). Another review (Baral 2013) was as
high as 19.1% (17.4–20.7) globally for transgender women. HIV thus remains a
significant health issue for transgender people.

Medical Aspects
In summary, the somatic medical aspect of “trans medicine” is based on a thorough
anamnesis, information about effects and side effects of hormonal support, but also
about irreversible operations, the prescription, and adjustment of appropriate
hormones, laboratory-chemical and somatic course controls, care of pre- and post-
operative interventions, as well as being accompanied in the transition process.
Finalizing the transition process is unnecessary, but it is very welcome to arrive.
The medical history should include questions about pronouns and first names (both
should be marked in the file so they can be used directly to address the patient in
the future). The transition history should include experiences (DIY use of hormones
so far?), social outing, peer group membership, psychotherapies, and counseling ses-
sions. The joint reflection of visions/exact ideas of what hormones should achieve
is elementary (avoid vague terms such as “more masculine/feminine” and record
concrete wishes such as “breast growth”, “cessation of menstruation”, and “beard
growth”). Which physical elements need to be transferred from dysphoria to hap-
piness? Can hormones sufficiently fulfill the desired vision (i.e., physical changes
will be more or less achievable depending on when the hormonal transition is ini-
tiated)?
The decisive factor is the person’s individual situation to be accompanied in their
process. There is a difference between the continuation of hormone substitution
established for years and the new setting of a previously hormone-naïve person.
People who present themselves with the wish for an initial prescription of hormones
can be adolescents or already in an advanced stage of life. Depending on this, ideas
and needs appear with different (side) effects, collateral changes, and risks.
Sexuality 595

Being supportive
Physical changes require time and patience. In addition, what part of life (when)
hormones are started needs to be understood and explored. Physical changes last
between 3–24 months, depending on body characteristics (Radix 2014). In the
beginning, deciding on a starting dosage is worthwhile, which is also constantly
maintained over the first 3–4 months. Especially at the beginning, there are often
all kinds of (side) effects, which subside after the first few weeks. After 2–3 months,
it is worthwhile to re-evaluate the changes consciously. Accordingly, dose adjust-
ments can be made.
Doctors, psychotherapists, psychiatrists, medical professionals, social workers,
nurses, medical assistants, and laboratory assistants should accompany and educate
during the transition without blocking the decisions of the transitioning person.
This is often not easy for the professionals either: on the one hand, most are social-
ized within the binary system, making it challenging to act medically outside of a
binary mindset. On the other hand, there is always a desire for reassurance (for legal
reasons). With the current medical guidelines, this problem has been significantly
minimized. It is essential to accompany and support the transitioning person to
enable them to make informed decisions.

Hormone substitution
Binary
In the binary model, there is a possibility of alignment from the gender that a person
was assigned at birth and likely socialized to the other gender (i.e., male to female
or vice versa). Many trans* patients are not satisfied until they are recognized in their
desired gender. “Passing” as male or female often plays an important role. More
diverse approaches, ways of looking at things, and “role models” also lead through
the transition process.
The rules of a binary-normed society are usually very narrowly defined. Often, a cis
man-born male is accused of effemination, for example, because he wears long hair
or nail polish, without defining himself as trans*. Trans* people are repeatedly
misread by societies that define them too narrowly. There is no “passing”, and the
desired attributes are perceived as insufficiently pronounced. A binary-thinking,
heteronormative society often has difficulties with re-assignment. This results in
problems for the trans* person. However, this assignment is essential for most trans*
people, giving support, security, clarity, and structure.

Non-binary
To acquire a sexual identity for oneself, to not have to place oneself in the binary,
requires a fundamental process of emancipation. But from what? It takes place on
several levels: educational gender (physiognomic gender plus education) – identity
formation referential to peer group – gender identity – sexual preference – to name
a few. This is not a complete mapping of the process of emancipation and coming
out; it is merely an attempt at conceptualization and is not static. This form of eman-
cipation can be perceived as both a potential and a burden. The resources the person
has in the process, what environment they grew up in, and how much social or
medical support they receive are decisive influencing factors. Last but not least, it
depends on how much resistance to the norm the person can muster of their own
accord and how much positive resonance and acceptance they receive to deal with
stressful situations and to become stronger.
596 Organs · Interdisciplinary Medicine

MtF (male to female)

Estrogens: are available on the German pharmacy market as valerate or hemihy-
drate in oral and transdermal form. Injections are not approved (due to frequent car-
diovascular events). It is recommended that the pill form be taken sublingually –
this is the most common starting application (convenience). After dose correction,
transdermal applications are often prescribed: gel, spray, or patches are applied in
this case to areas with little hairy skin, sweating should be avoided at least 1 hour
before and after application, and intimate contact should not be made in the
corresponding areas for at least 2 hours. The starting dose for a binary transitioning
individual is 2 mg estrogen sublingually/day and can reach up to 6–8 mg sublin-
gually, depending on progression. Appropriate conversion tables will help calculate
dosage when switching from sublingual to transdermal. The starting dose for
non-binary people may vary by half- or quarter-dose per day.
Testosterone blockers: are necessary according to need, sexual culture, and dys-
phoria. In the Anglo-American and Helvetic area, aldosterone is preferred: it has less
neurocognitive effects, less frequent liver disorders, and more polyuria and breast
growth (the latter is mainly desired). In the German area (an anti-androgen), cypro-
terone is often prescribed. Clarifications about possible liver disorders, mental side
effects, and unclear effects on dysplasias/neoplasias must be made, but the result is
much stronger. People in binary transition receive 100 mg of aldosterone in the
morning or, equivalently, 5 mg of cyproterone acetate. People in non-binary transi-
tion mostly forgo testosterone receptor (androgen) blockade.
Progesterone: Additional progesterone (rectal, oral, or transdermal) can be given
about six months after starting estrogen, depending on individual need. Breast
growth and increase in libido, often lost, are possible. However, progesterone always
has mental side effects that can be well-integrated or destabilizing, depending on
individual resilience. It can be taken cyclically and is more popular in the binary
transition context.

FtM (female to male)

Testosterone: is available as a topical gel, 4-week or 3-month injections. The gel has
the advantage of daily self-applications, creating less fluctuation, which aligns with
circadian rhythms. If there is an aversion to daily confrontation with transition, or
if stronger initiating processes (e.g., voice change or suppression of menstruation)
are desired, injections are used every four weeks or every three months as a depot.
The “hormone gap” (high values shortly after application and low values a few days
before the next application) should always be explained. Testosterone as a gel in
binary transition is mainly done with two strokes (approx. 20–40 mg) of gel as a start
and is mainly kept that way and only rarely increased. In the non-binary spectrum,
½ stroke or a knife tip is sufficient, depending on vision and physical dysphoria.
Testosterone as a monthly injection can be given intramuscularly every four weeks
and, with the advantage of self-application, offers more independence and less gap
between depot doses. Testosterone as a quarterly injection is not possible as a self-
administration. Still, it is sometimes done within the community with so-called
T-buddies (primarily medically trained people offering peer-to-peer support).
Significant gaps between depot doses are sometimes difficult to endure. They often
occur at the beginning with a surge of acne, mood swings, an increase in libido, and
usually the wait before the subsequent injections with a down or low feeling, lack
of concentration, and fatigue. Since low doses with injections are impossible (or
wasteful), no options are available for non-binary transitions.
Sexuality 597

Emancipation and empowerment

Part of the emancipation process may well be “empowering”: reclaiming terms that
are socially used negatively, as part of the individual non-conforming identity
discovery process, as a resource. Many transgender people feel invisible in the binary
model because they identify with their male and female parts. Dissolving this missing
visibility is difficult because one handles the terms masculinity and femininity
without questioning them or finding a definition for oneself. In addition, how then
is the leap to leave behind the binary model to define oneself anew, differently,
in-between, outside, or beyond?

Glossary, terms, labels

Especially during the time of questioning, coming out, and/or at the beginning of
a transition, it is essential for many trans* people to be addressed with the correct
name. This provides security and a sense of belonging. Therefore, it is essential to
respect labels. Important terms:
Asterisk: Symbol (*), which is used as a placeholder. Trans* thus stands for all terms
beginning with the prefix trans-, among others. The use of the asterisk is criticized
in the US.
Binary gender system: According to the heteronormative worldview, gender roles
are assigned, and identities other than male or female are negated.
I-flat: Inward majuscule to avoid the generic masculine and to address persons of
both genders (e.g., I-flat: students).
Cisperson (cis – Latin prefix for “this side”): Is a person whose gender identity
matches the sex assigned to them at birth.
Cross-dressers (also transvestites): Wear clothes of the opposite sex for various
reasons but usually identify with the sex assigned to them at birth.
Gender gap: This includes people who have a non-binary gender identity (e.g.,
students).
Gender: The “social sex”, describing the socially constructed genders. In English,
gender and sex (physical sex) are not equated, unlike in German.
Gender fluid: Attempts to describe a gender identity alternating between two or
more genders.
The *(gender star) denotes men, women, and all other gender identities simulta-
neously.
Gender reassignment: Also Gender adjustment, formerly sex reassignment. The
medical process intended to align the body or primary and/or secondary sex char-
acteristics with gender identity.
Gender identity or identity gender: Discribes inner consciousness of a person,
which gender they have. Possible gender identities include agender (no gender iden-
tity), androgynous (both female and male), bigender (alternating between the two),
demigender (only partial identification with one gender), gender fluid (alternating
between two or more), non-binary (an umbrella term for all gender identities that
are neither male nor female), pangender (presence of all gender identities).
Inter* or intersexuality: Describes people whose bodies do not correspond to what
is considered physically female or male in society due to primary and secondary sex
characteristics and/or chromosome set but who combine characteristics physically
constructed as both male and female.
598 Organs · Interdisciplinary Medicine

Non-binary: Does not fit into the two-part gender system, i.e., man and woman.
Instead, there would have to be another gender description or none at all for it.
TGNS ([Link] The Transgender Network Switzerland works with
various organizations, advises media, and supports trans* people in everything con-
cerning transition and legal advice.
Transwoman: A woman who was classified as a boy at birth because of her body.
Acronyms: AMAB (assigned/designated male at birth), MtF (male-to-female).
Transgender (previously, transsexual): Feeling that one does not belong, or only
partially belongs, to the sex assigned at birth. Trans* people are transgender. The
alternative is the gender variant.
Transition: The process of social, legal, and/or medical alignment with gender identity.
Transman: Male, classified as a girl at birth because of his body. Acronyms: AFAB
(assigned/designated female at birth), FtM (female-to-male).
Transperson: A person who does not identify or only partially identifies with the
sex assigned at birth.
Transsexual: Outdated term for transgender (see above). Medically correct, but
criticized because of the wrong connotation of sexual orientation.
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transsexualism. Eur Psychiatry 2015, 30:807–815
Baral SD, Poteat T, Strömdahl S et al. Worldwide burden of HIV in transgender women: a systematic review and
meta-analysis. Lancet Infect Dis 2013, 13:214–222
Becasen JS, Denard CL, Mullins MM, et al. Estimating the Prevalence of HIV and Sexual Behaviors Among the US
Transgender Population: A Systematic Review and Meta-Analysis, 2006 – 2017. Am J Public Health 2018:e1–e8
Beigang S, Fetz K, Kalkum D, et al. Diskriminierungserfahrungen in Deutschland. Ergebnisse einer Repräsentativ-
und einer Betroffenenbefragung. Nomos Verlag, Baden-Baden, 2017.
Berg RC, Weatherburn P, Ross MW, et al. The Relationship of Internalized Homonegativity to Sexual Health and
Well-Being Among Men in 38 European Countries Who Have Sex With Men. J Gay Lesbian Ment Health 2016,
19:285–302.
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10.02.2020)
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and Wellbeing through LGBT Sporting, Creative and Social Groups in Ireland. Int J Environ Res Public Health
2019, 16:3636
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Orientierungen in der Survey-Forschung. Z Sex-Forsch 2918, 31:277–294.
Hatzenbuehler ML. How does sexual minority stigma “get under the skin”? A psychological mediation frame-
work. Psychol Bull 2009, 135:707–730
Höhne SO, Finke R. Intersexualität bei Kindern. Uni-Med Verlag Ag, 2008 Bremen, London, Boston.
James SE, Herman JL, Rankin S, et al. The Report of the 2015 US Transgender Survey. National Center for
Transgender Equality, Washington, DC
Kost C. Geschlechter- und Altersverteilung bei Transsexualität 2021. 23.02.2022 [Link]
?p=17644
Krell C, Oldemeier K, Muller S. Coming-out – und dann…?! Ein DJI-Forschungsprojekt zur Lebenssituation von
lesbischen, schwulen, bisexuellen und trans* Jugendlichen und jungen Erwachsenen. Deutsches Jugendinstitut,
Munchen, 2015
Meyer IH. Prejudice, Social Stress, and Mental Health in Lesbian, Gay, and Bisexual Populations: Conceptual Issues
and Research Evidence. Psychol Bull 2003, 129:674–697.
Viehweger M. Beobachtung der Schwerpunktpraxis (Infektiologie und Transmedizin) ViRo zwischen 10/2020 –
10/2022
Wagenknecht P. Was ist Heteronormativität? Zu Geschichte und Gehalt des Begriffs. In: Hartmann J, Klesse C,
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Verlag fur Sozialwissenschaften, 2007. Wiesbaden, S. 17–34
SECTION 7

Prevention
600

32. Prevention of HIV infection

C H R I STO P H D. S P I N N E R , C H R I ST I A N H O F F M A N N

Even more than four decades after AIDS was first described, no effective prophylactic
vaccine is available. Several potentially promising vaccine candidates are currently
being tested (see Vaccines), although none has yet demonstrated sufficient efficacy.
Preventive measures will remain indispensable for the time being to avoid HIV
infections and to stop this pandemic. Those strategies focusing solely on ABC rules
(abstinence, being faithful, condom use) are known to have limitations and have
largely been put to one side: in 2020, according to UNAIDS, there were 1.5 million
new infections worldwide or about 4,000 per day. Treatment as Prevention (TasP)
alone will not be enough either. The “U=U” (undetectable equals untransmittable)
campaign, founded in 2016, is now supported by more than 400 organizations in
60 countries. Still, successful ART for all remains an unrealistic goal. The 90-90-90
target issued by UNAIDS in 2015 (90% of all HIV infections are detected, treated, &
below detection) was not achieved by the end of 2020, with actual levels at 81-87-91
(UNAIDS 2021), according to the Global AIDS Report.
In many Western countries, it is mainly the first 90 hurdle that causes problems: Of
the 91.400 infections in Germany, only about 90% were diagnosed in 2020. Even if
97% of these were treated and of these again, 96% had an undetectable viral load,
it can thus still be assumed that there are almost 15,000 viremic people in the country
– enough to keep an epidemic alive. In addition, phylogenetic studies revealed that
about 30% of new infections are caused by highly viremic recent seroconverters
(Chibo 2012).
Additional prevention strategies remain indispensable. With pre-exposure prophy-
laxis (PrEP), taking antiretroviral agents before a risk contact, another effective and
safe individual prevention has become available. PrEP is very successful – for example,
in England’s most prominent HIV clinic, “56 Dean Street”, they reduced new
diagnoses to a fraction of earlier years within a few months (Nwokolo 2017). About
845,000 people in at least 54 countries were using PrEP to protect against HIV infec-
tion in 2020. While this was 43% more than in 2019, it was nowhere near the tar-
geted 3 million worldwide. Most users were in the US, Europe, and a few African
countries such as Kenya and South Africa – significant coverage gaps remain in other
regions of the world (UNAIDS 2021).
This chapter will describe TasP, PrEP, and other medical prevention strategies such
as circumcision. Vaccines and post-exposure prophylaxis (PEP) will be discussed sep-
arately.

Treatment as Prevention (TasP)

Rarely has a study attracted so much attention in the medical community. The journal
SCIENCE declared the data the “breakthrough of 2011,” and “The Economist” even
wrote of the “end of AIDS.” What had happened? In HTPN052, 1763 HIV-discor-
dant (predominantly heterosexual) couples in the US, India, Brazil, Thailand, and
5 African countries were followed (Cohen 2011). The partners living with HIV had
to be antiretrovirally untreated and have CD4 T-cells between 350 and 550/µl. They
were subsequently randomized to start ART immediately or only when the CD4 T-
cells fell below 250/µl or if AIDS appeared. All couples received intensive education
and training on condom use. The primary endpoint was new infections occurring
in the negative partners, especially those attributable to the infected partners (“linked
infections”). After 1,7 years, 28 infections were identified as “linked”. The only infec-
Prevention of HIV infection 601

tion in the immediately treated group occurred either before or immediately after
ART initiation. Even when this case was counted as linked, the overall effect of ART
was 96% protection, unprecedented compared to all prevention interventions ever
studied (Karim 2011). Even with more extended observation, there was not a single
linked infection when the viral load was below the detection limit in the HIV-posi-
tive partner (Cohen 2016).
However, it has long been known that antiretroviral therapies contribute to pre-
vention. Here are a few studies on HIV-discordant couples:
• Among 415 couples in Uganda diagnosed with 90 new infections within 30 months,
there was not a single infection when the viral load was below 1,500 copies/mL in
the infected partner. With each log level rise, the risk increased by a factor of 2.45
(Quinn 2000).
• In a study of 493 couples from Thailand, the factor was 1.81, and no infection
below 1,094 copies/mL was observed (Tovanabutra 2002).
• A study in Spain of 393 heterosexual couples showed a transmission rate of 8.6%
from 1991 to 2003. Not a single infection was observed if the infected partners
were on ART (Castilla 2005).
• Among 534 MSM in San Francisco, the probability of transmission per partnership
decreased by 60% between 1994 and 1998 (Porco 2004). HIV incidence decreased
despite a higher number of partners and risk contacts.
• In a Spanish study, 76 pregnancies occurred naturally in 62 couples (22 positive
women, and 40 positive men, all on ART). Not a single new HIV infection was
observed (Barreiro 2006).
These studies clearly show that the lower the viral load in plasma, the lower the
infectivity. In a meta-analysis of 11 cohorts with 5,021 heterosexual couples (and
461 HIV transmissions), not a single transmission was seen below 400 copies/mL
(Attia 2009). Antiretroviral therapy has thus become the mainstay of prevention. In
2008, the Federal Commission on AIDS Issues (EKAF) was the first institution in the
world to respond publicly to these findings. “HIV-infected people without other STDs
are not sexually infectious under effective antiretroviral therapy” was the title of the
provocative EKAF paper; it can still be found at [Link]
EKAF stated that a person with HIV does not transmit the virus if the following con-
ditions are met:
1. The patient adheres to ART and is monitored regularly by physicians or medical
practitioners
2. The viral load has been below the detection limit for at least six months
3. There are no sexually transmitted infections
The EKAF paper initially caused a stir. Critics feared that, despite all the differentia-
tions, it would be misunderstood as an “all-clear” and that people would expose
themselves or others to the risk of HIV infection. In the end, these fears did not
prove true. Our Swiss colleagues were right. U=U was established.

ART and viral load in other body fluids

Viral load in other body fluids usually parallels that in plasma. Regardless of the
chosen ART regimen, decline and rebound occur during treatment interruptions
(Palich 2019). In a study of 205 women with plasma viremia below 400, 400–9999,
and above 10,000 copies/mL, rates of detectable HIV RNA in the genital tract were
3, 17, and 48%, respectively (Cu-Uvin 2000).
In a few people, HIV RNA remains detectable in bodily fluids despite a plasma viral
load of below 50 copies/mL. However, it is unclear whether these are intact, infec-
tious viruses. In ejaculate samples from 304 MSM, HIV RNA was detectable in 20
(6.6%) (Lambert-Niclot 2012) and about 8% in 195 heterosexual African men
602 Prevention

(Mujugira 2016). In anal mucosa, HIV RNA was still found in 2% of 143 Thai MSM
on ART (Phanuphak 2018), and in cervical swabs from 1,114 African women, it was
5.8%, with a decreasing trend with increasing ART duration (King 2017). In another
study in pregnant women, the rate was 2.5%; none of the 7 patients were detectable
(although low?) HIV transmitted the infection to the child (Frenkel 2022).

The PARTNER study

But how high is the residual risk when the viral load is below the detection limit?
A European study aimed to test the EKAF statement and answer this question.
PARTNER-1 enrolled 1,166 HIV-discordant couples (both heterosexual and MSM) in
which the infected partners were on ART < 200 copies/mL and who occasionally had
condomless sex. HIV-negative partners were tested every six months, and couples
also received a detailed questionnaire about their sex lives. After an observation
period of 1.3 years and approximately 58,000 condomless sexual contacts, an initial
evaluation showed that not a single linked HIV infection had occurred (Rodger 2016).
The PARTNER study thus impressively underscored the protective value of ART.
A follow-up study of exclusively MSM couples (PARTNER-2) also showed not a single
HIV infection transmitted by the positive partner, even when sexually transmitted
infections were present. The number of condomless sexual contacts was 76,000, of
which the number of contacts involving ejaculation was 20,500 (Rodger 2019).
Meanwhile, the Opposites Attract study is another large study in which not a single
infection from the infected partner was observed in 358 MSM couples during nearly
17,000 un-safer sex contacts (Bavinton 2018). Even if the criticism of the PARTNER
study remains that only couples were recruited in which transmission had not
occurred before the start of the study despite unprotected sex (selection bias?), the
transmission risk through condomless sex was quantified as “effectively zero” (Rodger
2019).
A systematic review of 8 studies comprising 7,762 serodiscordant couples across 25
countries recently concluded that there is “almost zero risk of sexual transmission
of HIV” with viral loads of less than 1,000 copies per mL (Broyles 2023). Among all
studies, two cases of transmission occurred when the index patient’s most recent
viral load was less than 1,000 copies per mL. However, the interpretation of both
cases was complicated by long intervals (i.e., 50 days and 53 days) between the trans-
mission date and the most recent index viral load result.

Counseling HIV discordant couples in times of TasP

So many studies have shown it clearly: effective HIV therapy leads to a negligible
risk of HIV transmission. In most cases, the viral load in bodily fluids and plasma
drops in parallel. Regarding occasional viruses detected in the ejaculate while on
ART, it remains unclear whether they are complete, infectious viruses (Nunnari 2002).
Although genital inflammation and the menstrual cycle may influence genital
viremia (Curlin 2013), the PARTNER study has shown that HIV transmission is very
unlikely even with concurrent STI.
This information can be a significant relief for patients. Nevertheless, there will still
be people who want more “security”. Clinicians should provide differentiated and
individual advice on this issue. No one can guarantee an absolute zero risk. Individual
cases are theoretically possible. Much also depends on the decision of the uninfected
partner. Pressure should not be exerted under any circumstances. People who con-
tinue to use or want a condom sometimes feel discriminated against. Sex should be
fun; fear is not a good companion. Clear communication always helps.
One question often helps at this point: Why does this minimal residual risk of becom-
ing infected with HIV remain such a big issue? Some very rational people are some-
Prevention of HIV infection 603

times not impressed even by robust data. Transmission risk of probably significantly
less than 1:100,000 is still perceived as threatening – at the same time, other risks
are consciously taken and calculated. People drive cars or ski, use drugs, smoke, drink,
box, dive – all things that probably involve at least similar or much higher health risks.
It is not uncommon for AIDS phobia to come to light in such conversations. An
irrational fear of HIV can also indicate unresolved conflicts, and the causes of the
phobic thoughts often lie deeper. In such cases, (HIV-experienced) psychological
counseling can be helpful.

Pre-exposure Prophylaxis (PrEP)

PrEP is the prophylactic use of antiretroviral drugs by people who are not HIV-
infected. Unlike PEP, the drugs are taken before and not after exposure. Continuous
PrEP must be distinguished from PrEP on demand. PrEP only makes sense if relevant
risks are taken – sex with PLWH whose viral load is below the detection limit is not
one of them.
Continuous PrEP with TDF/FTC: This is still the standard and the only approved
PrEP in Europe. Table 1 summarizes the data from randomized studies. The first break-
through study was published at the end of 2010: In iPrEx, 2499 MSM from six coun-
tries received either TDF/FTC or placebo. After 1.2 years, 36 versus 64 infections had
occurred, corresponding to a 44% reduction in risk of infection (Grant 2010). Only
in 3/34 patients with a new infection during the study, tenofovir or FTC was found
in the plasma. Other studies also found a similar protective effect (Thigpen 2011,
Baeten 2012). However, setbacks were also seen. The FEM-PrEP trial was stopped in
April 2011 due to ineffectiveness, and the three-arm VOICE trial in African women
also showed no benefit (Marrazzo 2015).

Table 1: Randomized trials (selection) of continuous PrEP with TDF and FTC.
Name, reference n Risk group, location: Type of PrEP Protective effect
Bangkok Tenofovir Study 2,415 IDU in Thailand: TDF 49% with TDF
Choopanyia 2013
PARTNERS PrEP 4,758 Heterosexual couples in Africa: 67% with TDF, 75%
Baeten 2012 TDF, TDF+FTC with TDF+FTC
iPREX 2,499 MSM worldwide: TDF+FTC 44% with TDF+FTC
Grant 2011
CAPRISA 004 889 Women in South Africa: 39% with TDF gel
Abdool 2010 Vaginal TDF Gel
TDF 2 1,219 Young women and men 62% with TDF+FTC
Thigpen 2012 in Botswana: TDF+FTC
FEM-PrEP 2,064 Women in Kenya, South Africa, None (study stopped)
van Damme 2012 and Tanzania: TDF+FTC
VOICE 5,029 Women in South Africa, Uganda, None, neither with TDF
Marrazzo 2015 and Zimbabwe: or TDF+FTC orally nor
TDF+FTC, TDF, vaginal TDF gel with the TDF gel.
PROUD 544 MSM in the UK: TDF+FTC 86% with TDF+FTC
McCormack 2016
DISCOVER 5,387 MSM in Europe and North America: IRR for TAF+FTC
Ogbuagu 2021 TDF+FTC versus TAF+FTC 0.54 (95% CI: 0.23–1.26)
604 Prevention

In some cases, it remained unclear why some studies were successful, and others
were not. The most important factor, however, is hardly surprising – adherence: If
you don’t take PrEP, you won’t be protected! In some trials, notably FEM-PrEP and
VOICE, adherence was poor for several reasons: the daily tablet or gel applications
may have been inconvenient for women, or there may have been insurmountable
social barriers. Protection was highest in trials when at least 70% of tablets were
taken (Fonner 2016).
However, success also depends on other factors, including HIV prevalence of poten-
tial and viral load of infected sexual partners, concurrent STDs, and various biolog-
ical factors. Sexual behavior and the risks of the situation (condom use, sexual pref-
erences, ChemSex) may also play a role. Finally, it depends on the setting. The higher
the risk, the higher the protection: in PROUD, an English study of a total of 544
MSM at increased risk for HIV (unprotected anal sex in the past three months), the
effect of TDF/FTC was so impressive (HIV incidence 1.2 versus 9.0/100 person-years)
that the study was stopped early (McCormack 2016).
According to a new meta-analysis, unanswered questions remain, especially about
efficacy in heterosexual contacts (Murchu 2022).

Frequently asked questions (and answers) about PrEP

• Who is eligible? → People at increased risk of HIV infection: MSM with incon-
sistent condom use, changing or untreated HIV-infected partners, and people with
intravenous drug use.
• How should these groups be identified? → For example, consider PrEP in all
patients with an STD or post-exposure prophylaxis in the past.
• How should PrEP be taken? → Approval is for continuous administration (1 x 1
tablet TDF/FTC daily).
• What about PrEP on demand? It is debatable for men with corresponding risk
constellation: 2 tablets 2–24 hours before, one each 24 and 48 hours later (“off
label” use!). Of note, this is not an option for women!
• Are there other options? A large number of on-demand regimens are circulating
that are based only on pharmacodynamic considerations but have not been
validated and are therefore unsafe
• Who can prescribe PrEP? → Ideally, those experienced in HIV medicine and other
specialist groups (pediatrics, gynecology, urology, dermatology) after training.
• How high is the risk of resistance with PrEP in undetected HIV infection?
→ According to previous experience and mathematical models, the risk is rela-
tively low.
• Who will pay for PrEP? → It depends on the country; see below.
• How to monitor PrEP? → See below.

PrEP on demand with TDF/FTC: Does it have to be daily, continuous use? Not
necessarily. In the IPERGAY trial, 400 negative MSM in France and Canada were
instructed to take two TDF/FTC or placebo tablets each before (2–24 hours) and one
tablet each 24 and 48 hours after high-risk sexual contacts. After nine months, only
2 HIV infections had occurred in the active arm, compared to 14 on placebo
(0.9 versus 6.6/100 person-years) – an 86% reduction (Molina 2015). There were more
gastrointestinal (14% vs. 5%, p=0.002) and renal adverse events (18% vs. 10%,
p=0.03) on TDF/FTC. In a more extended observation, the protective effect increased
even more, rising to 97% (Molina 2017). Although adherence was also far from
perfect in IPERGAY, protection was thus at least as high as in studies with continu-
ous PrEP. In women, on the other hand, occasion-based PrEP does not appear to be
Prevention of HIV infection 605

as effective (Bekker 2017). Compared with colorectal tissue, levels of TDF/FTC rise
more slowly in the female genital tract and fall more rapidly (Cottrell 2016). Thus,
on-demand PrEP with TDF/FTC is unsuitable for women and cannot be recom-
mended.

PrEP failure, risks, problems

Reports of true PrEP failures have been relatively rare to date. If they do occur, they
mainly occur with PrEP on demand, in those cases when PrEP was not taken or not
taken correctly. Meanwhile, some cases have been described in which infection with
multidrug-resistant strains of HIV occurred despite correctly taking PrEP (Knox 2017,
Markowitz 2017, Colby 2018). It does not have to be multidrug resistance – even the
combination of M184V and K65R is likely sufficient to nullify the effect of PrEP
(Koole 2022). In contrast, transmission of non-resistant viruses despite good PrEP
adherence has been a rarity to date (Cohen 2018).
The emergence of resistance through PrEP also appears to be a relatively rare phe-
nomenon. In a systematic review of 13 randomized trials in which 622 transmis-
sions occurred on PrEP or placebo, resistance to TDF or FTC was found in 19 (3%)
(Gibas 2019). According to a recent review, the risk was also relatively low; resist-
ance was observed mainly in acute HIV infection at study inclusion and mostly
involved FTC (Murchu 2022). In London, the rate of primary FTC resistance was 30%
if PrEP was used before infection, compared with 1% not having taken PrEP
(Girometti 2022). In contrast, in the IPERGAY trial, no resistance was found among
the 31 patients who became infected despite PrEP use (Delaugerre 2018).
In any case, the low risk of resistance is no argument against it: it is estimated that
for every case of FTC resistance caused by PrEP, between 5–40 new infections can be
prevented. It should be noted that with PrEP, if infection does occur, antibody for-
mation is delayed. It may therefore make sense to determine viral load immediately
in case of doubt. The viral load is often low on PrEP (Marzinke 2021).
Overall, PrEP is safe: in a systematic analysis, no more adverse events occurred with
TDF/FTC than with placebo (Fonner 2016). However, long-term observations over
more than three or five years are lacking. Experience with TDF/FTC from antiretro-
viral therapy may not always translate to PrEP. PrEP places exceptionally high
demands on physician education as a treatment for healthy individuals. Potential
risks such as bone density reduction or nephrotoxicity, but also a possible increased
STD risk, must be weighed against the individual HIV risk. However, the risk of renal
events seems very low, at least in young people with healthy kidneys. According to
a recent meta-analysis, it can be considered to limit renal monitoring to the elderly,
individuals with creatinine clearance less than 90 mL/min, and those with pre-exist-
ing renal disease (Schaefer 2022).
A significant problem is adherence. A review of 59 studies with nearly 44,000 par-
ticipants found a 41% dropout rate within six months (Zhang 2022). In a recent
study from Washington, 27% of all MSM with newly diagnosed HIV infection had
prior PrEP experience, and more than 50% had discontinued PrEP less than six
months earlier (Cannon 2022).

PrEP in practice
TDF/FTC has been licensed as continuous PrEP since 2016, but there is still a great
deal of variation among countries in terms of the scale of implementation. In around
20 European countries such as France, Belgium, Spain or Germany, PrEP is provided
or reimbursed. In others, generic PrEP is available in healthcare settings but is not
fully reimbursed or is only available through pilot, research, or demonstration
projects. There is no formal implementation of PrEP in numerous other countries in
606 Prevention

central Europe, the Baltic states, the Balkans, and Central Asia, in Russia or Turkey.
According to the European Centre for Disease Prevention and Control, 17 European
countries (five in the EU) had not formally implemented PrEP in their healthcare
systems. Specific key populations, such as people who inject drugs, prisoners, and
undocumented immigrants, remain ineligible for PrEP in many European countries
(ECDC 2023). However, the situation regarding PrEP implementation and availability
in Europe is fast-moving and evolving.
In some countries, PrEP care also includes the necessary laboratory tests, particularly
for HIV and syphilis. Individualized counseling with careful risk evaluation of potential
PrEP users remains essential to check the actual indication (repeatedly!) and avert
possible failure due to improper use. Checklists have proven helpful in this context.
Around 30 National PrEP guidelines were published very soon after approval in
Europe and are valuable tools (Spinner 2019).

Practical PrEP checklist (short version)

• Patients are tested at baseline with the 4th generation p24/HIV antibody test and
informed about indication, risks, costs, and controls.
• There is no replicative hepatitis B (check vaccination indication!) and no evidence
of acute retroviral syndrome.
• Four weeks after starting PrEP, repeat 4th generation p24 antigen/HIV antibody
test to exclude HIV infection in the diagnostic window.
• TDF/FTC is safe only if creatinine clearance or GFR > 80 mL/min, to be carefully
weighed at 60–80 mL/min, and is contraindicated if below 60 mL/min.
• Follow-up visits every three months (HIV, syphilis, renal function); if eGFR
> 80 mL/min and absence of other renal risk factors, creatinine monitoring can
be extended to 6–12 months.
• Three-month intervals apply for HIV and syphilis testing, even later, and also for
on-demand PrEP – HIV infections should not be overlooked!
• Risk-adapted testing for STIs such as gonococci, syphilis, chlamydia (swabs can
also be taken by patients if needed), and hepatitis C.

Future PrEP
Two approaches, in particular, can potentially replace TDF/FTC in the future. These
are TAF/FTC and the long-acting INSTI cabotegravir.
TAF/FTC: In DISCOVER, the largest PrEP study involving just over 5,000 MSM and
transgender women, continuous administration of TAF/FTC was non-inferior to
TDF/FTC in a double-blinded randomized comparison (Mayer 2020). The risk of
infection was nearly halved after 96 weeks (Ogbuagu 2021). In the US, PrEP with
TAF/FTC was approved for MSM and transgender women in August 2019. This does
not apply to Europe: in 2021, Gilead announced it would not pursue a marketing
authorization for PrEP in the European Union.
Due to the significantly higher costs of TAF/FTC (Descovy®) of > 500 euros per month
and the current lack of reimbursement for PrEP, this option continues to play little
role in most countries. However, TAF/FTC “on private prescription” may be an option
for nephroprotection – especially in older people with pre-existing renal disease. The
pharmacokinetic profile is comparatively favorable – protective levels can be achieved
faster and longer with TAF (Mayer 2020). It should be emphasized, however, that no
clinical studies have been conducted to date on TAF/FTC as PrEP on-demand.
Cabotegravir (Apretude®) is the first long-acting injectable PrEP, which is developed
by ViiV Healthcare. Apretude® does not contain tenofovir or FTC but the second-
Prevention of HIV infection 607

generation INSTI cabotegravir. In two large studies, long-acting cabotegravir 600 mg

(CAB-LA, injected intramuscularly every eight weeks) was tested against TDF+FTC,
including a global trial in 4,500 MSM (HPTN 083) and one in 3,200 women (HTPN
084). In HPTN 083, CAB-LA was superior, with an incidence of 0.41 versus 1.22 per
100 person-years (Landovitz 2021); the trial was terminated early. As a caveat,
however, the difference occurred primarily because many participants randomized
to TDF/FTC had not been taking their PrEP regularly. In addition, four unexplained
infections were observed with CAB-LA, surprisingly, despite timely injections and
adequate drug levels. Very similar results were also observed in HTPN 084 (Delany-
Moretlwe 2022). In this study, the protective effect of cabotegravir was also more
significant, primarily because adherence was poor in the TDF/FTC arm. Levels sug-
gesting daily use of TDF/FTC were found in only 42% of women.
Besides the acceptability of regular intramuscular injections, the critical question is
how to deal with the long “PK tail” – cabotegravir levels decline slowly over months
after administration. In one PrEP study, 23% of men and 63% of women still had
detectable levels 60 weeks after their last injection, and some still had detectable
levels two or even three years later (Landovitz 2018). These suboptimal levels could
mean a significantly increased risk of resistance, as shown in the monkey model
(Radzio-Basu 2019).
The so-called “Long-acting Early Viral Inhibition” (LEVI) Syndrome was first
described in early 2023. This means getting an HIV infection while on CAB-LA PrEP.
Due to the cabotegravir plasma levels, viral replication is much lower; often, people
have minimal or very few symptoms, if any. On an ultrasensitive RNA test, viremia
is usually low or still undetectable, leading to delayed antibody production.
Unfortunately, the development of resistance in LEVI cases is the rule rather than
the exception. Further research is needed to evaluate the use of HIV RNA screening
in this setting and if the LEVI syndrome occurs with other potent, long-acting PrEP
agents.
However, in December 2021, the FDA approved Apretude® for use in at-risk adults
and adolescents weighing at least 35 kilos for PrEP to reduce the risk of sexually
acquired HIV. Approval in Europe is expected by mid-2023. We will see whether the
availability of long-acting injectable PrEP will increase PrEP uptake and adherence
in these groups.
Taken together, CAB-LA PrEP represents a tremendous advance in HIV prevention
options. A potential “cost” of rolling out this prevention intervention may be the
risk of INSTI resistance among persons who acquire HIV while using CAB-LA (review
of pros and cons: Parikh 2022).
Other approaches: Of interest is the nucleoside reverse transcriptase translocation
inhibitor islatravir. It persists for a long time in PBMCs, with a half-life of over 100
hours. An initial study proved potential protective protection over 12 months with
a subdermal implant (Matthews 2021). Two significant Phase III trials, Impower-022
and -024, evaluated monthly doses of islatravir against TDF/FTC. However, after lym-
phopenias were observed, enrollment was initially halted in December 2021 (see New
Drugs). Likely, the islatravir as a PrEP option will not be pursued further. However,
besides TAF, cabotegravir, and islatravir, various other compounds are in clinical
testing, including lenacapavir and monoclonal antibodies (review: Cambou 2021).

Medical prevention, in addition to TasP and PrEP

The risk of sexual transmission of HIV is significantly lower than generally assumed.
According to a meta-analysis, it is estimated at 1.4% for receptive anal intercourse
per contact and markedly lower for vaginal intercourse (Patel 2014). It is reduced by
608 Prevention

99.2% by condoms and ART. Viral load, genital lesions, and STDs, as well as acute
HIV infection, can significantly increase the risk of transmission. And yet, HIV trans-
mission is a – relatively – rare event. Therefore, to test the effectiveness of a pre-
vention strategy, huge populations are often needed, which have to be observed over
a long period. It is all the more admirable how many excellent studies have been
conducted in recent years on PrEP, such as microbicides and circumcision.

Circumcision
Circumcision of the male foreskin reduces the risk of infection by various pathogens
during condomless sexual intercourse. This also applies to HIV. Large randomized
trials involving more than 10,000 heterosexual men in Uganda, Kenya, and South
Africa saw a 50–60% reduction in HIV transmission risk. A meta-analysis of 49 studies
found a relative risk of 0.58 for circumcision (Sharma 2018). This protection is
explained by the presence of CD4-positive Langerhans cells, the primary target cells
of HIV, in the male foreskin. However, in MSM, the protective effect of circumcision
is likely lower at 23% (Yuan 2019). WHO therefore recommends circumcision as a
preventive measure only for heterosexual men.
The procedure is not without problems. Surgical complications (infections, post-
operative bleeding) occur in about 3–4%. Sexual behavior after circumcision, and
ethical and logistical problems are only some issues (Lie 2006). It should be noted
that while the risk is reduced for circumcised heterosexual men, it is not reduced for
their female partners. In a randomized trial in Uganda, the wives of circumcised men
tended to become infected more often (Wawer 2009). The main reason was proba-
bly that couples had sex earlier than recommended after the procedure. Maintaining
a waiting period of several weeks after the procedure is essential.

Preventive treatment of HSV and other pathogens

Genital infections significantly increase the risk of contracting HIV. Bacterial
vaginosis, for example, increases the transmission from women to men by threefold
(Cohen 2012). Human herpesvirus 2 (HSV-2) is particularly relevant for prevention,
especially since this virus can be readily quantified and measured. Interestingly, HIV
viral load increases in plasma and vaginal fluid when HSV infection occurs (LeGoff
2007). According to a meta-analysis, HIV risk increases by 2.7 for men and 3.1 for
women when HSV-2 seropositivity is present – when antibodies to HSV-2 are
detectable in the blood (Freeman 2006).
Prevalent HSV-2 infection (HSV-2 seropositivity) is associated with a three-fold
increased risk of HIV acquisition among both men (relative risk 2,7) and women
(3.1) in the general population (Freemann 2006). Thus, a substantial proportion of
new HIV infections is attributable to concomitant HSV infection, with estimates of
38–69% for women and 8–49% for men. For this reason, several studies have inves-
tigated the protective value of herpes treatment in HIV-negative and HIV-positive
individuals.
People without HIV: Can HSV-2 suppression with acyclovir reduce the risk of HIV-
1 acquisition? HPTN 039, a Phase III study, addressed this question (Celum 2008).
A total of 1871 homosexual men from the US and Peru and 1380 women from
Zimbabwe, Zambia, and South Africa received 400 mg of oral acyclovir or placebo
twice daily. All participants were HIV-negative and HSV-2 positive at baseline.
Although fewer HSV ulcers were observed in the active arm, HIV incidence was not
reduced in the acyclovir arm (3.9/100 person-years) compared with placebo
(3.3/100). The disappointing results were confirmed by the Mwanza trial, which also
found no reduction in 821 women in Tanzania (Watson-Jones 2008). The reason for
this is unclear – resistance to acyclovir is probably not the reason. It is likely that
Prevention of HIV infection 609

genital HSV reactivation cannot be prevented by acyclovir (Johnston 2012). The

approach of using acyclovir to prevent HIV in HIV-negative individuals is invalid.
Azithromycin prophylaxis, which can at least prevent bacterial STIs, also had no pro-
tective effect (Kaul 2004).
People with HIV: Can transmission rates be reduced if partners with HIV, rather
than those who are HIV-negative, are treated with acyclovir? A large study of 3,408
discordant African couples had no effect despite a significantly reduced rate of genital
HSV ulcers (Celum 2010). However, this and other studies showed a weak but still
measurable effect of acyclovir on HIV viral load as an interesting side effect. According
to a meta-analysis, it is as high as 0.33 log levels with acyclovir or valaciclovir (Ludema
2011). This even led to a certain reduction in the risk of HIV progression in untreated
PLWH (Lingappa 2010, Reynolds 2012). Fortunately, standard dose acyclovir or vala-
cyclovir does not appear to select for HIV resistance (Baeten 2011). There is also evi-
dence of an antiretroviral effect in pregnant women (Roxby 2012) or in breast milk
(Drake 2012), which can be increased by higher doses of valacyclovir (Perti 2013).
The hope for new, potent acyclovir derivatives (Van de Perre 2008, Vanpouille 2010)
has not yet been realized.

Microbicides, lubricating creams, diaphragm

Microbicides are chemical agents, usually applied topically as vaginal gels, that kill
or immobilize HIV and other pathogens. Heterogeneous mechanisms are currently
being investigated. These include inactivating substances that destroy viral structures
and agents that inhibit docking to the target cell or antiretroviral drugs. The perfect
microbicides would not only be cheap, easy to use, and non-toxic but preferably also
active against other STIs, as these increase the risk for HIV transmission, as described
above.
Inactivating microbicides: No product has demonstrated a convincing protective
effect to date. In large randomized studies, the risk of HIV transmission even increased
in some cases, as under nonoxynol-9 or cellulose sulfate (van Damme 2008). PRO
2000 was also ineffective (McCormack 2010), as was the use of diaphragms and/or
lubricating creams (Padian 2007).
Antiretroviral microbicides: In September 2010, the results of the CAPRISA trial
gained much attention. In this study, a 1% tenofovir gel was studied double-blinded
in 889 HIV-negative women in South Africa (Abdool Karim 2010). HIV incidence
was reduced from 9.1 to 5.6/100 years by the gel versus placebo. There was as much
as a 54% reduction in transmission risk in women who used the gel regularly. The
safety and tolerability of tenofovir gel was excellent. Despite minimal use, hundreds
of thousands of infections could be prevented in countries like South Africa (Williams
2011). Following this initial success (“proof of concept”), microbicide research has
focused on antiretroviral agents, including, for example, the experimental NNRTI
dapivirine. Two large Phase III trials (ASPIRE and IPM 037) of dapivirine-containing
vaginal rings applied monthly showed 27% and 31% protection, respectively (Baeten
2016, Nel 2016). Nevertheless, many unanswered questions/problems remain,
including acceptance and adherence, bioavailability, and, most importantly, the
relatively moderate efficacy to date (Review: Traore 2018). No microbicide has yet
made it to the market.

Doxy-PEP
Is Doxy-PEP a new option to reduce the STD burden in the MSM community?
A large open-label, randomized study involving 501 PLWH or MSM and transgen-
der women who were taking PrEP were randomly assigned to take 200 mg of
610 Prevention

doxycycline within 72 hours after condomless sex (doxycycline post-exposure

prophylaxis, doxy-PEP) or receive standard care (PrEP) without doxycycline
(Luetkemeyer 2023). All participants had at least one STD in the past year. In the
intervention arm, the incidences of the three STIs evaluated were markedly lower
(combined by two-thirds), namely gonorrhea, chlamydia, and syphilis. Of the par-
ticipants with gonorrhea culture available, tetracycline-resistant gonorrhea occurred
in 5 of 13 in the doxycycline group and 2 of 16 in the standard care group. The
authors concluded that their findings “support its use among MSM with recent
bacterial STIs”. Doxy-PEP after condomless sex has also been beneficial against
syphilis and chlamydia, although not gonorrhea, in a study in France (Molina 2018).
By early 2023, it seems too early to recommend this strategy, as the long-term con-
sequences are unknown, especially the risk of selection and dissemination of syphilis
and chlamydia strains with doxycycline resistance. Another problem could be the
still unknown effects on the human microbiome. Finally, the decision for doxy-PEP
(other than HIV PrEP) is not private; one must consider that widespread imple-
mentation of doxy-PEP could generate antimicrobial resistance in non-target
pathogens and commensals. However, while leading to reductions in population-
level transmission of STDs, doxy-PEP could reduce population-level consumption of
antibiotics used to treat STDs, which might offset some of the increase in the use of
doxycycline for doxy-PEP. While markedly reducing STDs, this could also have ben-
eficial effects on HIV transmission. Clear guidelines for the community and clini-
cians on doxy-PEP’s utility and potential risks are urgently needed.

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614

33. Preventive HIV-1 vaccination: current status

THOMAS HARRER

The HIV-1 pandemic will only be brought under control by effective vaccination.
This chapter provides an overview of the current status of vaccine development.

Induction of HIV-1-specific antibodies

Analogous to other effective vaccines, initial attempts were made to develop vaccines
that could induce neutralizing antibodies against the envelope protein of HIV-1.
These vaccines used gp120, gp160, parts of gp160, or peptides from gp160 of different
HIV-1 variants. Antibodies were stimulated that could neutralize laboratory viruses
in vitro but poorly neutralize viruses from patients (Mascola 1996).
In two phase III studies (VAX003, VAX004), two different gp120 molecules
(Pitisuttithum 2006, Flynn 2005) failed to reduce new infection rates despite the
induction of antibodies to gp120. The envelope molecule gp160 can be poorly
neutralized by antibodies because prior to binding of gp120 to the CD4 receptor,
epitopes essential for biological function are hidden in indentations of the gp120
molecule. These epitopes are additionally masked by variable sequence loops and
glycan shields (Kwong 2002). As a result, antibodies can block the gp160 binding
site for the CD4 molecule only to a limited extent. Only after binding of a gp160
trimer to CD4 does a conformational change of the V3 loop expose the binding
domain for the coreceptors CCR5 or CXCR4. Antibodies against the V3 loop can
neutralize, but these activated binding sites are only detectable by antibodies for a
short time. They are spatially shielded, so high antibody concentrations are neces-
sary for neutralization (Labrijn 2003).
Infected individuals form neutralizing antibodies, mostly directed against variable
sequence segments of gp120 in which the viruses can rapidly develop mutations.
Therefore, the antibodies of most individuals neutralize only their own HI viruses,
but only insufficiently HI viruses from others. Only 10–30% of infected patients
develop cross-reactive neutralizing antibodies within 2 to 3 years of infection, but
most are directed against variable sequences in gp120. Only 1 to 2% of infected indi-
viduals generate very broadly neutralizing antibodies (bNAbs) that can neutralize
70–90% of HIV-1 variants. Target structures of these antibodies are conserved CD4
binding sites in gp120, the base of the V3 loop with glycan structures, glycopeptide
epitopes in the V1 and V2 loops, or a domain in gp41 essential for fusion.
It is still unclear why only a few people can produce these broadly neutralizing anti-
bodies. Some very effective antibodies show unusual properties such as long CDR3
regions, a high level of affinity maturation with many somatic mutations, or cross-
reactivity to human antigens. The breadth of recognition depends on contact with
viral variants, and long virus exposure is required for intense affinity maturation,
making it difficult to induce such antibodies with a vaccine.
Meanwhile, initial trials with broadly neutralizing antibodies derived from infected
individuals have demonstrated a strong antiviral effect in HIV-1-infected patients
(Lynch 2015, Caskey 2015+2017). In this context, the antibody 3BNC117 led to a
significant reduction in plasma viremia and a broader humoral immune response
against HIV-1 (Schoofs 2017). Since resistance mutations occurred with monother-
apies using bNAbs (Scheid 2016, Bar 2016), combinations are now being investigated
(Mendoza 2018). Modifications of antibodies isolated from infected individuals have
significantly increased potency (Rudicell 2014). A newly developed tri-specific anti-
body (SAR441236) that has binding sites of the three neutralizing antibodies vRC01,
Preventive HIV-1 vaccination: current status 615

PGDM1400, and 10E8v4 is currently being tested in clinical trials after showing very
potent activity in the SHIV monkey model (Xu 2017).
Two large studies (HVTN 704/HPTN 085, MSM/transgender in the Americas and
Europe; HVTN 703/HPTN 081, women in Africa) tested whether infusions of the
bnAb VRC01, given every eight weeks, could reduce HIV-1 infection rates over
22 months compared with placebo. VRC01 showed no significant protective effect
overall. Only viruses with high sensitivity to VRC01 (IC80 <1µg/mL) showed pro-
tection. This indicates that for effective protection by passive antibody administra-
tion, high concentrations of even more potent antibodies and combinations of anti-
bodies are needed to avoid resistance (Corey 2021).
Data from animal models and clinical studies suggest that non-neutralizing anti-
bodies may also have a role in controlling HIV-1 via Fc receptor-mediated immune
responses such as ADCC (antibody-dependent cellular cytotoxicity) (Horwitz 2017,
Rerks-Ngarm 2009). Although the protective effect of non-neutralizing antibodies
appears comparatively weak, attempts are being made to integrate the induction of
such antibodies into vaccination strategies (Costa 2016).
Another approach is passive genetic immunization by transferring genes of neutral-
izing antibodies. In rhesus monkeys, transfer of antibody genes into muscle cells
using an adeno-associated virus (AAV) vector induced the production of SIV-ENV
neutralizing antibody constructs that protected the monkeys against SIV infection
(Johnson 2009). Protection against HIV-1 infection was also achieved in the human-
ized mouse model by transferring genes for neutralizing antibodies using an AAV
vector (scAAV) (Balazs 2012).

Induction of HIV-1-specific T-cells

Difficulties in inducing neutralizing antibodies have focused interest on vaccines
that stimulate HIV-1-specific T-cells. Cytotoxic T-cells (CTL) play an important role
in controlling HIV-1 infection (Koup 1994, Harrer 1996a). However, CTL can only
recognize cells that are already infected, so unlike neutralizing antibodies, they do
not confer sterilizing immunity. However, the observation of HIV-1-specific CTLs in
HIV-1 exposed but uninfected subjects raised the hope that CTL could prevent an
ongoing HIV-1 infection by eradicating small foci of viral infection (Herr 1998,
Rowland-Jones 1998). Even if a T-cell-based vaccine could not prevent infection,
there is the chance that it could influence the course of infection by reducing the
viremia after infection, as seen in the SIV monkey models (Letvin 2006). HIV-1 can
evade detection by CTL by the development of mutations. Our observations in long-
term survivors demonstrated the importance of the quality of the CTL response with
the targeting of conserved CTL epitopes (Harrer 1996b). Therefore, it is crucial for
the effectiveness of a vaccine that sufficient highly conserved CTL epitopes are
present in the vaccine for the r individual HLA alleles.
Vaccination techniques capable of loading viral peptides onto HLA class I molecules
on the surface of dendritic cells, are needed to induce CTL. Attenuated live vaccines
are not considered for safety reasons. DNA vaccines are not very immunogenic on
their own, but in a prime-boost strategy can significantly increase the immuno-
genicity of subsequent vaccinations with viral vectors. Lipopeptides and the com-
bination of peptides with cytokines such as GM-CSF allow induction of CTL but may
present relatively few epitopes.
616 Prevention

Recombinant viral vectors

These vectors can induce CTL without relevant risks. Currently, adenovirus vectors,
Canary Pox virus (canary pox virus), MVA (Harrer 2005), NYVAC (Gomez 2007),
adeno-associated virus (AAV), and Sendai virus vectors (Nyombayire 2017) are being
evaluated.
A great disappointment was the termination of two placebo-controlled Phase IIb
trials, the HVTN 502 study (STEP trial) (Buchbinder 2008) and the HVTN 503 study
(Phambili Study) (Gray 2011). Both studies used a mixture of three Merck recombi-
nant non-replicative adenovirus type 5 vectors (MRKAd5 V520) expressing the HIV-1
proteins Gag, Pol, and Nef. The vaccine was immunogenic (McElrath 2008), but the
trial was stopped because of a lack of efficacy. There was even a trend for a higher
infection rate in the verum arm in the STEP trial in individuals with high titers of
preexisting antibodies to the adenovirus 5 vector. Since it could not be ruled out that
in the case of a strong immune response against adenovirus 5, this vaccine could
promote HIV-1 infection, the Phambili study was also discontinued, which by then
had also failed to show any protective effect of the MRKAd5 vaccine (Gray 2011).
A combination of priming with DNA vaccines and subsequent booster vaccinations
with recombinant adenoviruses can enhance the vaccination response (Jaoko 2010).
In the HVTN-505 study (Hammer 2013), circumcised men who lacked neutralizing
antibodies to adenovirus 5 were first vaccinated with a DNA vaccine (6 plasmids:
HIV-1 clade B Gag, Pol, Nef, and ENVs of clades A, B, and C) three times (weeks 0,
4, 8). This was followed by vaccination with four recombinant adenovirus 5 vectors
(Gag-Pol fusion protein and three ENVs of clades A, B, and C) at week 24. Despite
the induction of HIV-1-specific T-cells and antibodies, vaccination did not affect the
infection rate or the level of viremia in infected subjects. The vaccine did not induce
neutralizing antibodies and only modestly induced antibodies against the V1/V2
loop, which were associated with protection in the RV144 trial. However, subsequent
data analysis showed that the induction of a strong, polyfunctional CD8 T-cell
response against the envelope reduced the risk of infection (Janes 2017).
Because the increased risk of infection correlated with the antibody titer to the AD5
vector in the STEP study, new vectors derived from less common adenovirus serotypes
were developed. In addition, to cover viral variants, mosaic vaccines optimized for
the expression of epitopes of different HIV-1 subtypes were developed. An HIV mosaic
vaccine in an AD26 vector showed good immunogenicity and tolerability in monkey
experiments and in a phase 1/2 study in volunteers (Barouch 2018). In the Phase 2b
study (HPX2008/HVTN 705/Imbokodo study) in African women initiated in 2018,
the tetravalent [Link] vaccine containing four different mosaic constructs
([Link]-Pol, [Link]-Pol, [Link], [Link]) was
combined with a Clade C gp140 envelope trimer in a heterologous “double prime,
double boost” vaccination regimen. Still, this vaccination also did not confer
significant protection.
A Phase III trial (HPX3002/HVTN 706/Mosaico) in men and transgender individu-
als in the Americas and Europe, combining vaccination with the tetravalent
[Link] vaccine with administration of two envelope trimers (Clade C gp140
and Mosaic gp140 HIV) started in 2019 but was discontinued in 2023 because of lack
of efficacy.
The RV144 trial (Rerks-Ngarm 2009) in Thailand was the first HIV vaccination trial
to reduce new HIV-1 infections by approximately 31% significantly. In this trial, sub-
jects received four vaccinations with a Sanofi-Pasteur canarypox vector (ALVAC-HIV
vCP1521) expressing the HIV-1 subtype B Gag and protease proteins and the HIV-1
subtype E envelope protein and two booster vaccinations with the AIDSVAX B/E
Preventive HIV-1 vaccination: current status 617

gp120 glycoproteins. Among the 8198 individuals in the placebo arm, 74 new HIV-1
infections occurred within the three-year observation period, whereas only 51 new
HIV-1 infections were observed among the 8197 vaccinated individuals. The effec-
tiveness of the vaccination correlated with the risk of infection and was 42.4% at
low risk and only 3.7% at high risk after 42 months.
Vaccination did not affect viremia in the subjects infected in the study. Vaccination
induced only a weak T-cell response, whereas almost all vaccinated individuals
developed high titers of envelope-specific antibodies, which had only a weak to
moderate ability to neutralize different HIV-1 variants. Moreover, their detection did
not correlate with a lower infection rate. Interestingly, induction of high IgG titers
against the V1/V2 loop was associated with protection, whereas high IgA antibody
titers against gp120 were associated with increased infection rates (Haynes 2012).
Given these positive results, this vaccination approach using the ALVAC HIV vector
(vCP2438 as in RV144 but replacing the CRF01_AE gp120 gene with a subtype C
gp120 gene) was tested in the HVTN 702 phase III study (Uhambo study) in South
Africa. In this study, booster vaccinations were given with two monomeric subtype
C gp120 molecules (TV1.C and 1086.C) and with a different adjuvant (MF59) instead
of subtype B/E gp120 molecules. Unlike RV144, there was no effect on the infection
rate or the level of viral load at infection (Gray 2021). The reason for this discrep-
ancy with RV144 is thought to be a comparatively higher risk of infection in the
Uhambo study. The results were not influenced by the medical pre- and post-expo-
sure prophylaxis offered, which was used by only 3% of participants.

Combinations of vaccines with PREP

The success of drug-based pre-exposure prophylaxis (PrEP) has implications for
vaccine trial design. Therefore, the ongoing three-arm PREPVacc trial of 1,668 par-
ticipants in Africa is testing not only two experimental vaccination strategies (DNA-
HIV-PT123 + AIDSVAX B/E gp120 at weeks 0, 4, 24, 48) and DNA-HIV-PT123 +
CN54gp140 trimer (week 0, 4) + MVA/CN54gp140 (week 24, 48) against placebo. In
addition, all participants will be randomized to receive PrEP with TDF/FTC or
TAF/FTC for 26 weeks ([Link]

New approaches to vaccination

Despite intensive efforts in recent decades, no effective HIV-1 vaccine has yet been
developed. The main reasons for this are the biological properties of HIV-1, which
also means that almost all infected people without therapy ultimately die from the
infection. Only a few people are able to generate the very broadly neutralizing anti-
bodies necessary for vaccine protection, and conventional vaccination techniques
have not achieved induction of these broadly neutralizing antibodies. In addition,
HIV-1 can significantly limit the efficacy of cytotoxic T-cells (CTL) by causing the
viral protein Nef to downregulate HLA-A and HLA-B molecules from the surface of
infected cells, thereby inhibiting the recognition and destruction of infected cells.
In addition, certain variants of the viral protein Vpu can also block HLA-C-restricted
CTL by downregulating HLA-C molecules. As a result, although HIV vaccines can
induce HIV-1-specific CTL, they generally have only limited efficacy and thus cannot
prevent infection.
At least, important lessons could be learned from the failures of the large vaccina-
tion trials that will contribute to the development of new vaccination strategies:
In 2013, a study of rhesus monkeys immunized with a rhesus monkey CMV vector
(RhCMV68-1/SIV) attracted great interest (Hansen 2013a). Although vaccination
618 Prevention

with this SIV protein-expressing vector did not prevent SIV infection, approximately
half of the animals could eliminate SIV infection. The reason for this success was
the induction of unusual, “non-canonical” CD8 killer cells (Hansen 2013b). These
recognized their peptides not on HLA class I molecules, as is usual for CD8 T-cells,
but on HLA class II molecules or HLA E molecules (Hansen 2016), which are not
downregulated by the viral Nef molecule. Meanwhile, HLA-II-restricted HIV-1-spe-
cific CD8 CTL have also been described in a small subset of HIV-1-infected humans
(Ranasinghe 2016), although such cells’ role in effectively controlling HIV-1 in
humans remains to be defined. Induction of non-canonical CD8+ killer cells is not
a general property of rhesus monkey CMV. Still, it depends on certain properties of
the RhCMV68 vector used, which has restricted cell tropism for fibroblasts due to
the inactivation of eight genes. Restoration of these inactive genes in the rhesus
monkey CMV vector resulted in loss of induction of HLA-E-restricted CTL and loss
of protective effect against SIV. Since the RhCMV68-1/SIV vector does not infect
humans, human chimeric CMV vectors were developed, but in a human clinical
trial, they could only generate classical CTL and not non-canonical CTL (Murray
2017). Meanwhile, further studies led to a better understanding of the induction
mechanisms of HLA-E-restricted CTL (Verweij 2021), raising the hope that methods
can be developed to induce HLA-E-restricted HIV-specific T-cells.
The native gp160 trimer, in contrast to the gp120/gp160 monomers, contains
conformational epitopes to which neutralizing antibodies can bind. Therefore,
modified envelope trimers (gp140 SOSIPs) were developed to allow better presenta-
tion of antibody epitopes important for neutralization. The IAVIW001 trial, which
began in 2019, is currently testing whether an envelope trimer vaccine (BG505
SOSIP.664 gp140 in combination with adjuvant AS01B ) can induce neutralizing anti-
bodies.
Due to somatic mutations, the genes encoding broadly neutralizing antibodies in
B-cells differ significantly from the original germline genes. The original germline
genes encoding these antibodies are present in most individuals, but the antibodies
encoded by the germline genes do not bind adequately to the envelope of HIV-1.
Specific vaccines must stimulate B-cells expressing germline-encoded antibodies to
induce broadly neutralizing antibodies. Sequential inoculations with additional
modified vaccines are then used to induce affinity maturation of B-cells with somatic
mutations to simulate the natural development of broadly neutralizing antibodies.
For this purpose, vaccines (e.g., eOD-GT8 engineered Outer Domain Germline-
Targeting Version 8) have been developed that were able to stimulate and expand
germline-encoded B-cell receptors in mice (Lee 2022). According to a press release
from IAVI, in the IAVI G001 study, 97% of 48 subjects developed B-cells producing
VRC01 class IgG after two vaccinations with the eOD-GT8 60mer. Further studies
will attempt to induce broadly neutralizing antibodies by sequentially stimulating
these B-cells with modified vaccines.

Vaccination with mRNA

The development of mRNA technology represents a major advance in the development
of HIV-1 vaccines. The production and modification of complex large molecules such
as gp140 SOSIPs or eOD-GT8 is very time-consuming. In contrast, modifications of
proteins can be obtained very fast by changes in the coding mRNA sequence. This
considerably shortens development times. In addition, large amounts of mRNA can
be produced more easily and quickly than complex proteins, so necessary adapta-
tions of the vaccines to new virus variants can also be carried out quickly and effi-
ciently. Because mRNA vaccines induce viral protein production in the cell, they can
Preventive HIV-1 vaccination: current status 619

induce CTL very potently, unlike protein vaccines. Since mRNA can activate Toll-
like receptors that recognize viral nucleic acids, no further adjuvants are needed,
unlike protein vaccines. A disadvantage is the instability of the mRNA, which requires
storage at low temperatures in freezers, making it difficult to use in countries without
sufficient infrastructure.
The great success of SARS-CoV-2 specific mRNA vaccines has stimulated the use of
mRNA vaccines in HIV-1 vaccine development. For example, several Phase 1 studies
are currently testing the immunogenicity of mRNA vaccines encoding different HIV-1
envelope trimers. In addition, IAVI-led studies are testing whether sequential immu-
nization with mRNA-encoded vaccines can stimulate and affinity-mature B-cells with
germline receptors for neutralizing antibodies.

Outlook
Due to the sophisticated immune evasive properties of HIV, effective preventive HIV
vaccines could not be developed using vaccination methods effective in other infec-
tions. Therefore, new strategies to circumvent immune evasion of HIV-1 are needed.
Intensive basic research has now enabled the development of new technologies such
as vaccination with mRNA, production of envelope-trimers, sequential vaccination
for targeted affinity maturation of B-cells, and induction of non-canonical CTL.
However, it is currently unclear if and when new vaccination approaches will ulti-
mately lead to a universally applicable, effective preventive HIV-1 vaccine; there is
reasonable hope to make substantial progress through innovative research in the
coming years.
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621

34. Post-exposure prophylaxis (PEP)

SEBASTIAN NOE

HIV post-exposure prophylaxis (HIV PEP, hereafter simplified as PEP) is a measure

to reduce the risk of HIV infection. As the name suggests, it is used when an “event”
has occurred that involves a potential risk of infection for someone. It differs
significantly from pre-exposure prophylaxis (PrEP), taken before such an event
occurs. PEP and PrEP (therefore) also differ in the medications to be taken. PEP
corresponds to a complete antiretroviral therapy and can be the same used to treat
an HIV infection.
In principle, transmission of HIV is only possible if both of the following conditions
are met:
Virus-containing material (e.g., blood, seminal fluid, vaginal secretions) must enter
a person’s body (purely superficial contacts, e.g., contact with blood on intact skin,
are not sufficient in this regard)
AND
thereby have a sufficient amount of replicable virus (which is why, for example,
people with a viral load < 200 copies/mL cannot transmit HIV (sexually) (Rodger
2019).
In addition to the type of secretion and the amount of virus contained, the dura-
tion of contact and the potential entry site also play a role, among other factors.
Relevant exposure to HIV can essentially be assumed in the following events (DAIG
2018):
• Injury via HIV-contaminated instruments or injection equipment
• Wetting of open wounds and mucous membranes with HIV-contaminated fluid
• Condomless sexual intercourse with a PLWH
• Use of HIV-contaminated injection equipment
• Transfusion of HIV-contaminated blood or blood products

Apart from occupational events, in practice, it is primarily sexual contacts that lead
to medical consultation and the question of the need for PEP. HIV transmission rates
may markedly vary by the type of exposure. There is a broad range of transmission
risks in different contact settings. Table 1 provides an overview of HIV transmission
per contact.

Table 1: Probability of infection during unprotected sexual contact (German-Austrian recommendati-

ons on PEP 2018).
Type of (unprotected) contact Probability of infection per contact
Receptive anal intercourse with a known HIV-positive partner 0.24–2.76%
With ejaculation 0.48–2.85%
Without ejaculation 0.15–1.53%
Receptive anal intercourse with a partner of unknown HIV serostatus 0.06–0.49%
Insertive anal intercourse with a partner of unknown HIV serostatus 0.02–0.19%
Receptive vaginal intercourse 0.05–0.15%
Insertive vaginal intercourse 0.03–5.6%
Oral sex Case Reports
622 Prevention

Effectiveness and limits of PEP

At least 24 to 36 hours usually elapse before systemic disease is established after tissue
infiltration of HIV; this is the rationale for using antiretroviral drugs as PEP. The
understanding of “early therapy” also has legal relevance. In the absence of placebo-
controlled randomized trials – which would no longer be justifiable from an ethical
perspective – none of the antiretroviral combination therapies has been officially
approved as chemoprophylaxis.
PEP does not provide 100% protection against HIV infection, and transmission
despite PEP has been reported. Possible reasons could be transmitted resistance, lack
of adherence, misunderstandings regarding the intake, or starting PEP too late.
In general, it is recommended that a physician makes the indication with experi-
ence in HIV. However, (suspected) exposure to HIV often occurs when specialists
cannot be consulted (e.g., in the evening/at night or on weekends). Here, it is crucial
to initiate PEP in case of doubt. It can always be terminated prematurely later, after
a specialized medical consultation.
Central questions regarding the indication are the serostatus of the “index person”
and the exact course of the event. With this information, the risk of infection can
usually be estimated. The often unknown serostatus of the index person can also be
clarified if necessary. However, this can only be done if the index person is known,
can be contacted, and consents to an HIV test. Table 2 provides an overview of the
indication according to various events.

Immediate measures and initiation of PEP

After puncture wounds or cuts with contaminated needles or instruments, blood
flow and thus natural flushing of the wound should first be allowed; “ligation” is
obsolete. This should be followed by irrigation with an antiseptic or even soap and
water. In the case of contact with damaged or inflamed skin, water and soap and, if
necessary, generous application of a skin antiseptic will suffice. Contaminated eyes
should be rinsed immediately with copious amounts of water, and the same applies
to the oral cavity, which should preferably be rinsed several times for 15 seconds
each time. After exposure during penetrative anal or genital intercourse, the glans
and foreskin should be washed gently with soap under running water. Vaginal or
bowel rinses are not recommended due to the potential risk of injury.
Although this section deals with the prevention of HIV infection, it should not be
unmentioned that transmission of other infectious diseases is also possible. Above
all, with regard to the prevention of HBV infection, it must be determined whether
immune protection exists or whether active and passive immunization must be per-
formed in a timely manner. Serological tests for HIV should be accompanied by
serologies for hepatitis B and C and syphilis.

Introduction of PEP
Once the indication for PEP has been established, starting as soon as possible is essen-
tial. Ideally, PEP should be started within the first two hours after exposure. A timely
start can also be considered up to 24 hours post-event. If the exposure occurred more
than 72 hours ago, PEP is probably no longer useful.
Although the German-Austrian guidelines in the 2018 revised version recommend
a combination of TDF/FTC with raltegravir or dolutegravir, it should be noted that
adherence to PEP seems to be a significant problem (Fernandez 2020). In addition
to tolerability, the mode of intake is likely to play a major role. Therefore, in the
author’s opinion, there is much to be said for an integrase inhibitor-based single-
tablet regimen (see Table 3) used in HIV therapy.
Post-exposure prophylaxis (PEP) 623

Possible resistance must be considered if the index person is HIV-infected and viremic.
In these cases, an individual PEP regimen is useful, which should be compiled by
physicians experienced in HIV. In any case, possible interactions and contraindica-
tions of antiretroviral drugs must be considered. For example, regimens containing
TDF should not be used in cases of impaired renal function or osteoporosis, and
dolutegravir should be avoided if metformin is taken continuously at a dose of
> 1,700 mg daily. Caution should be exercised with boosted regimens (i.e., cobicis-
tat- or ritonavir-containing combinations), particularly in those with co-medication,
as interactions are likely.
The alternative to TDF+FTC previously recommended by the guidelines, namely
AZT/3TC, must be considered obsolete. It can be replaced by TAF+FTC in the author’s
opinion. The role of dual antiretroviral therapies in the context of PEP is unclear.
Promptly after initiation of PEP, testing for pre-existing HIV infection (as well as
hepatitis B and C) should be performed, but should not delay initiation of PEP.

Monitoring after initiation of PEP

Medical monitoring is not completed with the initiation of PEP. It is crucial to remain
in contact with the exposed person to identify and respond to possible intolerances
and/or side effects. Depending on the regimen used, this may also include moni-
toring of transaminases and renal function.
PEP can usually be terminated after 28 (-30) days. Serological control tests for HIV
and, if applicable, HBV and HCV should be performed again six and twelve weeks
after completion of PEP.
624 Prevention

Table 2: German-Austrian recommendations (2018) for the use of PEP.

Occupational circumstances (source secured HIV-positive)
Massive percutaneous inoculation (> 1 mL) of blood or body fluid Recommended, regardless
with high virus concentration of viral load
Deep, bleeding injury (cut or puncture) with a hollow needle or Recommended if VL
contaminated instrument (e.g., scalpel) > 50 copies/mL
Offer when VL
< 50 copies/mL
Superficial injury (e.g., with a surgical needle) Offer when VL
without bleeding > 50 copies/mL
Contact of mucous membrane or injured/damaged skin with fluids Not recommended if VL
with high virus concentration < 50 copies/mL
Percutaneous contact with body fluids other than blood Not recommended
(such as urine or saliva)
Contact of intact skin with blood (even with high virus concentration) Not recommended
Skin or mucous membrane contact with urine and saliva Not recommended
Non-occupational circumstances
Exposure with confirmed HIV-positive source
Transfusion of blood products containing HIV or receipt of blood Recommended
products that are highly likely to contain HIV
Use of HIV-contaminated injection equipment by several drug Recommended
addicts together or in succession
Unprotected vaginal or anal sexual intercourse (broken condom) Recommend if VL
with a person infected with HIV > 1,000 copies/mL
Offer when VL
50–1,000 copies/mL
No indication if VL
< 50 copies/mL
Exposure with unknown status of the index person/source
Unprotected homosexual anal intercourse especially in typical situations Offer
Unprotected heterosexual vaginal or anal intercourse with a partner
from a risk group (active IVDU, bisexual, high prevalence area) Offer
Unprotected heterosexual vaginal or anal intercourse with a partner Not recommended
without special risk (prostitution!)
Oral sex with ingestion of semen into the mouth (HIV positive or Not recommended
negative)
Kissing, other sexual practices without semen/blood/mucous-skin
contact, and S/M practices without blood-to-blood contact
Injury to used syringe equipment used to inject drugs, medications, Not recommended
or insulin

Monitoring in case of a decision against PEP

Even if one decides against PEP, serological controls should be performed at the time
of presumed exposure and six and twelve weeks thereafter. If symptoms of acute HIV
infection occur in the interim, HIV PCR is also warranted.
Do not forget to evaluate general HIV exposure risk and discuss PrEP options, if
appropriate.
Post-exposure prophylaxis (PEP) 625

Table 3: Antiretroviral combinations are recommended in the German-Austrian Guidelines for HIV post-
exposure prophylaxis. STR = single-tablet regimen.
NRTIs INSTI or Pis
TAF/FTC 25/200 mg plus Bictegravir (as STR Biktarvy® 1 x 50/200/25mg)
TDF + FTC (Truvada® or generic) plus Dolutegravir (Tivicay® ) 1 x 1 tbl. of 50 mg
1 x 1 tbl. of 245/200 mg either or
Raltegravir (Isentress®) 2 x 1 tbl. of 400 mg
or 1 x 2 tbl. of 600 mg
If not available:
TAF/FTC 10/200 mg plus Darunavir 800 mg and cobicistat 150 mg
either (as STR Symtuza® 1 x 800/150/200/10 mg)
or
Elvitegravir 150 mg and cobicistat 150 mg
(as STR Genvoya® 1 x 150/150/200/10 mg)
TDF/FTC plus Darunavir 800 mg and ritonavir 100 mg
(Truvada® or generic) (each once daily, to be taken together)
1 x 1 tbl. of 245/200 mg

Literature
Deutsche AIDS-Gesellschaft e.V. und Österreichische AIDS Gesellschaft. (2018). Deutsch-Österreichische Leitlinie
zur Postexpositionellen Prophylaxe der HIV-Infektion (update 2018). AWMF online.
Fernandez I, deLazzari E, Inciarte A, et al. Network meta-analysis of post-exposure prophylaxis randomized clin-
ical trials. HIV Med 2021, 22:218-224.
Rodger AJ, Cambiano V, Bruun T, et al. Risk of HIV transmission through condomless sex in serodifferent gay
couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a mul-
ticentre, prospective, observational study. Lancet 2019, 393:2428-2438.

(Earlier versions of this chapter were created by Thore Lorenzen)

SECTION 8

Drugs
628

35. Drug Profiles

C H R ISTIAN HOFFMAN N

The following chapter gives a brief overview of the most important (as of early 2023)
antiretroviral agents and some selected preparations that play a role in the treatment
of opportunistic infections, Kaposi’s sarcoma or hepatitis C. Please always refer to
the product information.

3TC (lamivudine)
Original manufacturer: ViiV Healthcare. Generics are available for some prepara-
tions.
Approval and indication: As part of combination therapy for untreated or pre-
treated PLWH. The lower dosage of 100 mg in Zeffix® (generics) approved for HBV
should be avoided in PLWH!
• Epivir® film-coated tablets: 150 or 300 mg 3TC (generic)
• Epivir® solution: 10 mg 3TC per mL (240 mL)
Combination preparations (all film-coated tablets) with 3TC:
• Combivir®: 150 mg 3TC + 300 mg AZT (generic)
• Delstrigo®: 300 mg 3TC + 300 mg TDF + 100 mg doravirine
• Dovato®: 300 mg 3TC + 50 mg dolutegravir
• Kivexa®: 300 mg 3TC + 600 mg abacavir (generics)
• Triumeq®: 300 mg 3TC + 600 mg abacavir + 50 mg dolutegravir
• Trizivir®: 150 mg 3TC + 300 mg AZT + 300 mg abacavir (only until 2024)
Dose: 1 x 300 mg or 2 x 150 mg daily. Children receive 4 mg/kg. Reduction in renal
insufficiency, below a GFR of 30 mL/min use the solution:

Creatinine clearance (mL/min) First dose Maintenance dose

>50, 30–49 150 mg (15 mL) 1 x 150 mg (15 mL)
15–29 150 mg (15 mL) 1 x 100 mg (10 mL)
5–14 150 mg (15 mL) 1 x 50 mg (5 mL)
<5 50 mg (5 mL) 1 x 25 mg (2.5 mL)

Adverse events: Rare with the single agent. Complaints such as fatigue, nausea, or
headache are primarily due to AZT and abacavir.
Comment: Well tolerated and still much-prescribed cytidine analog. Available in
diverse combinations and dosages. Rapid resistance, but reduces viral fitness. Also
effective against HBV (caveat: also immediate resistance, also the risk of HBV
rebounds).
Detailed discussion in this book: page 50

Abacavir
Manufacturer: ViiV Healthcare. Generics are available for some preparations.
Approval and Indication: As part of combination therapy in both untreated and
pretreated PLWH. Abacavir is a component of:
• Ziagen® film tablets: 300 mg abacavir (generic)
• Ziagen® solution: 20 mg abacavir per mL (240 mL)
Drug Profiles 629

Combination preparations with abacavir (all film-coated tablets)

• Kivexa®: 600 mg abacavir + 300 mg 3TC (generic)
• Triumeq®: 600 mg abacavir + 300 mg 3TC + 50 mg dolutegravir
• Trizivir®: 300 mg abacavir + 150 mg 3TC + 300 mg AZT (only until 2024)
Dose: 2 x 300 mg or 1 x 600 mg daily, with or without food. Although hepatically
metabolized, avoid in severe renal impairment (GFR <20 mL).
Adverse events: In 2–8% hypersensitivity reactions (HSR), usually in the first six
weeks, slowly increasing. Itching and rash may be absent, sometimes only fever and
feeling of illness. Also, gastrointestinal symptoms, rarely elevated transaminases,
dizziness, sore throat, or cough. In addition to HSR, an increased risk of myocardial
infarction should be noted, probably due to the thrombogenic effects of abacavir on
platelets (activation).
Warnings: Negative HLA-B*5701 genetic testing (written informed consent!) is
mandatory; it significantly but does not ultimately reduce the risk of HSR. Abacavir
is contraindicated after therapy interruption if HSR cannot be retrospectively ruled
out. HSR is potentially life-threatening if re-exposed!
Comment: NRTI with good CNS penetration. HSR (HLA testing mandatory!). It is
less used than in the past because of cardiovascular risk. Some generics are available.
Detailed discussion in this book: page 49

Acyclovir
Manufacturer: Various. Trade names e.g. Aciclobeta®, Aciclovir®, Zovirax®.
Approval and indication: herpes zoster. Additionally, for the prevention of severe
herpes simplex infections in severely immunosuppressed adults.
Dose: In monosegmental herpes zoster, 5 x 800 mg orally daily for one week. In mul-
tisegmental or complicated herpes zoster, 3 x 10 mg/kg i.v is better. In renal insuf-
ficiency, the dose is lower: if creatinine clearance is 25–10 mL/min, 3 x 800 mg; if
<10 mL/min, 2 x 800 mg.
For genital HSV infection: 5 x 400 mg daily. In severe cases (ulcerating genital herpes),
intravenous treatment with daily 3 x 5–10 mg/kg i.v. For HSV encephalitis or
esophagitis, 3 x 10 mg/kg i.v.
Adverse events: Rare. Headache, nausea, and creatinine elevations occur. With intra-
venous administration, phlebitis.
Comment: Well-tolerated HZV/HSV drug. Cheap generics are available! Start therapy
for HSV within the first 24 hours of the onset of symptoms if possible (4 days for
VZV). Ensure adequate fluid intake.

Agenerase® see Amprenavir (withdrawn from the market)

630 Drugs

Amphotericin B
Manufacturers: Bristol-Myers Squibb (Amphotericin B®), Gilead Sciences (Ambisome®),
Dermapharm (Ampho-Moronal®). In some countries, generics are available.
Approval and indication: Amphotericin B for organ and generalized mycoses,
especially candidiasis, aspergillosis, cryptococcosis, and histoplasmosis. The
liposomal-modified AmBisome® (significantly more expensive) is also approved for
secondary therapy in visceral leishmaniasis, whereas suspension and tablets are
approved only for oral thrush. Amphotericin is a component of the following prepa-
rations:
• Amphotericin B® 50 mg powder vials
• AmBisome® vials with 50 mg dry substance
• Ampho-Moronal® suspension containing 100 mg/mL
• Ampho-Moronal® 10 mg lozenges
Dose: For amphotericin B®, always test the dose first (see below). For aspergillosis,
1.0–1.5 mg/kg; for the other mycoses, 0.5–1 mg/kg is usually sufficient. No more
than 1.5 mg/kg, as overdose may cause fatal respiratory and cardiac arrest! For
AmBisome®, the initial daily dose of 1 mg/kg can be gradually increased to 3 mg/kg.
Adverse events: Nephrotoxicity! Hypokalemia! Gastrointestinal complaints.
Frequent fever, chills, and circulatory problems 10–20 min after the start of infusion.
Thrombophlebitis (CVC!). With Ambisome®, side effects are less pronounced.
Warnings: Daily electrolytes (always ZVK because of hypokalemia! Keep sodium high
normal), creatinine, urea, GPT, blood count. Do not combine with nephrotoxic
substances. Always pre-water with 1000 mL NaCl 0.9%. At first administration, test
dose 5 mg in 250 mL glucose 5% over 30–60 min, measure blood pressure, and pulse.
Half of the planned dose after tolerating the test dose on the same day. In case of
fever/ chills (can be impressive!): Pethidine (e.g., Dolantin®) half an ampoule i.v.
(50 mg) plus one ampoule clemastine (e.g., Tavegil®), repeat after 30 min if neces-
sary, additional prednisolone 1 mg/kg only if persistent. In case of severe side effects,
switch to Ambisome®, which is probably not more effective but less nephrotoxic
than amphotericin B (no test dose, no prewashing, no CVC required). Never mix
infusions; always darken. The slower (>3 hrs) infused, the better it is tolerated! Always
use glucose 5% as a solution!

Amprenavir (Agenerase®) – PI discontinued in 2008, replaced by fosamprenavir

Apretude® – see cabotegravir

Atazanavir
Original manufacturer: BMS. Meanwhile, only generics are available in many coun-
tries.
Approval and Indication: In HIV-positive adults and children 6 years of age and
older as part of a combination. Atazanavir is a component of the following prepa-
rations:
• Atazanavir (generic) hard capsules 200 mg, 300 mg
• Reyataz® powder with 50 mg in each 1.5 g
• Evotaz® 300 mg with 150 mg cobicistat (EU approval, not marketed in many EU
countries).
Drug Profiles 631

Dose: Daily 1 x 300 mg combined with 100 mg ritonavir or 150 mg cobicistat,

unchewed, with a meal. If unboosted, use 1 x 400 mg (consider limitations: No teno-
fovir, no prior virologic failure, no PPIs). With efavirenz and probably nevirapine,
the atazanavir dose should be increased to 400 mg even when boosted. In children
by weight: 15–20 kg: 150 mg, 20–40 kg: 200 mg, at least 40 kg: 300 mg, each plus
100 mg ritonavir.
Adverse events: Very frequently, bilirubin increase (up to 50%!) also with icterus,
rarely transaminase increase. Relatively rarely gastrointestinal complaints, headache.
In contrast to other PIs, there are probably fewer dyslipidemias.
Interactions: Caution in liver cirrhosis (Child B, C). Cave PPI, antacids (see inter-
actions)! Do not combine with midazolam, simvastatin, lovastatin, ergotamine,
rifampicin, calcium antagonists. Life-threatening interactions are possible with amio-
darone, lidocaine (systemic administration), tricyclic antidepressants, and quinidine
(level determination!). Clarithromycin: no combination with boosted atazanavir.
Dose reduction of rifabutin by 75% (instead of 300 mg/day only 150 mg every other
day or three times per week).
Comment: Formerly much prescribed PI, which, among other things, due to its side
effects (hyperbilirubinemia, icterus!) hardly plays a role anymore, the original prepa-
ration was taken off the market. Relevant interactions have to be considered, espe-
cially with PPIs, but also with tenofovir.
Detailed discussion in this book: page 68

Atovaquone
Manufacturer: GlaxoSmithKline.
Approval and indication: acute treatment of moderately severe PCP in cases of
intolerance to cotrimoxazole. Combined with proguanil, it is also for treating and
preventing malaria. Off Label: PCP prophylaxis (as a reserve), acute treatment of cere-
bral toxoplasmosis. Atovaquone is a component of the following preparations:
• Wellvone® suspension containing 750 mg atovaquone/5 mL (210 mL).
• Malarone® film-coated tablets containing 250 mg atovaquone and 100 mg
proguanil
Dose: As PCP (or toxo) therapy daily 2 x 750–1,500 mg (2 x 1–2 scoops to 5 mL) for
21 days. For prophylaxis, 2 x 750 mg (2 x 1 scoopful at 5 mL) or 1 x 1,500 mg daily.
For malaria therapy, see FA. Take with a meal, the bioavailability increases 2–3 times.
Adverse events: Frequently gastrointestinal, skin exanthema. Less commonly,
headache insomnia. Increased liver enzymes and amylase. Anemia, leukopenia (rare).
Interactions: Take with a high-fat meal as this improves absorption. Rifampicin, pos-
sibly also rifabutin, reduces plasma levels of atovaquone by about 50%. Fluconazole
is likely to increase levels.
Comment: Only rarely used now. Considerably more expensive than other drugs
for PCP prophylaxis!
632 Drugs

Atripla®
Manufacturer: The Gilead/BMS/MSD co-production was withdrawn from the market
in 2021; only generics are now available.
Approval and Indication: Adult PLWH who have had a viral load below 50
copies/mL on current ART for over three months and have no prior virologic failure
or resistance.
• Efavirenz/emtricitabine/tenofovir disoproxil (formerly Atripla®) with 600 mg
efavirenz, 200 mg FTC, 300 mg TDF
Dose: One tablet daily in the evening, unchewed, on an empty stomach.
Notes: Note the above indication restriction and side effects; see especially Efavirenz
(CNS) and TDF (kidney). Numerous generics are available but much more expensive
than single substances.
Comment: Atripla® was the first single-tablet regimen, now off the market. The
generics are rarely used; efavirenz is no longer recommended.
Detailed discussion in this book: page 172

Azithromycin
Manufacturer: Various. Trade names, e.g., Azithromycin®, Zithromax ®, Ultreon®.
Approval and indication: treatment and prevention of MAC infection. Upper and
lower respiratory tract infections, otitis media. Uncomplicated gonorrhea, uncom-
plicated genital infections due to Chlamydia trachomatis, ulcus molle. Azithromycin
is a component of the following preparations (selection):
• Ultreon® film-coated tablets 600 mg
• Zithromax® 250 mg and 500 mg, film-coated tablets
• Zithromax® powder for oral suspension (containing 200 mg per 5 mL)
Dose: Primary prevention of MAC infection: Weekly 1,200 mg (1 x 2 tablets Ultreon®
600 mg per week). MAC therapy: Daily 1 x 1 tablet Ultreon® 600 mg, only in com-
bination with ethambutol and rifabutin.
Respiratory infections: Total dose 1500 mg, distributed over three days (1 x 500 mg
each).
Gonorrhea (with ceftriaxone!), Chlamydia (not LGV!): 1500 mg as a single dose.
Adverse events: Gastrointestinal with stomach cramps, nausea, vomiting, diarrhea!
Rarely increased transaminases and cholestasis. Reversible ototoxicity at high doses.
Rarely taste irritation or discoloration of the tongue. Allergies.
Comment: Macrolide antibiotic with a long half-life and good tissue penetration. A
single dose is sufficient for many STDs and 3–5 days for respiratory infections.
Formerly commonly used for MAC infections, it is also used as continuous therapy.
Drug Profiles 633

AZT (zidovudine)
Manufacturer of the original preparations: ViiV Healthcare. Also generics!
Approval and Indication: As part of combination therapy for both untreated and
pretreated patients. AZT is a component of the following preparations:
• Retrovir® hard capsules: 100 mg AZT and 250 mg AZT
• Retrovir® film-coated tablets: 300 mg AZT
• Retrovir® solution: 100 mg AZT per 10 mL (200 mL)
• Retrovir® concentrate: 10 mg AZT per mL (5 vials of 200 mg each).
• Combivir® film tablets: 300 mg AZT + 150 mg 3TC
• Trizivir® film tablets: 300 mg AZT+150 mg 3TC+300 mg abacavir
Dose: 2 x 250 mg daily. In Combivir® and Trizivir® 2 x 300 mg daily. Severe renal
insufficiency (creatinine clearance less than 20 mL/min, hemodialysis): 300 mg daily.
Hepatic insufficiency: 3 x 100 mg daily.
Adverse events: Nausea, vomiting, bloating, headache, muscle pain. Macrocytic
anemia (MCV almost always elevated), rarely neutropenia. Also, LDH, CK elevations,
and elevated transaminases. Rarely lactic acidosis.
Interactions: Increased myelotoxicity with ganciclovir, cotrimoxazole, dapsone,
pyrimethamine, sulfadiazine, and various chemotherapeutic agents, among others.
In particular, avoid combination with ribavirin. Initially, monthly checks of blood
count, transaminases, CK, and bilirubin. Gastrointestinal symptoms usually subside
after a few weeks. Anemia may take months to develop.
Comment: The first NRTI (thymidine analog, approval 1987!) is rarely used due to
side effects and twice-daily administration.
Detailed discussion in this book: page 49

Bictegravir
Manufacturer: Gilead Sciences.
Approval and indication: Adult PLWH (pretreated or naive) without known resist-
ance to single agents.
• Biktarvy® film-coated tablets containing 50 mg bictegravir, 200 mg FTC, 25 mg TAF
Dose: 1 x 1 tablet daily, regardless of food intake. There is no dose adjustment in
renal insufficiency (up to a GFR of 30 mL/min) or moderate hepatic impairment.
Adverse events: Overall well tolerated, mainly tested against dolutegravir in pivotal
studies; so far, hardly any differences in tolerability, also about possible sleep dis-
turbances and other CNS side effects (relatively rare). In some cases, significant weight
gain, causes and mechanisms are unclear.
Interactions: Fewer interactions are expected due to the lack of a booster than with,
for example, Genvoya®. However, levels decrease in combination with rifampicin
(contraindicated). Rifabutin is also not recommended, nor is carbamazepine, St.
John’s wort. Relatively small tablets. A safety interval of 2 hrs is recommended with
antacids. There is a high resistance barrier, which is also effective against many pre-
existing resistances, but approval restrictions (see above).
Comment: Approved in 2018, a much-used fixed combination of TAF+FTC plus an
unboosted INSTI with a high resistance barrier. Has largely replaced Genvoya®. There
are no plans to introduce the single agent bictegravir.
Detailed discussion in this book: page 74, 174
634 Drugs

Cabenuva® – see cabotegravir

Cabotegravir
Manufacturer: ViiV Healthcare.
Approval and indication: In combination with rilpivirine injection (Rekambys®) in
adults virologically suppressed on stable ART without resistance or failure to NNRTIs
or INSTIs. Both drugs are packaged in the US, with the single trade name Cabenuva®.
• Vocabria® vials of 400 mg (2 mL) or 600 mg (3 mL)
• Vocabria® 30 mg film-coated tablets (lead-in and oral bridging only).
• Apretude® vials of 600 mg (3 mL) for PrEP (every 8 weeks)
• Apretude® 30 mg film-coated tablets (for PrEP lead-in and oral bridging only)
Dose: As “lead-in” (may be omitted), one tablet daily for 28 days, the initial dose of
600 mg i.m. on the last day, another 600 mg dose after one month, 600 mg every
two months after that (400 mg if given monthly), up to 7 days before/after the target
date. Oral bridging is possible for up to two months. See detailed package info if
doses are missed. Start classic ART if discontinued within one month. No dose adjust-
ment in renal or hepatic insufficiency.
Adverse events: Overall, well tolerated. Pain at injection sites (approx. 80%, swelling,
redness) is usually mild and rarely leads to discontinuation. Headache, depression
(neuropsychiatric adverse events).
Warnings, interactions: Shake vials vigorously for 10 seconds. Use longer needles
in obese patients. Use with caution in HIV subtype A and BMI >30. Strictly gluteal,
always the same buttock. Do not use with rifabutin, carbamazepine, phenytoin.
Comment: In 2020, the first approved long-acting therapy. Use only with rilpivirine
and not with other antiretroviral agents. Note indication restrictions.
Detailed discussion in this book: page 75

Caelyx® see Doxorubicin, liposomal

Cidofovir
Original manufacturer: Gilead Sciences. Originator (Vistide®) was discontinued in
2014; generics are still available.
Approval and indication: CMV retinitis in PLWH without renal dysfunction when
other therapies are unsuitable (resistance or contraindications to ganciclovir or fos-
carnet).
• Cidofovir vials containing 375 mg in 5 mL (= 75 mg/mL)
Dose: Weekly 5 mg/kg i.v. as induction, from day 21 maintenance with 5 mg/kg i.v.
Every two weeks. Plan (comedication, hydration, see below) required!
Adverse events: Renal insufficiency, possible even after a single dose. Rarely neu-
tropenia, dyspnea, alopecia, decreased intraocular pressure, iritis, and uveitis. Fever,
shivering, headache, rash, nausea/vomiting are more likely due to probenecid,
usually resolved within 12 hours, and are relieved by food intake, antipyretics, and
antiemetics.
Warnings, interactions: Beware of nephrotoxicity! Before each administration,
check renal function (serum creatinine, electrolytes, proteinuria). If serum creatinine
increases by more than 0.3 mg/dl, reduce the dose to 3 mg/kg (discontinue at
Drug Profiles 635

0.5 mg/dl increase)! Cidofovir is contraindicated if serum creatinine >1.5 mg/dl,

creatinine clearance <55 mL/min, or proteinuria >100 mg/dl. Always ensure adequate
hydration!
In case of normal renal function, the following regimen is recommended (protocol!):
Std –3 2 g probenecid (4 tbl. of 500 mg), possibly 20 tr. Novamin sulfone plus 50 mg
prednisolone beforehand
Std –3 to –1 1000–2000 mL NaCl 0.9%
Std 0 to +2 Cidofovir in 500 mL NaCl 0.9% over 1–2 h Parallel 1,000 mL NaCl 0.9
Std +4 1 g probenecid (2 tbl. of 500 mg), possibly 20 tr. novamine sulfone beforehand
Std +10 1 g probenecid (2 tbl. of 500 mg), possibly 20 tr. novamine sulfone beforehand

Discontinue nephrotoxic drugs such as amphotericin B, foscarnet, or vancomycin

(7 days prior). Probenecid is necessary to reduce nephrotoxicity – cave interactions
with paracetamol, acyclovir, ACE inhibitors, ASA, benzodiazepines, clofibrate,
methotrexate, furosemide, and theophylline.
Comment: Reserve drug for CMV disease, now very rarely used due to nephrotoxi-
city. The effect in PML is questionable.

Clarithromycin
Manufacturers: Various. Trade names, e.g., Clarithromycin-CT®, Klacid®, Mavid®.
Approval and indication: prevention and treatment of MAC infection. Infections
of the respiratory tract, ENT area, and skin. Clarithromycin is a component of the
following preparations (selection):
• Mavid® 500 mg film-coated tablets
• Klacid® 250 mg film-coated tablets
Dose: MAC 2 x 500 mg daily, in primary and secondary prophylaxis. From creati-
nine clearance <30 mL/min, dose reduction by 50%. For respiratory infections, a
dose of 2 x 250 mg is sufficient.
Adverse events: Mainly gastrointestinal complaints. Allergic reactions, headache,
elevation of liver enzymes.
Interactions: Numerous interactions. Do not co-administer rifampicin, carba-
mazepine, cisapride, terfenadine, pimozide, or other macrolides. Lopinavir and riton-
avir increase clarithromycin levels.
Comment: Macrolide antibiotic with a shorter half-life than azithromycin. The daily
dose should not exceed 2 x 500 mg. Hardly used anymore.

Clindamycin
Manufacturer: Various. Trade names e.g. Clindabeta®, Sobelin®.
Approval and indication: In HIV, especially in cerebral toxoplasmosis. Otherwise,
it is also for severe infections by anaerobes or staphylococci (due to good penetra-
tion into tissue and bone, also frequently used in dentistry).
Dose: Daily 4 x 1 Amp. à 600 mg i.v. or 4 x 1 Tbl. à 600 mg (always plus Daraprim®
and Leukovorin®). As maintenance therapy (oral) with half the dose. In renal insuf-
ficiency, reduction to one-quarter to one-third of the usual dose.
636 Drugs

Adverse events: Diarrhea in 10–30%. Allergies are also common and often require
discontinuation. In Clostridium difficile infection, pseudomembranous colitis: the
spectrum ranges from mild to severe, mucous-bloody diarrhea that can lead to peri-
tonitis, shock, and toxic megacolon.
Interactions, warnings: Clindamycin is contraindicated in inflammatory bowel
disease and antibiotic-induced -colitis. Caution in impaired liver -or kidney func-
tion, asthma. Cave concurrent administration of antiperistaltics! In case of diarrhea
under clindamycin, discontinue clindamycin and start treatment with metronida-
zole, possibly vancomycin.
Comment: It is still partly indispensable for toxoplasmosis but should be used cau-
tiously because of the risk of colitis.

Cobicistat
Manufacturer: Gilead Sciences, partly co-productions
Approval and indication: as a pharmacoenhancer for elvitegravir, atazanavir, and
darunavir. Cobicistat is a component of the following preparations:
• Tybost® 150 mg film-coated tablets
Fixed combinations of 150 mg each of cobicistat:
• Evotaz®: plus 300 mg atazanavir (approved in the EU but not marketed in many
countries).
• Genvoya®: plus 150 mg elvitegravir + 200 mg FTC + 10 mg TAF
• Rezolsta®: plus 800 mg darunavir (approved in the EU but not marketed in many
countries).
• Stribild®: plus 150 mg elvitegravir + 200 mg FTC + 300 mg TDF
• Symtuza®: plus 800 mg darunavir + 200 mg FTC + 10 mg TAF
Dose: Once daily, with a meal. No dose adjustment is required for renal impairment.
Creatinine increases (usually <0.4 mg/dl) due to inhibition of creatinine secretion
do not indicate renal function deterioration.
Adverse events: more hyperbilirubinemia with atazanavir than with ritonavir.
Interactions: As booster (potent CYP3A inhibitor and substrate), numerous inter-
actions! Do not combine with efavirenz, nevirapine, etravirine, and PIs other than
atazanavir or darunavir. No dose adjustment with rilpivirine. For maraviroc, 2 x 150
mg is sufficient. Contraindicated drugs include carbamazepine, rifampicin, ergota-
mine, amiodarone, simvastatin, lovastatin, St. John’s wort. Also, avoid sildenafil. The
list of contraindications is long!
Comment: The first pharmacoenhancer was developed only for boosting. Approval
for Elvitegravir, Darunavir (and Atazanavir). The single substance is hardly ever used
– as a rule, it makes no sense to take fixed combinations apart, and atazanavir is no
longer needed.
Drug Profiles 637

Combivir®
Original manufacturer: ViiV Healthcare. Various generics are available.
Approval and indication: In HIV infection as part of combination therapy in both
untreated and pretreated patients.
• Combivir® film tablets: 300 mg AZT + 150 mg 3TC (generic)
Dose: 2 x 1 tablet daily, regardless of meals. In case of impaired renal function (cre-
atinine clearance below 50 mL/min) or anemia, the single substances should be given
in reduced doses instead of Combivir®. For side effects, see especially AZT.
Comment: In 1998, the first combination drug, now an alternative only in rare
resistance situations. The twice-daily administration and the potential side effects of
AZT are significant drawbacks.

Cotrimoxazole
Manufacturer: Diverse, hence numerous trade names such as Cotrimstada® and
Eusaprim®.
Approval and indication: Prevention and therapy of Pneumocystis pneumonia.
Prophylaxis and treatment reserve in cerebral toxoplasmosis. Also, for other infec-
tions, for example urinary tract infections.
• Cotrim forte® tablets containing 160/800 mg trimethoprim/sulfamethoxazole
• Cotrim 480® tablets with 80/400 mg trimethoprim/sulfamethoxazole
• Eusaprim® oral suspension for adults (= 16/80 mg/mL), children (8/40 mg/mL)
• Cotrim ampoules® with 80/400 mg
Dose: As PCP prophylaxis, 80/400 mg daily or 160/800 mg trimethoprim/sul-
famethoxazole three times a week. As PCP therapy, 5 mg/kg (based on trimetho-
prim) orally or i.v. every 8 hours for 21 days, so usually 3 x 5 to 6 amp. of 80/400
mg. Toxoplasmosis prophylaxis: 160/800 mg daily. Halve dose at a creatinine clear-
ance of 15–50 mL/min, below which cotrimoxazole is contraindicated.
Adverse events: Allergies. In high doses, myelotoxicity (anemia, neutropenia!),
nausea, vomiting, headache, transaminase elevations. In the case of mild allergies,
treatment can often be continued.
Comment: Caution in case of sulfonamide allergy! Oral suspension can be used to
desensitize from 12.5, 25, 37.5, 50, and 75 to 100% of the dose of the 480 mg tablet
within six days. Cotrimoxazole may increase the effect of anticoagulants and reduce
that of oral contraceptives.

Crixivan® – first-generation PI, withdrawn from the market in 2019

Cymeven® see Ganciclovir

Daclatasvir, Daklinza® – rarely used HCV NS5A inhibitor

D4T, stavudine – toxic NRTI, was withdrawn from the market in 2019
638 Drugs

Dapsone
Manufacturer: Fatol.
Approval and indication: Prophylaxis of PCP and toxoplasmosis. It is rarely used
in dermatology (bullous pemphigoid), rheumatology, and leprosy.
• Dapsone-Fatol® 50 mg tablets
Dose: 100 mg daily after a meal. Alternative: 1 x 1 tbl. à 50 mg plus pyrimethamine
1 x 2 tbl. à 25 mg/wk plus folinic acid 1 x 2 tbl. à 15 mg/wk.
Adverse events: Allergies (itching, rash), fever. Frequently also hemolytic anemia
(LDH elevation almost obligatory!), hepatitis.
Comment: Reserve drug, contraindicated in severe anemia and G6PD deficiency.
LDH below dapsone is not diagnostically useful. Rifabutin and rifampicin decrease
dapsone levels.

Daraprim® see pyrimethamine

Darunavir
Original manufacturer: Janssen-Cilag. Generics for the single substance
Approval and indication: Untreated and pretreated adults (as single agent) and chil-
dren with HIV infection.
• Prezista® film-coated tablets of 400, 600, and 800 mg
• Prezista® 75 and 150 mg film-coated tablets, suspension (100 mg/mL) for children
• Rezolsta®: 800 mg plus 150 mg cobicistat (EU approval, not marketed in many
countries)
• Symtuza®: 800 mg plus 150 mg cobicistat, 200 mg FTC, 10 mg TAF
Dose: Daily 1 x 800 mg plus 1 x 100 mg ritonavir (or 1 x 150 mg cobicistat) each
with meal. In case of PI resistance mutations better 2 x 600 mg + 2 x 100 mg riton-
avir. Children: dose according to body weight. 20–30 kg 375 mg/50 mg RTV BID,
30–40 kg 450/60 mg, >40 kg 600 mg/100 mg BID.
Adverse events: Moderate gastrointestinal symptoms, especially diarrhea.
Dyslipidemia may not be as pronounced as with other PIs. Skin rash in up to 7% in
first two weeks, usually mild (therapy can be continued in most cases).
Interactions: Caution with sulfonamide allergy; do not start concurrently with
NNRTI (DD of allergic exanthema difficult). Various interactions – do not combine
with other PIs, St. John’s wort, simvastatin, terfenadine, midazolam, ergotamine,
rifampicin, phenobarbital, phenytoin, carbamazepine. Caution with anticoagulants,
no ticagrelor. Dose adjustment also with efavirenz (due to low darunavir levels 2 x
600/100 mg), rifabutin (reduce to 150 mg every other day), calcium antagonists
(increased levels), methadone (decreased). Interactions with contraceptive pills. Use
low doses of PDE5 inhibitors! Start atorvastatin and rosuvastatin at the lowest dose.
Comment: Well-tolerated, universally applicable PI with high resistance barrier and
activity also against PI-resistant viruses. Also available as STR since 2017. There are
numerous interactions to consider. The single agent is generic.
Detailed discussion in this book: page 69

Dasabuvir (Exviera®) – HCV NS5A inhibitor that is hardly ever used anymore
Drug Profiles 639

Daunorubicin (liposomal)
Manufacturer: Gilead Sciences, Fresenius.
Approval and indication: AIDS-associated Kaposi’s sarcoma with less than 200 CD4
T-cells/µl and extensive mucocutaneous or visceral involvement.
• DaunoXome® vials of 50 mg each (25 mL)
Dose: 40 mg/m2 in 250 mL 5% glucose solution (no other solutions!), intravenously
over 30–60 min, repeated every 2–3 weeks.
Adverse events: During infusion, back pain, flushing (flushing, up to 14%), dyspnea,
usually in the first few minutes, rapidly remitting with infusion stopped. Fatigue,
headache, myelosuppression, cardiomyopathy. Extravasation.
Warnings: Contraindicated in severe cardiomyopathy. Cardiac monitoring (ECG,
echo) before and during therapy is essential. Myelosuppression (neutrophils
<1,000/µl, platelets <50,000/µl).
Comment: In KS, an alternative to pegylated liposomal doxorubicin probably
slightly lower remission rates.

DDC (zalcitabine, HIVID®) – sales were discontinued in 2006

DDI (didanosine, Videx®) – sales were discontinued in 2020

Delavirdine (Rescriptor®) – NNRTI was never approved in Europe

Delstrigo®
Manufacturer: MSD.
Approval and indication: For adults and children 12 years of age and older (at least
35 kg) whose viruses do not show resistance to the individual substances.
• Delstrigo® film-coated tablets: 200 mg FTC + 300 mg TDF + 100 mg doravirine
Dose: 1 x 1 tablet daily, regardless of a meal. Do not use in renal dysfunction with
GFR less than 50 mL/min.
Adverse events: Rather rarely, sleep disturbances, abnormal dreams (less common
than with efavirenz), headache, and occasionally rash (see doravirine). Occasional
nausea. For renal dysfunction and osteoporosis, see tenofovir.
Interactions: Do not combine with rifabutin, rifampicin, various anticonvulsants
(including carbamazepine), and St. John’s wort (doravirine levels decrease). Caution
in severe hepatic insufficiency (Child C). No dose adjustment is necessary when com-
bined with PPIs. Effective in some typical NNRTI resistance despite indication restric-
tion (see above).
Comment: This fixed combination licensed in late 2018 has shed some of the draw-
backs of NNRTIs (higher resistance barrier, PPIs possible, no food restrictions).
Because of TDF, renal function must be considered.
Detailed discussion in this book: page 171
640 Drugs

Descovy®
Manufacturer: Gilead Sciences.
Approval and indication: HIV infection. Adults and adolescents (12 years and older,
weight at least 35 kg).
• Descovy® film-coated tablets: 10 mg or 25 mg TAF + 200 mg FTC
Dose: One tablet daily, meal-independent, unchewed. Two doses, depending on con-
comitant therapy! With boosted PIs (atazanavir, darunavir, lopinavir) and some other
substances (itraconazole!), 10 mg TAF (gray tablet!) is sufficient; otherwise, 25 mg
(blue!). Advise patients of the two doses to avoid mistakes.
Adverse events: Well tolerated, less nephrotoxic than Truvada®, and can be used up
to moderate renal impairment (GFR 30–60 mL/min). Less unfavorable effects on bone
density than TDF. Instead, there are no lipid-lowering effects, possibly slightly more
headache and probably also weight gain, especially in INSTI combinations (mecha-
nisms unclear).
Interactions: The 10 mg TAF should also be used with concomitant administration
of ketoconazole itraconazole. The concomitant administration of carbamazepine,
St. John’s wort, tipranavir, rifampicin, and rifabutin is not recommended (TAF levels
decrease!).
Comment: Approval in May 2016. TAF is less nephrotoxic than TDF (see Tenofovir)
but probably causes more weight gain. However, Descovy® has a cost problem since
the price drop of Truvada® generics; without a well-founded application to the health
insurance company, considerable co-payments loom! Note two dosages, frequent
source of error. Also HBV-effective.
Detailed discussion in this book: page 55

Dolutegravir
Manufacturer: ViiV Healthcare.
Approval and indication: PLWH, including adolescents over 6 years of age (at least
40 kg, dose-adapted), in combination with other agents. Dolutegravir is a compo-
nent of the following preparations in the dose of 50 mg:
• Dovato® Tablets 50 mg plus 300 mg 3TC
• Tivicay® tablets 50 mg (for children also 10 mg, 25 mg – only until 2024, also
5 mg dispersible tablets for preparation of a suspension)
• Triumeq® tablets50 mg plus 300 mg 3TC + 600 mg abacavir
• Juluca® tablets 50 mg plus 25 mg rilpivirine
Dose: 1 x 1 tablet of 50 mg daily, with or without a meal (Juluca® with a meal, because
of rilpivirine!). To overcome resistance or with certain comedications (see below),
increase the dose to 50 mg twice daily. No dose adjustment is necessary for renal
insufficiency. The pediatric dose is based on body weight.
Adverse events: CNS symptoms, including sleep disturbances, dizziness, and pares-
thesias lead to discontinuation in approximately 5% (more common than among
other INSTIs). Occasional headache, nausea, increase in transaminases and CK.
Weight gain (mechanism unclear).
Interactions: In combination with efavirenz, nevirapine, fosamprenavir, tipranavir
and rifampicin, 2 x 50 mg dolutegravir should be given. Avoid these combinations
if the dolutegravir dose must be increased anyway due to resistance! Combination
Drug Profiles 641

with etravirine only in the presence of boosted PIs. Do not combine with St. John’s
wort, antiepileptic drugs. Antacids only to be taken with a significant time delay.
Reduce metformin dose if necessary (metformin levels rise!).
Comment: In 2014, it was the first integrase inhibitor that does not require a booster
and can still be given once daily. Universal and flexible use in various fixed combi-
nations or dual therapies, mostly well tolerated, with few interactions and a high
resistance barrier.
Detailed discussion in this book: page 76

Doravirine
Manufacturer: MSD.
Approval and indication: Adult PLWH and children 12 years and older (at least
35 kg) without resistance to NNRTIs.
• Pifeltro® 100 mg film-coated tablets
• Delstrigo® film-coated tablets: 100 mg doravirine + 300 mg TDF + 300 mg 3TC
Dose: 1 x 100 mg daily, regardless of meals.
Adverse events: Relatively well tolerated, fewer CNS symptoms (dizziness, sleep
disturbances) than with efavirenz. Headache, gastrointestinal complaints, and
exanthema/rash are all relatively rare. For the fixed combination, see also tenofovir.
Interactions: Strong enzyme inducers such as carbamazepine, rifampicin, rifabutin,
and St. John’s wort are contraindicated. Combination with PPIs, however, is possi-
ble. There is no data for pregnancy. Doravirine can be combined with all antiretro-
viral drugs without dose adjustment. The combination tablets are relatively large.
Comment: New NNRTI that has overcome some weaknesses of this substance group.
Relatively high resistance barrier, no food restrictions, combination with other anti-
retroviral agents and PPIs possible.
Detailed discussion in this book: page 60

Dovato®
Manufacturer: ViiV Healthcare.
Approval and indication: HIV infection, adults and adolescents over 12 years of
age (at least 40 kg), without resistance to INSTIs and 3TC.
• Dovato® film-coated tablets: 300 mg 3TC + 50 mg dolutegravir
Dose: One tablet daily, regardless of meals. Avoid a creatinine clearance of less than
30 mL/min; here, use the single substances and dose individually.
Adverse events: Overall, well tolerated; see single agents for details. Occasional sleep
disturbances are possible with dolutegravir.
Interactions, warnings: In case of INSTI resistance and in salvage regimens with
efavirenz, etravirine, nevirapine, and tipranavir, rather avoid (dolutegravir would
have to be doubled to BID here). This also applies to rifampicin, carbamazepine, or
St. John’s wort. It is not recommended for moderate to severe hepatic impairment.
Caution with metformin (reduce dose if necessary). In first-line therapy, only in
people without hepatitis B, with less than 500,000 copies/mL and more than
200 CD4 T-cells/µl.
642 Drugs

Comment: This was the first dual regimen for treatment-naïve patients in 2019.
Equivalent to triple combinations even in pretreated, high resistance barrier. Caution
in active hepatitis B (3TC alone is not sufficient).
Detailed discussion in this book: page 177, 201

Doxorubicin (liposomal)
Manufacturer: Janssen-Cilag.
Approval and indication: including AIDS-associated Kaposi’s sarcoma with <200
CD4 T-cells/µl and extensive mucocutaneous or visceral involvement.
• Caelyx® 10 mL (20 mg) and 25 mL (50 mg) vials
Dose: 20 mg/m² i.v. in 250 mL 5% glucose over 30 min, every 2–3 weeks.
Adverse events: Cardiomyopathy. Myelosuppression and stomatitis (rarely severe),
palmar-plantar erythrodysesthesia (PPED, hand-foot syndrome), therapy: cooling of
affected areas. Cave extravasation (never s.c./i.m./bolus administration!).
Interactions, warnings: Contraindicated in severe bone marrow depression (neu-
trophils <1,000/µl, platelets <50,000/µl), cardiomyopathy, prior therapy with anthra-
cycline doses above the cumulative dose. ECG and cardiac echo (EF?) before and
during treatment, cumulative dose of 450 mg/m² and above before each cycle. PPED
is promoted by sweating – avoid tight gloves, sun, sauna, and long showers with hot
water. Detailed instructions for dose modification for PPED in the package insert.
The substance is expensive.

Dutrebis® see raltegravir

Edurant® see rilpivirine

Efavirenz
Manufacturers: BMS (Sustiva®); MSD (Stocrin®); Gilead/BMS/MSD (Atripla®). Generic
drugs are also available.
Approval and indication: HIV infection.
• Sustiva® 600 mg film-coated tablets (Generic)
• Sustiva® 50 mg, 100 mg, 200 mg hard capsules
• Sustiva® Oral solution (30 mg/mL, 180 mL = 5.4 g)
• Atripla® film-coated tablets 600 mg plus 200 mg FTC + 300 mg tenofovir DF
Dose: 600 mg daily just before bedtime, on an empty stomach. See the Pediatrics
chapter for dose adjustment in children/adolescents under 40 kg.
Adverse events: CNS symptoms common in the first few weeks: nightmares, con-
fusion, dizziness, lightheadedness, depression, difficulty concentrating, insomnia,
and feelings of depersonalization. Also, exanthema (15%) within the first weeks,
usually mild, usually further treatment possible. Increase in liver and bile levels (yGT).
Dyslipidemia, occasionally painful gynecomastia.
Interactions, warnings: Caution in women of childbearing age. Do not take with
high-fat meals (possibly higher absorption and side effects). No concomitant admin-
istration with ergotamines, astemizole, cisapride, midazolam, terfenadine and tria-
zolam. If combined with rifampicin, increase efavirenz to 800 mg; if combined with
rifabutin, increase the rifabutin dose by 50%. If combined, dose increases of darunavir
Drug Profiles 643

(2 x 600 mg BID) and maraviroc (2 x 600 mg if not given boosted PI). Combination
with atazanavir is not recommended.
Comment: This NNRTI has been prescribed for a long time but is rarely used due to
CNS adverse events. It is to be considered in first-line therapy only with concurrent
TB therapy. Inexpensive generics available.
Detailed discussion in this book: page 61

Elbasvir see Zepatier®

Elvitegravir
Manufacturer: Gilead Sciences.
Approval and indication: Adult PLWH without integrase resistance. Elvitegravir is
a component of the following film-coated tablets:
• Vitekta® with 85 or 150 mg elvitegravir (not marketed in many countries)
• Stribild® with 150 mg elvitegravir, 150 mg cobicistat, 200 mg FTC, 300 mg TDF
• Genvoya® with 150 mg elvitegravir, 150 mg cobicistat, 200 mg FTC, 10 mg TAF
Dose: With each meal, unchewed. The single agent elvitegravir (EU approval, but
not marketed in most countries) must be dosed differently: Either 85 mg (for
atazanavir/r, lopinavir/r) or 150 mg (darunavir/r 600/100 BID, fosamprenavir/r).
Once daily, with the first dose of the day for PIs.
Adverse events: Well tolerated, most likely nausea, diarrhea, headache.
Nephrotoxicity is to be noted, especially with Stribild® and Genvoya® (see there).
Probably also weight gain.
Interactions: Elvitegravir is metabolized by CYP3A and others. Do not combine with
rifampicin, carbamazepine, phenytoin, St. John’s wort. Caution also with efavirenz
and nevirapine! Plasma concentration is strongly increased by atazanavir and
darunavir, therefore, dose reduction (see above).
Comment: Integrase inhibitor that needs to be boosted. Broad cross-resistance with
raltegravir. Single-agent is irrelevant; FDCs Stribild® and Genvoya® are rarely initi-
ated due to interaction issues.
Detailed discussion in this book: page 77

Emtricitabine (FTC)
Manufacturer: Gilead Sciences (collaborations with Janssen, among others), gener-
ics.
Approval and indication: HIV infection.
Emtriva® hard capsules: 200 mg FTC, solution: 10 mg FTC per mL
With 200 mg of each component of the following combination preparations (film-
coated tablets)
• Descovy®: plus 10 or 25 mg TAF
• Truvada®: plus 300 mg tenofovir DF (TDF), generic!
Each containing 200 mg of the following STRs/fixed combinations (film-coated
tablets)
644 Drugs

• Atripla®: plus 300 mg TDF + 600 mg efavirenz (generic).

• Biktarvy®: plus 25 mg TAF + 50 mg bictegravir
• Eviplera®: plus 300 mg TDF + 25 mg rilpivirine
• Genvoya®: plus 10 mg TAF + 150 mg elvitegravir + 150 mg cobicistat
• Odefsey®: plus 25 mg TAF + 25 mg rilpivirine
• Stribild®: plus 300 mg TDF + 150 mg elvitegravir + 150 mg cobicistat
• Symtuza®: plus 10 mg TAF + 800 mg darunavir + 150 mg cobicistat
Dose: 1 x 200 mg daily. In case of decreased creatinine clearance, use single prepa-
ration, dose as follows: 200 mg every two days for GFR 30–49 mL/min, 15–20 mL/min
every three days, below 14 mL/min, or dialysis every four days.
Adverse events: Rare, most likely headache, nausea, diarrhea, rash. Possibly also
hyperpigmentation.
Comment: Well-tolerated cytidine analog, biochemically and in the resistance spec-
trum similar to 3TC, but with a longer half-life. Component of various combination
preparations, the single preparation has no significance. Generics are available for
some preparations.
Detailed discussion in this book: page 51

Enfuvirtide see T-20

Epivir® see 3TC (at the beginning of the drug section)

Epclusa®
Manufacturer: Gilead Sciences.
Approval and indication: Chronic hepatitis C, all genotypes. Combine with rib-
avirin in certain situations (see chapter Hepatitis).
• Epclusa® film-coated tablet: 400 mg sofosbuvir and 100 mg velpatasvir
Dose: 1 x 1 tablet daily, regardless of food intake. No dose adjustment in mild/mod-
erate renal impairment or in moderate or severe hepatic impairment.
Adverse events: Well-tolerated, nausea, headache, fatigue, hardly more frequent
than with placebo.
Interactions: 12 weeks (in compensated cirrhosis and GT3 with additional ribavirin).
Do not combine with efavirenz, etravirine, nevirapine (decrease velpatasvir con-
centration), St. John’s wort. Maintain time intervals with PPIs. Combination with
boosted PIs is possible.
Comment: Combination (NS5A inhibitor and polymerase inhibitor) approved in
July 2016 for chronic hepatitis C. Effective against all genotypes. Similar efficacy and
safety profile to Harvoni®, but equally high cost.
Drug Profiles 645

Ethambutol
Manufacturer: Riemser, Fatol and others.
Approval and indication: Tuberculosis and MAC infections, always in combina-
tion!
• EMB-Fatol® Film bl. containing 100 mg, 250 mg, 400 mg and 500 mg (N2:50;
N3:100).
• EMB-Fatol® solution for injection with 1 g in 10 mL (N2:10)
• Myambutol® film-coated tablets 400 mg (N2:50; N3:100)
• Myambutol® Injection solution containing 400 mg/4 mL (N2:10) and 1,000 mg/
10 mL (N2:5).
Dose: Daily 15 to 25 mg/kg (maximum 2 g), usually 1 x 3 tablets of 400 mg. In com-
bination therapies only. Dose reduction if creatinine clearance is below 75 mL/min
to 15 mg/kg, below 40 ml/min to 15 mg/kg every other day. Above a GFR of
30 mL/min individually, level determinations.
Adverse events: Optic neuritis with visual disturbances (decreased vision, visual field
loss, and loss of red-green color vision) is reversible if ethambutol is discontinued
immediately. Nausea, vomiting, abdominal pain, headache, dizziness. Pruritus, joint
pain, elevated serum uric acid levels (acute gout attacks possible!), abnormal liver
function tests.
Warnings: Ethambutol is contraindicated in the presence of pre-existing optic nerve
damage. Ophthalmologic examination before initiation of therapy and at 4-week
intervals thereafter (color vision, visual field, visual acuity). If drug-induced visual
disturbances occur, discontinue the drug immediately to avoid optic atrophy. Check
liver values and uric acid monthly.

Etravirine
Manufacturer: Janssen-Cilag.
Approval and Indication: Pretreated adults and children 6 years of age and older.
Only in ART combinations containing a boosted PI.
• Intelence® 200 mg and 100 mg (25 mg tablets for children)
Dose: 2 x 200 mg (2 x 1 pill) after a meal.
Adverse events: Mostly mild rash in the second week, rarely nausea. In mild man-
ifestations, treatment can usually be continued. Discontinue immediately in severe
exanthema, isolated cases of TEN and DRESS syndrome.
Interactions: The tablets are dissolvable in water. Etravirine is a substrate of the CYP
P450 enzyme system, but at the same time, an inducer of CYP3A4 and an inhibitor
of CYP2C9 – thus, numerous interactions are expected. Do not combine with
atazanavir, tipranavir, other NNRTIs. Also, avoid rifampicin, carbamazepine, phe-
nobarbital, phenytoin, and St. John’s wort.
Comment: The first second-generation NNRTI was approved in 2008 for pretreated
patients. It is well tolerated and effective against NNRTI-resistant viruses (K103N!).
Always combine with a boosted PI (darunavir!).
Detailed discussion in this book: page 62
646 Drugs

Eviplera® (USA: Complera®)

Manufacturer: Gilead Sciences.
Approval and indication: Adult PLWH (if untreated, only if less than 100,000 HIV-
RNA copies/mL).
• Eviplera® film-coated tablets: 200 mg FTC + 300 mg TDF + 25 mg rilpivirine
Dose: 1 x 1 tablet daily, with a meal (at least 400 calories) to achieve adequate absorp-
tion. Do not use in renal dysfunction with creatinine clearance <50 mL/min.
Adverse events: Rare, most likely rash (see rilpivirine). Occasionally nausea. It is
better tolerated than efavirenz, but CNS disturbances occur (depression). For renal
dysfunction, see tenofovir.
Interactions: Do not combine with rifabutin, rifampicin, various anticonvulsants
(including carbamazepine), PPIs, and St. John’s wort (rilpivirine levels decrease). Keep
time away from H2 antagonists and antacids. Due to the increased risk of resistance,
do not use it if the viral load is high.
Comment: Approved as a second single-tablet regimen in 2011. Avoid if viral load
is high; always ensure adequate absorption (meal! No PPIs!). Has been replaced mainly
by Odefsey® (TAF instead of TDF) since 2016.
Detailed discussion in this book: page 171

Evotaz® see atazanavir or cobicistat

Exviera® – no longer plays a role in hepatitis C

Fluconazole
Manufacturer: Pfizer and various other companies. Many trade names.
Approval and indication: Candidiasis, cryptococcosis, and some rare mycoses.
• Fluconazole capsules® with 50, 100, 150 and 200 mg
• Diflucan® 40 mg/mL and 10 mg/mL, powder for oral suspension
• Fluconazole infusion vials with 100, 200 and 400 mg
Dose: Orally 1 x 100 mg daily for oropharyngeal candidiasis, 1 x 200 mg for 7–10
days for esophagitis. Double the dose on the first day. If persistent after 10 days, try
a higher dose (up to 800 mg daily).
Cryptococcal meningitis: Initially 400–800 mg daily, combined with flucytosine and
amphotericin B. After acute treatment (6 weeks), 200 mg daily. Reduce dose to 50%
(25%) at creatinine clearance of 10–50 mL/min (<10).
Adverse events: Rarely gastrointestinal discomfort and transaminase elevations.
Reversible alopecia in about 10% at doses above 400 mg/day.
Interactions: No effect against C. krusei, aspergilli. Use higher doses for C. glabrata.
Reduced fluconazole levels with rifabutin/rifampicin. Fluconazole increases levels of
rifabutin, atovaquone, clarithromycin, theophylline, opiates, marcumar, benzodi-
azepines, cyclosporine, anticonvulsants, and AZT.
Comment: Agent of choice for candidiasis and for secondary prophylaxis of
cryptococcosis (also acute therapy). The tablets are well absorbed; infusions are only
useful in case of poor adherence/absorption or severe mucositis.

Fortovase® see Saquinavir

Drug Profiles 647

Fosamprenavir
Manufacturer: ViiV Healthcare (formerly GlaxoSmithKline).
Approval and indication: Adult PLWH and children 6 years of age and older, treat-
ment-naïve and pre-treated.
• Telzir® 700 mg film-coated tablets (US: Lexiva®)
• Telzir® Suspension with 50 mg/mL (225 mL bottle)
Dose: 2 x 700 mg + 2 x 100 mg ritonavir (2 x 2 pills), independent of a meal. Other
dosages are not approved in Europe.
Adverse events: most commonly diarrhea. Less commonly, nausea, vomiting, and
rash (up to 20%). Rarely Stevens-Johnson syndrome (<1%).
Interactions: Numerous interactions! Contraindications include midazolam, ergot-
amine, flecainide, propafenone, rifampicin, St. John’s wort, simvastatin, carba-
mazepine. Life-threatening interactions are possible with amiodarone, lidocaine, tri-
cyclic antidepressants, and quinidine.
Comment: formerly much-used PI that no longer has a role due to diarrhea and
twice-daily administration. Distribution is expected to be discontinued in 2024.

Foscarnet
Manufacturer: AstraZeneca.
Approval and indication: Reserve agent for induction and maintenance therapy of
CMV retinitis. Severe, acyclovir-resistant herpes or varicella-zoster infections.
• Foscavir® infusion bottles of 250 mL containing 24 mg/mL
Dose: During induction therapy (2–3 weeks) of CMV retinitis, 2 x 90 mg/kg i.v. daily
over at least 2 hours. Maintenance therapy: 1 x 90–120 mg/kg daily over 2 hours.
HSV and VZV: 2 x 60 mg/kg i.v. for 2 weeks.
Adverse events: Nephrotoxicity! Mostly reversible after discontinuation. Electrolyte
shifts (hypocalcemia, hypokalemia) are also common. Less commonly, anemia, neu-
tropenia, fever, rash, headache, nausea, vomiting, diarrhea. Often painful penile
ulcers (washing after each urination!).
Notes, rating: Hydration! At least 2.5 liters daily. To prevent hypocalcemia, infuse
one ampule of 10% calcium solution in 100 mL of 5% glucose immediately before
infusion. Give 500–1,000 mL of 5% glucose before or after administration. Do not
mix infusions. Initially check Na, K, Ca, creatinine, and blood count 3 x/week.
Do not combine with other nephrotoxic substances; adjust the dose in case of renal
insufficiency.

Fostemsavir
Manufacturer: ViiV Healthcare.
Approval and Indication: In Europe, approval is “for the treatment of adults with
multidrug-resistant HIV-1 infection for whom no other suppressive antiretroviral
treatment regimen is available.”
• Rukobia® 600 mg sustained-release tablets
Dose: One tablet twice daily, with or without meal. No dose adjustments are neces-
sary for renal or hepatic insufficiency.
648 Drugs

Adverse events: Well-tolerated in studies to date. Rarely headache, nausea, vomit-

ing, diarrhea, mostly mild. CK and GPT elevations.
Interactions: No experience in pregnancy. Do not combine with potent enzyme
inducers such as carbamazepine, rifampicin, phenytoin, mitotane, enzalutamide,
and St. John’s wort, including elbasvir/grazoprevir. The TAF dose should be 10 mg.
Comment: With its approval in 2021, it has been the first oral attachment inhibitor
on the market. Important, well-tolerated option for multidrug-resistant viruses. Very
limited indication.
Detailed discussion in this book: page 83, 218

Fuzeon® see T-20

Ganciclovir
Original manufacturer: Hoffmann-La Roche. Generics.
Approval and indication: CMV retinitis.
• Cymeven® Injection vials containing 500 mg
Dosage: Acute therapy with normal renal function: Daily 2 x 5 mg/kg as i.v. infu-
sion over one hour. Duration of treatment: 14 to 21 days. Maintenance therapy:
Daily 1 x 6 mg/kg i.v. 5 days a week.
Adverse events: Leukopenia, anemia, and thrombocytopenia are dose-limiting. Less
frequently, nausea and vomiting. Central nervous complaints such as confusion.
Interactions: Check blood counts every two days. Discontinue if neutrophils are
below 500/µl (G-CSF if necessary). Contraindication in case of neutropenia <500/µl,
thrombocytopenia <25,000/µl, and concurrent chemotherapy. Caution with AZT
(increased toxicity!). Teratogenic. Adjust the dose if renal function is impaired.
Comment: Often preferred to oral valganciclovir in acute virus-threatening lesions,
otherwise used only in exceptional cases.

Genvoya®
Manufacturer: Gilead Sciences.
Approval and indication: Adult PLWH, including children of 12 years and older
(35 kg) without resistance mutations.
• Genvoya® film-coated tablets containing 150 mg elvitegravir, 150 mg cobicistat,
200 mg FTC, 10 mg tenofovir AF
Dose: One tablet daily, with food, unchewed.
Adverse events: Overall well tolerated, most likely headache, diarrhea. Cobicistat
inhibits tubular secretion of creatinine and thus may mimic mild renal dysfunction.
Weight gain (mechanism unclear).
Interactions: Can be given up to a GFR of 30 mL/min (discontinue below that!);
Stribild® strict renal monitoring is not required. However, cobicistat is a potent CYP3A
inhibitor. Substances such as lovastatin, simvastatin, midazolam, carbamazepine,
rifampicin, and St. John’s wort should be avoided. No other antiretroviral agents.
Drug Profiles 649

Distance of 4 hours from antacids and multivitamins. Choose low doses for azoles,
rifabutin, calcium antagonists, and PDE-5 inhibitors.
Comment: In January 2016, the first TAF-containing combination. Has replaced the
TDF-containing (otherwise identical) Stribild®. However, it is rarely used due to the
booster (interactions) and a relatively low resistance barrier. In recent years, it has
been mainly replaced by Biktarvy®.
Detailed discussion in this book: page 83

Glecaprevir see Maviret®

Grazoprevir see Zepatier®

Harvoni®
Manufacturer: Gilead Sciences.
Approval and indication: a fixed-dose combination of the NS5B polymerase
inhibitor sofosbuvir and the NS5A inhibitor ledipasvir, usually for 12 weeks in geno-
types 1, 4, 5, 6. In therapy-naive patients with GT1 without cirrhosis and low viral
load, 8 weeks are also possible.
• Harvoni® film-coated tablets containing 400 mg sofosbuvir and 90 mg ledipasvir
Dose: 1 x 1 tablet daily, regardless of meals. No dose adjustment in renal impair-
ment up to a GFR of 30 mL/min; avoid below.
Adverse events: Headache, fatigue, nausea (usually mild).
Interactions: Life-threatening cardiac arrhythmias with amiodarone. Sofosbuvir and
ledipasvir are not metabolized by the cytochrome P450 system and can be combined
with most ART regimens. Tenofovir levels may increase with boosted regimens. Avoid
potent intestinal P-gp inducers such as carbamazepine, St. John’s wort, or rifampicin.
Comment: Well-tolerated fixed combination that is very effective, especially in geno-
types 1 and 4. Few interactions with ART. Like all DAAs, it is expensive. In recent
years, it has been largely displaced by pangenotypic DAAs.

HIVID® see DDC – no longer on the market

Ibalizumab
Manufacturer: TaiMed Biologics (together with Theratechnologies)
Approval and Indication: Reserve agent indicated for “adults with multidrug-resis-
tant HIV-1 infection in whom no other suppressive antiviral regimen can be com-
posed.”
Dose: Starting dose of 2,000 mg i.v. (10 ampoules) over at least 30 min, followed by
a maintenance dose of 800 mg (4 ampoules) over at least 15 min every 2 weeks, after
dissolution in 250 mL NaCl each. There is no data on hepatic and renal insufficiency,
but administration is probably possible.
Adverse events: Limited experience in a few hundred people. The most common
are diarrhea, dizziness, nausea, and rash. Infusion Reactions: Monitor for one hour
after loading dose; maintenance doses possible over 15 min if well tolerated.
650 Drugs

Notes: Ampoules should be stored in the refrigerator (2–8 degrees). Dissolved prepa-
ration can be stored at room temperature for a maximum of 4 hours and in the refrig-
erator for 24 hours. Resaturation is necessary if maintenance administration is
delayed by at least three days. There is no data on interactions, but these are rather
unlikely.
Comment: Monoclonal antibody against CD4 that must be infused every two weeks.
Narrow indication, very expensive, no longer marketed in Europe since 2022, only
available as an import.

Indinavir – PI withdrawn from the market at the end of 2019

Intelence® see Etravirine

Interferon alpha 2a/2b

Manufacturers: Various, such as Roche Schering Plough.
Approval and indication: chronic hepatitis C (no longer in use), chronic hepatitis B
(rarely used). It is also effective in Kaposi’s sarcoma (if CD4 T-cells >250/µl), but no
official approval.
• Pegasys®: prefilled syringes with 135, 180 µg interferon alpha-2b
Dose: Pegasys® 180 µg 1 x per week. Subcutaneous administration. No longer in use
for HCV. HBV: 48 weeks. Treatment duration in KS depends on success.
Adverse events: Fever, muscle pain. Depression (suicidality!), fatigue, sleep, and per-
sonality disorders. Anemia, thrombocytopenia, and leukopenia. Autoimmune thy-
roiditis. Reversible hair loss.
Interactions, warnings: flu-like symptoms a few hours after administration are alle-
viated by paracetamol. Contraindications are severe cardiac, hepatic, thyroid, or renal
dysfunction, bone marrow damage, and CNS disorders (e.g., seizure disorders and
depression). Check blood count initially every two weeks, later monthly. TSH every
three months. Interferons must be stored in the refrigerator. Has also a moderate
antiretroviral effect.
Comment: Obsolete for hepatitis C, rarely used in hepatitis B. For KS and multidrug-
resistant HIV infection, it is still useful in rare cases. However, use is off-label (and
has many side effects).

Invirase® see Saquinavir

Isentress® see Raltegravir

Isoniazid
Manufacturer: Various. Different trade names.
Approval and indication: Combination treatment of tuberculosis. Prophylactic
therapy for people with a high risk of TB (positive reaction to a skin test, close contact
with persons with newly diagnosed infectious TB, etc.; recommendations may vary)
• Isozid comp® film-coated tablets containing 200, 300, 400 mg INH and 40, 60, 80 mg
vitamin B6 (pyridoxine HCl)
• Also in various combination preparations (see rifampicin).
Drug Profiles 651

Dose: 1 x 200 to 300 mg (4 to 5 mg/kg, maximum 300 mg) orally daily, i.v. only in
severe cases during the first two weeks of therapy. For prevention of peripheral neu-
ropathies, 100 mg pyridoxine orally once daily. In children: 1 x 6 (up to 10) mg/kg
daily, maximum 300 mg.
Adverse events: Toxic hepatitis is more frequent in the elderly, people with liver
disease, and alcohol abuse. Cave peripheral neuropathy! INH should then be dis-
continued, followed by several weeks of pyridoxine and vitamin B12. Psychosis, CNS
symptoms. Fever, rash, nausea/vomiting, pancytopenias.
Interactions, warnings: Contraindicated in acute hepatitis and with a history of
INH-induced hepatopathy, pronounced febrile reactions, peripheral neuropathy, and
macrohematuria. Always combine with vitamin B6.
Various interactions with barbiturates, cycloserine, theophylline, phenytoin, and
rifampicin, the dose of which may need to be reduced due to CNS disturbances.
Decreased absorption with concomitant administration of aluminum-containing
antacids. Caution with alcohol.
Initially, check blood count, transaminases (TA), bilirubin, and kidney function every
two weeks. Discontinue isoniazid if TA increases to more than three times baseline
and symptoms occur; if it increases 5-fold, discontinue even without symptoms.

Itraconazole
Manufacturer: Various. Various trade names.
Approval and indication: Histoplasmosis, aspergillosis, resistant Candida infections
(2nd choice). Also for derma/nail mycoses.
• Sempera Capsules® à 100 mg
• Sempera Liquid® 10 mg/mL suspension (150 mL)
Dose: Fluconazole-resistant candidiasis: 1–2 x 100 mg (up to 2 x 200 mg) daily, prefer-
ably as suspension. Histoplasmosis, aspergillosis daily 2 x 200 mg/day.
Adverse events: Nausea, vomiting, exanthema, dizziness. Toxic hepatitis.
Notes: To increase absorption, take capsules immediately after a full meal. Do not
co-administer with H2 blockers, antacids, rifampicin, rifabutin, carbamazepine,
phenytoin, simvastatin, lovastatin, and INH (decrease bioavailability of itracona-
zole). Itraconazole increases serum levels of cyclosporine, calcium antagonists,
digoxin, lovastatin, simvastatin, and indinavir. Negative inotropic effect, do not use
in heart failure.
Comment: Due to numerous interactions and uncertain plasma levels, it hardly
plays a role anymore. However, compared to fluconazole, it is effective against many
non-albicans strains, aspergilli, and histoplasmosis.

Juluca®
Manufacturer: ViiV Healthcare (a joint distribution with Janssen-Cilag).
Approval and Indication: Adult PLWH on stable, virologically successful ART (at
least six months), without prior treatment failure or resistance to rilpivirine or dolute-
gravir.
• Juluca® film-coated tablets containing 50 mg dolutegravir plus 25 mg rilpivirine
Dose: 1 tablet daily, unchewed, with a meal. No dose adjustment up to a creatinine
652 Drugs

clearance of 30 mL/min; administration is also possible in mild to moderate hepatic

impairment.
Adverse events: In the SWORD trials, predominantly mild or moderate at the switch,
rarely leading to discontinuation. Mainly gastrointestinal and neuropsychiatric (see
also individual substances).
Interactions: No concomitant administration with PPIs (see also rilpivirine), some
anticonvulsants (carbamazepine), St. John’s wort, and rifampicin, among others.
When combined with rifabutin, an additional 25 mg of rilpivirine is recommended.
Caution with metformin (maximum dose 1,000 mg). Individuals with hepatitis B
may show rebounds as Juluca® does not contain HBV active substance.
Comment: The first NRTI-free, dual “maintenance therapy” in a fixed combination
was approved in 2018. Indication restrictions (only with “stable” pretreatment) and
dietary restrictions must be considered.
Detailed discussion in this book: page 200

Kaletra® see Lopinavir

Kivexa® (US: Epzicom®)

Original manufacturer: ViiV Healthcare. Generics available.
Approval and indication: HIV infection.
• Kivexa® film-coated tablets containing 600 mg abacavir plus 300 mg 3TC
Dose: 1 tablet daily. In case of impaired renal function (GFR below 50 mL/min),
we prefer to give single substances to adjust the 3TC dose.
Adverse events: Hypersensitivity reaction (HSR) to abacavir (see there!). Probably
slightly increased risk of myocardial infarction (abacavir).
Comment: Formerly much-used combination preparation, recently used less fre-
quently. HLA testing is obligatory, probably because of its prothrombogenic prop-
erties, and therefore, to be used with caution in cardiovascular risk. See otherwise
also under 3TC and abacavir.
Detailed discussion in this book: page 55

Lamivudine see 3TC (at the beginning of the drug section)

Ledipasvir see Harvoni®

Lenacapavir
Manufacturer: Gilead.
Approval and Indication: Adults with multidrug-resistant HIV-1 infection for whom
a suppressive ART regimen cannot otherwise be established.
• Sunlenca® vial (463.5 mg lenacapavir in 1.5 mL)
• Sunlenca® Tablets 300 mg
Dose: On days 1 and 2, each 600 mg as tablets; on day 8 then 300 mg as a tablet,
each independent of a meal. On day 15, then 927 mg as a subcutaneous abdominal
injection (2 x 1.5 mL injections). Continue 927 mg every 6 months (± 2 weeks). No
dose adjustment up to a GFR of 15 mL/min.
Drug Profiles 653

Adverse events: Overall, well tolerated. Pain and swelling at injection sites are very
common but rarely lead to discontinuation. Median duration six days. Nodules and
indurations may persist for months, however. Also nausea.
Interactions: Lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1. Do not co-
administer rifampicin, rifabutin, carbamazepine, phenytoin, St. John’s wort. Also not
with efavirenz, nevirapine, etravirine, atazanavir/c, or tipranavir/r! Steroids low dose,
also simvastatin.
Comment: In 2022, lenacapavir was the first-in-class capsid inhibitor, with six-
month subcutaneous injections. Important new option in multidrug resistance,
limited indication.
Detailed discussion in this book: page 92, 219, 274

Lopinavir
Original manufacturer: AbbVie. Generic available.
Approval and indication: HIV infection, in adults and children over 2 years of age.
• Kaletra® film-coated tablets containing 200 mg lopinavir + 50 mg ritonavir
• Kaletra® film-coated tablets containing 100 mg lopinavir + 25 mg ritonavir
• Kaletra® solution containing 80 mg lopinavir + 20 mg ritonavir per mL
Dose: 1 x 4 tablets (800 mg lopinavir/200 mg ritonavir) regardless of meals. In the
case of PI resistance, it is better to use 2 x 2 tablets. The 100 mg tablets were devel-
oped for children (also as Aluvia®). In combination with efavirenz (probably also
nevirapine), the dose must be increased to 2 x 500/125.
Adverse events: Primarily diarrhea, nausea, dyslipidemias. Less commonly headache,
elevations of transaminases.
Notes: The solution contains ethanol and should be stored in the refrigerator.
Numerous interactions! Many drugs metabolized CYP3A- or CYP2D6-mediated are
contraindicated, including flecainide, propafenone, terfenadine, ergotamine, cis-
apride, and midazolam. Rifampicin and St. John’s wort reduce efficacy. Cave sim-
vastatin, carbamazepine, phenobarbital, or sildenafil (blood pressure drop), amio-
darone, Marcumar, lidocaine, tricyclic antidepressants, cyclosporine, tacrolimus.
Level determinations in case of impaired liver function.
Comment: Formerly much-used PI. Now rarely used due to common side effects
(diarrhea and dyslipidemias), interactions, and pill count.
Detailed discussion in this book: page 69

Maraviroc
Manufacturer: ViiV Healthcare.
Approval and indication: Pre-treated adults with CCR5-tropic HIV (in the US also
therapy-naïve). Also, children 2 years and older (at least 10 kg).
• Celsentri® 150 and 300 mg tablets (25 and 75 mg for children).
• Celsentri® solution with 20 mg/mL
Dose: 300 mg twice daily regardless of food intake (in children, the dose is based on
body weight). Dose adjustments depending on concomitant ART:
654 Drugs

Concomitant drug Maraviroc dose

Doravirine, tenofovir, other NRTIs, dolutegravir, fostemsavir 2 x 300 mg
Efavirenz (or rifampicin without concomitant PI or other potent 2 x 600 mg
CYP3A4 inhibitors
Strong CYP3A4 inhibitors: boosted PIs and elvitegravir/c, but also 2 x 150 mg
itraconazole, ketoconazole, and clarithromycin
Efavirenz plus concurrent PI 2 x 150 mg
In the combination, the dose is based on the PI; in the combination of inhibitor and inducer, the
inhibitor dominates

In impaired renal function, no dose adjustment is necessary up to a GFR of 30 mL/min;

avoid below. With concomitant administration of a potent CYP3A4 inhibitor above
a GFR of 80 mL/min, only 150 mg once daily.
Adverse events: Well-tolerated, rarely headache, dizziness, fatigue, nausea. In high
doses, orthostatic hypotension. Isolated reports of CK elevations.
Hints: A prior tropism test (also from proviral DNA) is obligatory! Concomitant
administration of maraviroc with rifampicin plus efavirenz is not recommended.
Caution with concomitant administration of INH plus cotrimoxazole (hepatotoxic-
ity). St. John’s wort may decrease maraviroc levels; avoid it.
Comment: The only CCR5 antagonist in HIV therapy to date. Pretreatment only.
Excellent tolerability, but complicated dose regimen depending on concomitant
therapy. Prior tropism determination is mandatory.
Detailed discussion in this book: page 87

Maviret®
Manufacturer: AbbVie.
Approval and indication: Chronic hepatitis C, 12 years and older.
• Maviret® film-coated tablets containing 100 mg glecaprevir and 40 mg pibrentasvir
Dose: 1 x 3 tablets (300/120 mg) daily, together with a meal. No dose adjustment in
any renal impairment up to dialysis. No adjustment in mild hepatic impairment;
not recommended in cirrhosis child B/C.
Adverse events: Like all DAAs, quite well tolerated, most likely headache, diarrhea,
fatigue, asthenia.
Interactions: Duration of therapy is 8 weeks; in case of compensated liver cirrhosis,
12 weeks. With pretreatment and genotype 3 also 16 weeks. Many interactions: com-
bination with efavirenz, etravirine, nevirapine, boosted PIs, or elvitegravir/c is not
recommended. Also, dabigatran, carbamazepine, rifampicin, rifabutin, St. John’s
wort, PPIs, some statins (atorvastatin, simvastatin), and ethinylestradiol.
Comment: This combination of PI and NS5A inhibitor was approved in 2017 for
chronic hepatitis C. Effective for all genotypes. Consider interaction and costs.

Mycobutin® see Rifabutin

Drug Profiles 655

Nelfinavir
Manufacturer: Pfizer (US).
Approval and indication: HIV infection.
• Viracept® film-coated tablets 625 mg available as import only
Dose: Daily 2 x 1,250 mg (2 x 2 tablets) with meals.
Adverse events: Diarrhea is very common! Meteorism, nausea.
Comment: Roche withdrew approval in 2013 due to a lack of demand. In the US,
the substance is still available through Pfizer. It should no longer be used.

Nevirapine
Manufacturer: Boehringer-Ingelheim. Generics, various trade names.
Approval and indication: HIV infection. Therapy-naïve individuals with good
immune status (females >250, males >400 CD4 T-cells/µl) should rather avoid nevi-
rapine due to an increased risk of hepatotoxicity (see below).
• Viramune sustained-release tablets® 400 mg, 200 mg, in pediatrics also 50, 100 mg
• Viramune suspension® with 10 mg/mL
Dose: Daily 1 x 1 sustained-release tablet of 400 mg or 2 x 1 tablet of 200 mg each,
independent of meals. A two-week phase-in period (1 x 200 mg/day – starter pack!)
reduces the exanthem rate. In children, the dose is according to weight.
Adverse events: Hepatotoxicity (10–15%) and drug exanthema, especially in primary
therapy with good CD4 T-cells (females >250/µl, males >400/µl). Use with caution
in hepatic dysfunction. With prolonged administration, the GGT is almost always
elevated (levels up to 150 U/l are tolerable).
Interactions: Do not combine with rifampicin, ketoconazole, St. John’s wort, and
the “pill.” Favorable lipid profile.
Comment: As with all NNRTIs, resistance develops rapidly. Initially burdened by
allergies and hepatotoxicity (dose creep), therefore rarely prescribed. Good long-term
tolerability. Generics available.
Detailed discussion in this book: page 62

Norvir® see Ritonavir

Odefsey®
Manufacturer: Gilead Sciences.
Approval and indication: HIV infection. Adults, children 12 years and older,
without resistance to single agents, untreated only if below 100,000 copies/mL.
• Odefsey® film-coated tablets: 200 mg FTC + 25 mg TAF + 25 mg rilpivirine
Dose: 1 x 1 tablet daily, unchewed, with a meal! Do not use in severe renal impair-
ment (GFR below 30 mL/min).
Adverse events: Rare, most likely rash (see rilpivirine). Occasionally, sleep problems
and nausea. For renal dysfunction, see tenofovir.
656 Drugs

Interactions: Do not combine with rifabutin, rifampicin, anticonvulsants (includ-

ing carbamazepine), PPIs, St. John’s wort (rilpivirine and/or TAF levels decrease). H2
antagonists should be taken 12 hours apart, and antacids at least 2 hours before or
4 hours after. Do not use if viremia is high due to the increased risk of resistance.
Comment: Has largely replaced Eviplera® since approval in 2016, as TAF is slightly
less nephrotoxic than TDF. It is often used as “maintenance” therapy in patients
with good adherence (excellent long-term tolerability). Resistance risk is unaccept-
ably high in first-line treatment, especially with high viremia.
Detailed discussion in this book: page 177

Pegasys®, PegIntron® see Interferon

Pentamidine
Manufacturer: Sanofi Aventis/GlaxoSmithKline.
Approval and indication: Treatment and secondary prophylaxis of PCP if cotri-
moxazole is not possible or available. Also, for visceral leishmaniasis.
• Pentacarinate® 300 mg vials
Dose: 200–300 mg i.v. for 5 days (4 mg/kg), then half dose. In very mild cases, daily
inhalations of 300 mg. In renal impairment with creatinine clearance of 50 to 10
mL/min: 4 mg/kg every 24 to 36 hours; below 10 mL/min: 4 mg/kg every two days.
As prophylaxis inhalations of 300 mg 1–2 x / month.
Adverse events: Frequent with intravenous administration! Nausea, vomiting, metal-
lic taste, nephrotoxicity (creatinine increase in the 2nd week of therapy) up to renal
failure. Hypo- or hyperglycemia (possible for months after end of treatment),
hypotension, cardiac arrhythmias, pancreatitis. Leukopenia, thrombocytopenia.
With inhalation, occasionally cough irritation, rarely asthma attack.
Interactions, notes: Inhalation: Pentamidine is contraindicated as an aerosol in
bronchial asthma and therapy with beta-blockers. Inhalation is ineffective in various
pulmonary diseases. Before inhalation, a ß-mimetic (e.g., Berotec®) may be helpful
to open airways. Infusions: Caution in hepatic or renal insufficiency, hyperglycemia,
cytopenia. Adequate electrolyte and fluid intake. Cave nephrotoxic drugs! During
and after infusion (slowly over 2 hours!), the person should lie down (blood pres-
sure drop). Daily control of kidney/electrolytes, blood count, blood sugar, weekly
bilirubin, alkaline phosphatase, and transaminases.

Pibrentasvir see Maviret®

Pifeltro® see Doravirin

Pyrimethamine
Manufacturer: GlaxoSmithKline.
Approval and indication: Prophylaxis and treatment of cerebral toxoplasmosis.
Prophylaxis of Pneumocystis pneumonia.
• Daraprim® 25 mg tablets
Dose: Toxoplasmosis treatment: Daraprim® 2 x 2 tablets at 25 mg (for 3 days, then
halve dose) plus leucovorin® 3 x 1 tablet at 15 mg/wk plus either sulfadiazine, clin-
damycin, or atovaquone (second choice).
Drug Profiles 657

In PCP prophylaxis with dapsone: Daraprim® 1 x 2 tablets at 25 mg/wk plus dapsone-

fatol® 1 x 1 tablet at 50 mg plus leucovorin® 1 x 2 tablets at 15 mg/wk.
Adverse events: Nausea, colic, vomiting, diarrhea, leukopenia, anemia, or throm-
bocytopenia (folinic acid!). Rarely seizures, tremors, or ataxia.
Warnings: Contraindicated in megaloblastic anemia following folic acid deficiency.
Caution in seizures, renal insufficiency, bronchial asthma, or G6PD deficiency.
Always substitute folinic acid (not folic acid!) to reduce bone marrow suppression.
Initially, blood count weekly.

Raltegravir
Manufacturer: MSD.
Approval and indication: Pretreated and untreated adults, including children 4
weeks of age and older.
• Isentress® film-coated tablets of 600 mg, 400 mg. For children, chewable tablets of
25 mg and 100 mg, also granulated sachets (100 mg)
• Dutrebis® 400 mg plus 150 mg 3TC (approved but not marketed in many coun-
tries).
Dose: 1 x 2 tablets of 600 mg (1200 mg) or 2 x 1 tablets of 400 mg daily (800 mg),
with or without meals. No dose adjustment is required for impaired renal or mod-
erately impaired hepatic function. In children, dosage is based on body weight (see
Children’s Chapter).
Adverse events: Very well tolerated. Occasional dizziness and sleep disturbances.
Transaminase elevations. Rash (mild, very rare). Case reports of CK elevations and
rhabdomyolysis. Weight gain possible.
Interactions: Raltegravir is eliminated via UGT1A1-mediated glucuronidation, so
relevant interactions with other antiretroviral agents are unlikely. Caution with
potent inducers of UGT1A1 – rifampicin decreases plasma levels, possibly doubling
the raltegravir dose. Omeprazole or other antacid medications increase plasma levels
of raltegravir. Combine only if unavoidable.
Comment: Raltegravir was the first integrase inhibitor in HIV therapy; it is well tol-
erated and has few interactions. Single dosing is possible with the 600 mg tablet, but
no STR exists. The resistance barrier seems to be lower than for dolutegravir or bicte-
gravir.
Detailed discussion in this book: page 78, 175

Rebetol® see ribavirin

Rekambys® (US: Cabenuva®)

Manufacturer: ViiV Healthcare.
Approval and Indication: Only in combination with cabotegravir injection
(Vocabria®) in adults virologically suppressed on stable ART without resistance or
failure to NNRTIs or INSTIs. Both drugs, rilpivirine and cabotegravir LA, are pack-
aged in the US with the single trade name Cabenuva®.
• Rekambys® Rilpivirine 600 mg (2 mL) or 900 mg (3 mL) vials
658 Drugs

Dose: “Lead in” (may be omitted) with one tablet of rilpivirine 25 mg daily for 28
days each with a meal, then an initial dose of 900 mg i.m. on the last day, another
900 mg dose after one month, then 900 mg every two months (600 mg also given
monthly) up to 7 days before/after the target date. Oral bridging is possible for up
to 2 months. Start conventional ART within one month if doses are missed or dis-
continued. No dose adjustment in renal or hepatic insufficiency.
Adverse events: Overall, well tolerated. Pain at injection sites (approx. 80%, swelling,
redness) is usually mild and rarely leads to discontinuation. Headache, depression.
Notes, interactions: Shake vials vigorously for 10 seconds. Use longer needles in
obese patients. Caution with subtype A, caution with BMI >30. Strictly gluteal, always
the same buttock. Do not use with rifabutin, carbamazepine, phenytoin, dexam-
ethasone, St. John’s wort.
Comment: In 2020, the first approved long-acting therapy only with cabotegravir,
not other antiretroviral agents. Note the indication restrictions.
Detailed discussion in this book: page 216

Rescriptor® – NNRTI never approved in Europe

Retrovir® see AZT

Reyataz® – 2019, withdrawn from the market; see atazanavir

Rezolsta® see Darunavir

Ribavirin
Manufacturer: Roche and Essex. Numerous generics!
Approval and indication: Chronic hepatitis C, only in combination with inter-
feron. The approval for HIV/HCV co-infection explicitly applies only to Copegus®.
Dose: 800 mg daily for body weight <65, 1,000 mg for 65–85, 1,200 mg for >85 kg.
Capsules are divided into two daily doses and taken with food. Duration of therapy
depends on genotype and therapy success.
• Copegus Film-Coated Tablets® 200 mg, 400 mg
• Rebetol hard capsules® 200 mg
• Rebetol solution® with 40 mg/mL (100 mL)
Adverse events: Hemolytic anemia is most common (Hb drop of at least 2 g/dL),
along with gastrointestinal symptoms, headache, and fatigue. In combination with
NRTIs, rarely lactic acidosis, pancreatitis.
Interactions, warnings: Ribavirin is contraindicated in severe heart disease, renal
insufficiency, decompensated cirrhosis, and hemoglobinopathies. Potentially
teratogenic, no use during pregnancy.
If hemoglobin values <10 g/dL or drop significantly more than 2 g/dL, reduce the
dose to 600–800 mg/day. Discontinue at <8.5 g/dl. Consider erythropoietin or trans-
fusions before reduction/discontinuation: Dose reductions with ribavirin jeopardize
therapeutic success.
Depression occurring with efavirenz may be exacerbated by ribavirin.
Blood checks (blood count, OT, PT, amylase, lipase) are initially every two weeks,
then monthly. Determine lactate in case of unspecific symptoms!
Comment: Used only in exceptional cases in hepatitis C therapy.
Drug Profiles 659

Rifabutin
Manufacturer: Pfizer.
Approval and indication: Infections with Mycobacterium avium complex (MAC)
in combination with other substances (mostly ethambutol and azithromycin).
Possibly also in tuberculosis.
• Mycobutin® 150 mg capsules
Dose: 300 mg rifabutin (+ azithromycin + ethambutol) daily.
Renal impairment: dose reduction of 50% if creatinine clearance <30 mL/min. Dose
adjustments with concomitant administration of antiretroviral drugs:

Drug Recommendation
Atazanavir/r, Darunavir/r, Lopinavir/r, Rifabutin: 150 mg three times per week
Tipranavir/r (some guidelines recommend trying 150 mg daily)
Elvitegravir/c, Bictegravir Avoid, plasma levels markedly reduced
Efavirenz Rifabutin: 450 mg/day or 2–3 x 600 mg/week
Nevirapine, doravirine, etravirine, raltegravir, Standard dosage
dolutegravir, fostemsavir

Adverse events: Nausea, increase in liver enzymes. Uveitis usually occurs with a daily
dose of > 300 mg and combination with clarithromycin or fluconazole. Red
coloration of urine, skin, and body secretions (inform affected persons!).
Interactions, warnings: contraindicated in case of hypersensitivity to rifabutin and
rifampicin; also in case of thrombocytopenia and severe liver dysfunction. Initially
biweekly, later monthly checks of blood count and liver enzymes. Rifabutin may
reduce the effectiveness of the following drugs, among others: Analgesics, anticoag-
ulants, corticosteroids, cyclosporines, digitalis (except digoxin), dapsone, oral antidi-
abetics, oral contraceptives, narcotic analgesics, phenytoin, and quinidine.
Erythromycin, ketoconazole, itraconazole, fluconazole, and clarithromycin may
increase plasma levels of rifabutin. Take antacids no earlier than three hours after
rifabutin.
Comment: Various interactions, should only used by experienced physicians.

Rifampicin
Manufacturer: Various. Many trade names, also in combinations (see below).
Approval and indication: Tuberculosis. Only in combination therapies!
• Rifa® tablets containing 150, 300, 450, 600 mg rifampicin
• Eremfat® syrup containing 20 mg rifampicin per mL
• Eremfat® 300 mg and 600 mg injection vials
• Rifinah® or Tebesium duo®: film-coated tablets, each containing 300 mg rifampicin
and 150 mg isoniazid
• Rifater® or Tebesium trio®: coated or film-coated tablet, each containing 120 mg
rifampicin, 50 mg isoniazid, 300 mg pyrazinamide
Dose: Daily 600 mg (body weight >50 kg) or 450 mg (body weight <50 kg). They are
preferably taken in the morning and fasting!
660 Drugs

Adverse events: Toxic hepatitis (up to 20%), cholestasis. Red coloration of urine and
other body fluids. Soft contact lenses may turn permanently reddish. Allergies are
common. Gastrointestinal complaints.
Interactions, warnings: Caution in chronic liver disease. Discontinue rifampicin in
case of GPT >100 U/l (gradual re-exposure after normalization possible), furthermore
in case of severe and persistent diarrhea (caution: pseudomembranous colitis!).
Rifampicin should not be combined with NNRTIs (except efavirenz), PIs, or elvite-
gravir/c. Doses for dolutegravir and raltegravir should be doubled. Rifampicin accel-
erates the metabolism of many other pharmaceuticals, reducing their effectiveness.
This applies to atovaquone, coumarins, barbiturates, benzodiazepines, beta-blockers,
clarithromycin, contraceptives, steroids, oral antidiabetics, cyclosporine, dapsone,
digitalis, doxycycline, erythromycin, haloperidol, ketoconazole, methadone, pheny-
toin, theophylline, trimethoprim, verapamil. Combination with ketoconazole or
voriconazole is contraindicated.
Antacids, opiates, and anticholinergics reduce the bioavailability of concomitant
orally administered rifampicin (time interval!). Do not use it during pregnancy. Check
blood count and liver values every two weeks.
Comment: See rifabutin. Combine only with NRTIs, efavirenz, and possibly ralte-
gravir.

Rilpivirine
Manufacturer: Janssen-Cilag.
Approval and indication: Previously untreated HIV infection, less than 100,000
copies/mL. Since 2013, it has also been licensed for pretreated patients with viro-
logical suppression and without resistance.
• Edurant® film-coated tablets with 25 mg rilpivirine
The following fixed combinations (film-coated tablets) also contain 25 mg of
rilpivirine:
• Eviplera®: plus 200 mg FTC + 300 mg TDF
• Odefsey®: plus 200 mg FTC + 25 mg TAF
• Juluca®: plus 50 mg dolutegravir
Component of the depot combination (long-acting) with cabotegravir.
• Rekambys®: 600 mg (2 mL) or 900 mg (3 mL) vials of rilpivirine (in the US as
Cabenuva®)
Dosage: 1 x 1 tablet daily, unchewed, necessarily with a meal.
Adverse events: Rare, most likely rash (mostly mild, less than with efavirenz!), occa-
sionally nausea. It is better tolerated (fewer CNS side effects, more favorable lipid
profile) than efavirenz. CNS disturbances and depression may occur, however.
Occasionally elevated bilirubin. At high doses, QT prolongations (not increased at
the approved dose).
Interactions: Do not combine with rifabutin, rifampicin, various anticonvulsants
(including carbamazepine), PPIs, and St. John’s wort (rilpivirine levels decrease). H2
antagonists should be taken 12 hours apart, and antacids at least 2 hours before or
4 hours after rilpivirine. Use with caution in severe hepatic impairment. Partial but
not complete cross-resistance to other NNRTIs.
Comment: Was the 5th NNRTI used in November 2011, primarily as a single-tablet
regimen Odefsey®. Increased resistance risk with high viral load, therefore most likely
Drug Profiles 661

to be used in pretreated PLWH with viral suppression. Good absorption is essential

(with a meal, no PPIs).
Detailed discussion in this book: page 63

Ritonavir
Manufacturer: AbbVie. Generics available.
Approval and indication: HIV infection. It is also used as an ingredient in Kaletra®
(see lopinavir), the HCV drug Viekirax®, and the SARS-CoV-2 drug Paxlovid®.
• Norvir® 100 mg tablets
• Norvir® oral solution containing 80 mg per mL
Dose: Use only as a pharmacoenhancer/booster. Daily dosages:
• Atazanavir (generics, 1 x 300 mg): 1 x 100 mg ritonavir.
• Darunavir (Prezista®, 2 x 600 mg): 2 x 100 mg ritonavir
• Darunavir (Prezista®, 1 x 800 mg): 1 x 100 mg ritonavir
• Fosamprenavir (Telzir®, 2 x 700 mg): 2 x 100 mg ritonavir
• Lopinavir (Kaletra®): Fixed combination, see lopinavir.
• Saquinavir (Invirase®, 2 x 1000 mg): 2 x 100 mg ritonavir
• Tipranavir (Aptivus®, 2 x 500 mg): 2 x 200 mg ritonavir
Adverse events: Dose-dependent frequent nausea, vomiting, diarrhea, perioral pares-
thesias (tingling), electrifying sensations in arms/legs. Increased liver enzymes, dys-
lipidemia, lipodystrophy, and rarely diabetes mellitus.
Interactions: Numerous interactions, even at the low booster doses! Contraindicated
are rifampicin, amiodarone, astemizole, bepridil, terfenadine, flecainide, cisapride,
triazolam, ergotamine, simvastatin, lovastatin, quinidine, St. John’s wort. Sildenafil
should also be avoided. Caution or, if possible, level measurement with methadone,
immunosuppressants (cyclosporine, tacrolimus), macrolides (erythromycin, clar-
ithromycin), steroids, calcium antagonists, tricyclic and other antidepressants, neu-
roleptics (haloperidol, risperidone,), antifungals (keto/itraconazole), carbamazepine,
tolbutamide, rifabutin, theophylline, Marcumar.
Comment: One of the first PIs. Therapeutic doses should be avoided because of gas-
trointestinal side effects; at lower doses suitable as a “booster” for almost all other
PIs. Numerous interactions.
Detailed discussion in this book: page 67

Rukobia® see Fostemsavir

662 Drugs

Saquinavir
Manufacturer: Hoffmann-La Roche.
Approval and indication: Adult PLWH.
• Invirase 500® film-coated tablets containing 500 mg saquinavir
Dose: 2 x 1000 mg saquinavir + 2 x 100 mg ritonavir. The package insert recom-
mends an introductory dose over 7 days with 2 x 500/100 mg for therapy-naive
patients.
Adverse events: Primarily gastrointestinal, rarely increased liver enzymes, headache.
As with all PIs with prolonged use, lipodystrophy, dyslipidemia, and decreased
glucose tolerance. QT prolongation!
Interactions: Contraindicated for concomitant treatment with rifampicin, astemi-
zole, terfenadine, triazolam, ergotamine, simvastatin, St. John’s wort. If saquinavir
is not combined with other PIs, it must be taken with meals. Cave QT prolongation.
Concomitant use with drugs that prolong the QT or PR interval is contraindicated!
ECG before starting therapy (QT >450 ms contraindication) and after 10 days.
Comment: The first PI on the market in 1995. No longer in use due to the number
of pills and QT prolongation (ECG controls).

Sempera® see Itraconazole

Simeprevir (Olysio®) – was withdrawn from the market in 2018

Sobelin® see Clindamycin

Sofosbuvir
Manufacturer: Gilead Sciences.
Approval and Indication: As part of combination therapy for untreated or pre-
treated chronic hepatitis C.
• Sovaldi® film-coated tablets of 400 mg (1 bottle of 28).
Ingredient of the following combination preparations (all film-coated tablets)
• Epclusa® 400 mg plus 100 mg velpatasvir
• Harvoni® 400 mg plus 90 mg ledipasvir
• Vosevi® 400 mg plus 100 mg velpatasvir plus 100 mg voxilaprevir
Dose: 400 mg once daily, with a meal. Dose reduction is generally not recommended.
The dose in severe renal impairment is unclear; no dose adjustment is necessary for
liver impairment.
Adverse events: Well-tolerated, adverse events primarily due to the combination
partners. No specific side effect is known so far. Most likely exhaustion, headache,
nausea, and insomnia.
Notes, interactions: Like all DAA, it should be prescribed only by a physician expe-
rienced in HCV therapy. Duration of treatment and combinations depend on geno-
type, degree of liver fibrosis, and type of prior treatment. No dose adjustments are
necessary with NRTIs, rilpivirine, efavirenz, darunavir/r, and raltegravir. However,
sofosbuvir is a P-gp substrate, so do not combine with P-gp inducers such as carba-
mazepine, rifampicin, or St. John’s wort.
Drug Profiles 663

Comment: Well-tolerated HCV polymerase inhibitor, now hardly plays a role as a

single agent. Due to its considerable costs, like all DAAs, it should be prescribed only
by experienced physicians.

Sovaldi® see Sofosbuvir

Stavudine® – toxic NRTI, withdrawn from the market in 2019

Stocrin® see Efavirenz

Stribild®
Manufacturer: Gilead Sciences.
Approval and indication: adult PLWH, either not pretreated or, if pretreated,
without resistance mutations.
• Stribild® film-coated tablets containing 150 mg elvitegravir, 150 mg cobicistat,
200 mg FTC, 300 mg tenofovir DF
Dose: One tablet daily, with food, unchewed.
Adverse events: Well-tolerated. Nephrotoxicity, in particular, should be noted. Above
<70 mL/min, Stribild® should be avoided; monitor renal values monthly for the first
year. Cobicistat inhibits tubular secretion of creatinine and may mimic mild renal
dysfunction. Discontinue if GFR <50 mL/min. Nausea (slightly more common than
with other combos), diarrhea, headache, and occasional depression. See otherwise
for tenofovir.
Interactions: Cobicistat is a potent CYP3A inhibitor. Substances such as atorvas-
tatin, lovastatin, simvastatin, midazolam, carbamazepine, rifampicin, and St. John’s
wort should be avoided. No other antiretroviral agents. Distance of 4 hours from
antacids and multivitamins. Choose low doses for azoles, rifabutin, calcium antag-
onists, and PDE-5 inhibitors.
Comment: In May 2013, the first complete ART with an integrase inhibitor in a
single tablet per day. Care must be taken with the kidney. It has been replaced mainly
by Genvoya® since 2016 (contains TAF instead of TDF).

Sulfadiazine
Manufacturer: Heyl.
Approval and indication: Treatment and prophylaxis of cerebral toxoplasmosis,
only in combination with pyrimethamine.
• Sulfadiazine-Heyl® tablets containing 500 mg
Dose: As therapy daily 4 x 2–3 tablets of 500 mg (daily dose 4–6 g). As prophylaxis
use half dose (4 x 1 tablet of 500 mg)! At creatinine clearance of 10–50 mL/min half
dose, below one-third of the dose.
Adverse events: Very commonly allergies with pruritus, fever, and urticaria, often
therapy-limiting. Rarely Stevens-Johnson syndrome. Gastrointestinal complaints.
Renal problems with renal insufficiency, crystalluria, and nephrolithiasis in up to
7%. Anemia, leukopenia, thrombocytopenia, elevation of liver enzymes.
664 Drugs

Interactions, warnings: Contraindicated in sulfonamide hypersensitivity and

allergy to sulfonylurea-type antidiabetics, acetazolamide, or thiazide diuretics; also
in G6PD deficiency, renal insufficiency, and severe liver damage or liver dysfunction
(e.g., acute hepatitis); and during pregnancy and lactation. Sulfadiazine may increase
the effect of sulfonylureas (oral antidiabetics), anticoagulants, and diphenylhydan-
toin. Ensure adequate fluid intake (at least 2 l per day). Initially, check blood count,
GPT, creatinine, and urea at least weekly. Urine checks! In the case of crystalluria,
alkalize urine.

Sunlenca® see Lenacapavir

Sustiva® see Efavirenz

Symtuza®
Manufacturer: Janssen-Cilag (with Gilead Sciences).
Approval and indication: HIV infection, adults and adolescents 12 years and older
(body weight of at least 40 kg).
• Symtuza® film-coated tablets containing 800 mg darunavir + 150 mg cobicistat +
FTC 200 mg plus 10 mg TAF
Dose: 1 tablet daily with a meal. In case of impaired renal function, no dose adjust-
ment is necessary up to a creatinine clearance of 30 mL/min. Do not use in severe
hepatic impairment.
Adverse events: Diarrhea, dyslipidemias, allergies (see individual substances).
Interactions, notes: Boosted PI; therefore, some interactions should be noted; see
darunavir. Approval is limited to those without darunavir resistance.
Comment: Since approval in October 2017, it has been the only PI-containing single-
tablet regimen. Apart from diarrhea, it is well tolerated. A very high resistance barrier.
However, some interactions need to be considered.
Detailed discussion in this book: page 173

T-20 (enfuvirtide)
Manufacturer: Hoffmann-La Roche.
Approval and indication: Pre-treated PLWH with treatment failure or intolerance
on ART regimens with at least PI, NRTI, or NNRTI.
• Fuzeon® 90 mg/mL powder and solvent
Dose: 2 x 90 mg subcutaneously daily.
Adverse events: Generally well tolerated. Almost obligatory skin reactions at the
injection site: redness, inflammation, induration, exanthema. Possibly increased risk
of bacterial pneumonia, cave risk factors (low CD4 count, high viral load, drug
addicts, smokers, history of lung disease).
Interactions, notes: Interactions not known. Injection sites: upper arm, anterior hip,
abdomen. Change injection sites! There may be less irritation on the back. Do not
inject at sites with signs of inflammation from previous injections, in nevi, scars, or
skin abrasions. T-20 is expensive.
Drug Profiles 665

Comment: Entry inhibitor is now only used in individual cases with intensive pre-
treatment. T-20 must be injected subcutaneously twice daily. Limited mainly by the
mode of application and by local skin reactions.
Detailed discussion in this book: page 88

Tenofovir-DF (TDF) and Tenofovir-AF (TAF)

Manufacturer: Gilead Sciences. Generics for TDF.
Approval and indication: HIV infection. Chronic hepatitis B (TDF). To be distin-
guished are the two prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxil
fumarate (TDF, generic; some manufacturers do not use the fumarate but other salts
such as succinate or maleate).
• Viread® film-coated tablets: 300 mg TDF (generics)
• Vemlidy® film-coated tablets: 25 mg TAF (not licensed for HIV, hepatitis B only)
TDF is a component of the following combination preparations (all film-coated tablets):
• Atripla® : 300 mg TDF + 200 mg FTC + 600 mg efavirenz (generic)
• Delstrigo® : 300 mg TDF + 300 mg 3TC + 100 mg doravirine
• Eviplera® : 300 mg TDF + 200 mg FTC + 25 mg rilpivirine
• Stribild® : 300 mg TDF + 200 mg FTC + 150 mg elvitegravir + 150 mg cobicistat
• Truvada® : 300 mg TDF + 200 mg FTC (generic)
TAF is a component of the following combination preparations (all film-coated tablets):
• Biktarvy® : 25 mg TAF + 200 mg FTC + 50 mg bictegravir
• Descovy® : 10 mg or 25 mg TAF + 200 mg FTC
• Genvoya® : 10 mg TAF + 200 mg FTC + 150 mg elvitegravir + 150 mg cobicistat
• Odefsey® : 25 mg TAF + 200 mg FTC + 25 mg rilpivirine
• Symtuza® : 10 mg TAF + 200 mg FTC + 800 mg darunavir
Dose: Daily 1 x 300 mg TDF or 1 x 10–25 mg TAF, depending on concomitant med-
ication. Reduce TDF at GFR 30–49 mL/min (only every 48 hours). No dose adjust-
ment for TAF. Avoid both TDF and TAF below 30 mL/min.
Adverse events: Mostly well tolerated. Renal side effects are rare (renal failure, tubu-
lopathies including Fanconi syndrome, nephrogenic diabetes insipidus), such as
bone density reduction osteomalacia. Both are much less common under TAF. Typical
of TDF are CK elevations (up to 48%, macro-CK, disease value unclear). Possibly more
headaches, cholesterol elevations, and weight gain with TAF than with TDF.
Notes, interactions: With TDF, checks of creatinine clearance and serum phosphate
(before initiation of therapy, then every four weeks in the first year of treatment,
and every three months thereafter) are crucial. Checks are not that strict with TAF.
Concomitant administration with drugs that are also excreted by active tubular secre-
tion may result in increased serum concentrations of both agents: Cidofovir,
acyclovir, valaciclovir, ganciclovir, valganciclovir. Atazanavir and lopinavir increase
tenofovir levels. Tenofovir decreases plasma levels of atazanavir (always boost with
100 mg ritonavir).
Comment: TDF and TAF are the orally bioavailable prodrugs of tenofovir, an acyclic
nucleotide analog and one of the most widely used agents in HIV therapy. The slightly
less toxic (kidney, bone) TAF has partially replaced TDF. However, TDF is available
generically, which is usually much cheaper than TAF.
Detailed discussion in this book: page 51, 52
666 Drugs

Tipranavir
Manufacturer: Boehringer-Ingelheim.
Approval and indication: Adult PLWH with multiple prior treatments and resist-
ance to various PIs.
• Aptivus® Soft Capsules 250 mg
• Aptivus® 100 mg/mL solution (95 mL)
Dose: 2 x 500 mg tipranavir plus 2 x 200 mg ritonavir with meals.
Adverse events: mainly diarrhea and nausea. Transaminase elevations, rarely clini-
cal hepatitis to liver failure. More frequently than with other PIs, dyslipidemias (20%).
Rarely skin rash (urticarial or maculopapular). Isolated reports of intracranial hem-
orrhage (causality unclear).
Interactions, warnings: Tipranavir is metabolized via CYP3A, and various interactions
are to be expected. Do not combine with other PIs. Fluconazole and clarithromycin
increase serum levels of tipranavir (TDM!), and antacids reduce them by 30%: stagger
dosing. Tipranavir/r massively increases serum levels of atorvastatin (use pravastatin
or fluvastatin). Dose reduction of at least 75% also for rifabutin. Numerous
contraindications such as rifampicin, amiodarone, flecanide, terfenadine, etc.
Contraindicated also in liver cirrhosis, caution in hepatitis B/C. Monthly checks of
transaminases.
Comment: Only useful in particular resistance situations. Hepatotoxicity, must also
be boosted with increased doses of ritonavir. Numerous interactions must be taken
into account.
Detailed discussion in this book: page 71

Tivicay® see dolutegravir

Triumeq®
Manufacturer: ViiV Healthcare.
Approval and indication: HIV infection, in adults and adolescents over
12 years of age (at least 40 kg).
• Triumeq® film-coated tablets: 600 mg ABC + 300 mg 3TC + 50 mg dolutegravir
Dose: One tablet daily, regardless of meals. Avoid from a creatinine clearance of less
than 50 mL/min; here, it is better to use the single substances and dose individually.
Adverse events: Overall well tolerated; see single agent, especially abacavir (HRS,
cardiovascular events). Neuropsychiatric adverse events (sleep disturbances, insom-
nia, etc.) due to dolutegravir.
Notes, interactions: The warnings for abacavir must be considered; HLA typing is
obligatory! In case of INSTI resistance and in salvage regimens with efavirenz,
etravirine, nevirapine, and tipranavir rather avoid (dolutegravir would have to be
increased to BID). This also applies to rifampicin, carbamazepine, or St. John’s wort.
It is not recommended for patients with moderate/severe hepatic impairment.
Comment: This was the first single-tablet regimen without tenofovir in 2014. Very
effective, high resistance barrier. HLA screening for abacavir-HRS is mandatory.
However, it is now often replaced by Dovato® or Biktarvy® because of abacavir. It
hardly plays a role in first-line therapy anymore.
Drug Profiles 667

Trizivir®
Manufacturer: ViiV Healthcare (formerly GlaxoSmithKline).
Approval and indication: HIV infection.
• Trizivir film-coated tablets® containing 150 mg 3TC + 300 mg AZT + 300 mg
abacavir
Dose: 2 x 1 tablet daily. In case of impaired renal function (creatinine clearance
below 50 mL/min), giving the single substances (adjust dosage of 3TC and AZT) is
better.
Adverse events: Mainly gastrointestinal; see also the individual substances. With
regard to mitochondrial toxicity, there may be additive effects.
Comment: No longer needed, distribution will be discontinued by 2024.

Trogarzo® see Ibalizumab

Truvada®
Manufacturer: Gilead Sciences. Numerous, significantly less expensive generics.
Approval and indication: HIV infection.
• Truvada® film tablets: 300 mg tenofovir DF + 200 mg FTC
Dose: 1 x 1 tablet daily, regardless of food intake. Caution in renal dysfunction, in
this case, generally avoid Truvada®. If no alternatives are possible: if creatinine clear-
ance is 30–49 mL/min, dose reduction to 1 tablet every two days, below which do
not use Truvada®.
Adverse events: Monitoring of renal values; see tenofovir.
Interactions: See tenofovir. Useful in co-infection with chronic hepatitis B, as both
tenofovir and FTC have HBV activity – exacerbation of hepatitis is possible if dis-
continued.
Comment: One of the standard backbones, subjectively well tolerated. Moderate
renal and osseous problems (see tenofovir). Numerous generics are available, some
inexpensive (under 50 euros per month).
Detailed discussion in this book: page 53

Tybost® see Cobicistat

Valganciclovir
Manufacturer: Hoffmann-La Roche. Generics available.
Approval and indication: Oral induction and maintenance therapy of CMV retinitis.
• Valcyte® 450 mg tablets
Dose: As induction, 2 x 900 mg daily for 3 weeks (or until scarring of CMV lesions),
then suppression therapy 1 mg daily. It should be taken with meals! In case of renal
function impairment, the following dosages apply:
668 Drugs

Crea Cl (mL/min) Induction therapy Maintenance therapy

≥ 60 900 mg twice a day 900 mg once a day
40–59 450 mg twice a day 450 mg once a day
25–39 450 mg once a day 450 mg every other day
10–24 450 mg every other day 450 mg twice a week

Adverse events: frequently leukopenia, but also thrombocytopenia or anemia.

Gastrointestinal complaints with nausea, vomiting, and diarrhea are more frequent
than with intravenous therapy with ganciclovir.
Warnings, interactions: Check blood count at least 2–3 times/week during induc-
tion. Discontinue if neutrophils are below 500/µl (G-CSF if necessary!). Contra-
indication in case of neutropenia <500/µl, thrombocytopenia <25,000/µl, and con-
current chemotherapy (Kaposi’s sarcoma, NHL). Valganciclovir is potentially
teratogenic and carcinogenic. Generic drugs are preferred. Discontinue when
immune reconstitution is sufficient (see chapter AIDS).
Comment: The first orally well-acting CMV drug. It has largely displaced all other
CMV therapies as a prodrug of ganciclovir; a similar side effect profile is expected:
neutropenia, anemia, and thrombocytopenia.

Velpatasvir see Vosevi® and Epclusa®

Videx® see DDI

Vikierax® – no longer plays a role in hepatitis C

Viracept® see Nelfinavir

Viramune® see Nevirapine

Viread® see Tenofovir

Vistide® see Cidofovir

Vitekta® see Elvitegravir

Vocabria® see Cabotegravir

Vosevi®
Manufacturer: Gilead Sciences.
Approval and indication: Chronic hepatitis C, all genotypes.
• Vosevi® film-coated tablets: 400 mg sofosbuvir, 100 mg velpatasvir, 100 mg voxi-
laprevir.
Dose: 1 x 1 tablet daily, unchewed, with a meal. No dose adjustment in moderate
renal impairment up to a GFR of 30 mL/min. No administration in moderate hepatic
impairment.
Adverse events: Fairly well tolerated, most likely nausea, headache, fatigue, myal-
gias, and bilirubinemia.
Drug Profiles 669

Notes, interactions: Duration in untreated patients is 8 weeks; in patients with DAA

pre-treatment, it is 12 weeks. Many interactions: Combinations with efavirenz,
etravirine, nevirapine, atazanavir, and lopinavir are not recommended. Also, amio-
darone, dabigatran, edoxaban, phenytoin, carbamazepine, rifamycin, St. John’s wort,
rosuvastatin, and ethinylestradiol.
Comment: Triple fixed combination for chronic hepatitis C (all genotypes), licensed
in summer 2017. Useful, especially in cases of prior DAA failure. High costs!

Zepatier®
Manufacturer: MSD.
Approval and indication: chronic hepatitis C, genotypes 1 and 4.
• Zepatier® film-coated tablets: 50 mg elbasvir and 100 mg grazoprevir.
Dose: 1 x 1 tablet daily, regardless of food intake. No dose adjustment, even in severe
renal insufficiency, even in hemodialysis. No administration in moderate or severe
hepatic impairment.
Adverse events: Fairly well tolerated, nausea, headache, fatigue.
Interactions, notes: Duration of therapy is usually 12 weeks (in case of interferon
pretreatment and NS5A polymorphisms in GT1a therapy, extension to 16 weeks and
addition of ribavirin recommended). In GT1a, resistance testing is essential before-
hand. Combination with efavirenz, etravirine, nevirapine, elvitegravir/c and boosted
PIs is not recommended due to significant interactions.
Comment: Fixed combination (of NS5A inhibitor and protease inhibitor) for chronic
hepatitis C approved in summer of 2016. Effective only in GT1/4. It has a similar
efficacy and safety profile to Harvoni® but is cheaper. Useful in patients with hepa-
titis C and renal insufficiency.

Zerit® – toxic NRTI, withdrawn from the market in 2019

Ziagen® see Abacavir

Zidovudine see Retrovir

Zovirax® see Acyclovir

670

36. Drug interactions

TIM UMLAND AND ANDREAS HINTZ

Interactions play a significant role in HIV therapy. This is due, on the one hand, to
the more or less extensive concomitant medication of many PLWH and, on the other
hand, to the fact that ART itself has a clinically relevant potential for interactions
depending on the agents used. In particular, PIs and NNRTIs, like many other agents,
are metabolized via the CYP3A4 isoenzyme. In this context, the inhibitory effect of
boosted HIV therapy can lead to toxic drug level changes of the concomitant
medication. On the other hand, the inducer effect of some NNRTIs can cause sub-
therapeutic drug levels of co-medication by accelerating its elimination.
The following section shows a tabular overview of the harmless (+) drug combina-
tions and those that should be avoided (–). If changes in drug activity levels occur
due to the HIV drugs, this is indicated by arrow symbols “↑” or “↓”.
In individual cases, unfavorable combinations may be unavoidable due to lacking
alternatives. Monitoring of possible side effects and close monitoring of drug levels
is then recommended. If interactions are uncertain or not sufficiently tested, this is
indicated by a question mark “?”. The following overviews are not a substitute for
a detailed look at the specialist information and your research but are intended to
provide a supplementary, rapid, and practical decision-making aid. They are based
on the current information on the University of Liverpool website ([Link]-inter-
[Link]). For individual questions, the interaction hotline (number?) of the IFI
Institute, Hamburg, is also available.

Abbreviations:
+ Combination of these drugs possible
– Combination of these drugs should be avoided
↑ ↓ increased or decreased active drug level
? interactions uncertain or not verified, a combination perhaps possible –
monitoring recommended
Drug interactions 671

Combinations of ART + ART

Combining two NRTIs and one NNRTI or INSTI is usually done in fixed combina-
tions. If these are broken up, or a combination with another backbone is required,
there are practically no restrictions (see also national guidelines). The combination
of two NRTIs and a usually boosted PI is also problem-free. Darunavir (DRV) is
assumed to be boosted with ritonavir or cobicistat (Symtuza®). If a PI/NNRTI,
PI/INSTI, or NNRTI/INSTI combination is required, check the interactions in the
Liverpool database (see above). This also applies if maraviroc is part of the anti-
retroviral therapy. For reasons of space, the tabular presentation of these combina-
tions is omitted here.

ART + concomitant medications

Gastrointestinally active substances
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Antacids4 + + + + + ↓/↓1 + ↓3 ↓3 ↓3 ↓3 +
Cimetidine + + + + + +/↓1 + + + + + +
Famotidine + + + + + +/↓1 + + + + + +
Loperamide ↑ + + + + +/+ + + ? + + +
MCP + + + + + +/+ + + + + + +
Mesalazine + + + + + +/+ + + + + + +
Ondansetrone5 + + + + + +/?2 + + ↑ + + +
Ranitidine + + + + + +/↓1 + + + + + +
PPIs4 + + + + + +/– + + + + + +
1 When combining RPV with antacids/H2 antagonists, observe time interval (loss of effect).
2 Caution due to possible QT time prolongation
3 Due to the complex formation of INSTIs with some minerals, observe time intervals (technical info).
4 No interactions for CAB/RPV as injection with antacids / H2 antagonists / PPI.
5 Caution with the combination of CAB/RPV as an injection with ondansetron.

Antiarrhythmics
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Amiodarone – + ? ↓ ↓ +/? + + – ↑1 + ↑
Flecainide – + + ↓ + +/? + + ↑ + + ?2
Lidocaine ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Propafenone – + ↓ ↓ ↓ +/+ + + ↑ + + +
1 Bictegravir levels may increase with amiodarone; for the fixed combination TAF/FTC, an increase in
TAF levels with amiodarone should also be considered
2 QT prolongation possible
672 Drugs

Antibiotics/tuberculostatics
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Amikacin + + + + + +/+ + + + + + +
Amoxicillin + + + + + +/+ + + + + + +
Azithromycin + + + + + +/+ + + ? + + ?8
Bedaquilin ↑1 + ↓ ↓ + +/? + + ↑ + + ?8
Ciprofloxacin + + + + + +/+ + + + + + ?8
Clarithromycin ↑2 ? ↓ ↓ ? +/? ↑5 + ↑ ? + ↑
Clindamycin ↑2 + ↓ ↓ ↓ +/+ + + ↑2 + + +
Cotrimoxazole + + + + + +/+ + + + + + +
Dapsone + + + + + +/+ + + + + + +
Ertapenem + + + + + +/+ + + + + + +
Erythromycin + ? ? ? ? +/? + + ? ? + ↑
Ethambutol + + + + + +/+ + + + + + +
Gentamycin + + + + + +/+ + + ? + + +
Isoniazid + + + + + +/+ + + + + + +
Levofloxacin + + + + + +/?1 + + + + + ?6
Linezolid + + + + + +/+ + + + + + +
Meropenem + + + + + +/+ + + + + + +
Metronidazole + + + + + +/+ + + + + + +
Moxifloxacin + + ↓ ↓ + +/?1 + + + + + ?8
Ofloxacin + + + + + +/+ + + + + + (↑)
Pentamidine + + + + + +/?1 + + + + + +
Pyrazinamide + + + + + +/?1 + + + + + +
Pyrimethamine + + + + + +/+ + + + + + +
Rifabutin ↑3 ↓4 ↓ ? ? +/? ? + ↑3 – + (↑)
Rifampicine – – +7 – – –/– ↓6 ↓6 – – ↓6 –
Rifapentine – – + – – –/– ↓6 ? – – ? –
Streptomycin + + + + + +/+ + + + + + +
Tetracyclines + + + + + +/+ + + + + + +
Vancomycin + + + + + +/+ + + + + + +
1 QT prolongation possible
2 Dose reduction should be considered (clindamycin) or may be considered (clarithromycin); caution
especially in impaired renal function
3 According to the package insert, the combination is not recommended; in case of concomitant use,
dose reduction of rifabutin to 150 mg/day x three days a week
4 Doravirine ↓, therefore increase the dose to 100 mg in the morning and 100 mg in the evening
5 Level of the HIV drug increases
6 Active level of the HIV drug decreases; increase the dose (see technical information)
7 If necessary, dose increase of EFV to 800 mg/d in > 60 kg bw (see technical information)
8 QT prolongation possible
Drug interactions 673

Antidepressants
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Amitriptyline ↑ + + + + +/+ + + ↑ + + +
Bupropion ↓ + ↓ + ↓ +/+ + + + + + +
Citalopram ↑ + ↓ ↓ ↓ +/+ + + ↑ + + ?1
Desipramine ↑ + + + + +/+ + + ↑ + + +
Doxepin ↑ + + + + +/+ + + ↑ + + +
Fluoxetine ↑ + + + + +/+ + + ↑ + + +
St John’s Wort – – – – – +/– – – – – – –
Lithium + + + + + +/+ + + + + + +
Mirtazapine ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Nortriptyline ↑ + + + + +/+ + + ↑ + + +
Paroxetine ? + + + + +/+ + + ? + + +
Sertraline ? + ↓ ↓ + +/+ + + + + + +
Trazodone ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Venlafaxine ↑ + ↓ ↓ ↓ +/+ ? + ↑ + + +
1 QT prolongation possible

Antidiabetics (oral)
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Glibenclamide ↑ + ↓ ↓ ↓ +/+ + + ↑ + + ↑
Glimepiride ? + ↑ ↑ + +/+ + + ↓ + + ↑
Metformin ? + + + + +/+ + ↑1 ↑1 ↑1 + +
Repaglinide ↑ – ? ↓ ↓ +/+ + + ↑ + + ↑
Rosiglitazone + + + + + +/+ + + + + + +
Sitagliptin + + ↓ ↓ ↓ +/+ + + + + + +
1 Please refer to the technical information, especially in case of impaired renal function

Antihelmintics
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Albendazole ↓ + ↓ ↓ ↓ +/+ + + ↓ + + +
Diethylcarbamazine + + + + + +/+ + + + + + +
Ivermectin ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Levamisole (ergamisole) + + + + + +/+ + + + + + +
Niclosamide + + + + + +/+ + + + + + +
Oxamniquine ? + + + + +/+ + + ↑ + + +
Praziquantel ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Pyrantel + + + + + +/+ + + + + + +
Suramin + + + + + +/+ + + + + + +
Triclabendazole ↑ + ? ? ? +/+ + + ↑ + + +
674 Drugs

Antihistamines
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Cetirizine + + + + + +/+ + + + + + +
Fexofenadine ↑ + + ↑ + +/+ + + ↑ + + +
Levocetirizine + + + + + +/+ + + + + + +
Loratadine ↑ + + + + +/+ + + ↑ + + +

Anticoagulants/antiplatelet agents
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Apixaban – + ↓ ↓ ↓ +/+ + + – + + (↑)
Aspirin/ASS + + + + + +/+ + + + + + +
Clopidogrel ↓1,3 + ↑ ↓ ? +/+ + + ↓1,3 + + +
Dabigatran ? + + ↑ + +/? + + ↑ + + +
Dipyridamole ? + ↓ ↓ + +/+ + + + + + +
Edoxaban ↑ + + + + +/+ + + ↑ + + +
Enoxaparin + + + + + +/+ + + + + + +
Fondaparinux + + + + + +/+ + + + + + +
Heparin + + + + + +/+ + + + + + +
Phenprocoumon ?2 + ↓ ?2 ↓ +/+ + + ?2 + + +
Prasugrel + + + + + +/+ + + + + + +
Rivaroxaban – + ↓ ↓ ↓ +/+ + + – + + (↑)
Ticagrelor – + ↓ ↓ ↓ +/+ + + – + + +
Warfarin ?2 + ?2 ↑ ?2 +/+ + + ↓ + + +
1 Check the package insert
2 Control of INR value recommended
3 Clopidogrel ↓ due to decreased conversion to active metabolites; use alternatives

Anticonvulsants
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTRL
RPV
Carbamazepine – – ↓ – ↓ –/– ?1 ?1 – – ?1 –
Gabapentine + + + + + +/+ + + + + + +
Lamotrigine ? + ↓ + + +/+ + + + + + +
Levetiracetam + + + + + +/+ + + + + + ?2
Oxcarbazepine – – + ? ? –/– ?1 ?1 ?1 – ?1 –
Phenobarbital – – – – – –/– – – – – – –
Phenytoin – – – – – –/– – – – – – –
Pregabaline + + + + + +/+ + + + + + +
Topiramat + + + + + +/+ + + + + + +
Valproate ? + + + + +/+ + + ? + + +
1 Active level of the HIV drug decreases! Increase the dose in combination with carbamazepine; see
the package insert.
2 QT prolongation possible
Drug interactions 675

Antifungals
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Amphoter. B + + + + + +/+ + + + + + +
Caspofungin + + ↓ ↓ ↓ +/+ + + + + + ↑
Fluconazole + ↑1 + ↑1 ↑1 +/↑1 + + ↑2 + + ↑
Flucytosin + + + + + +/+ + + ? + + +
Itraconazole ↑2 ↑1 ↓ ↓ – +/↑1 ↑1 + ↑2 ↑1 + (↑)
Ketoconazole ↑2 ↑1 – ↑1 – +/↑1 ↑1 + ↑2 ↑1 + (↑)
Nystatin + + + + + +/+ + + + + + +
Posaconazole ↑1 ↑1 ↓ ↑1 ↑1 +/↑1 ↑1 + ↑2 ? + (↑)
Terbinafine ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Voriconazole ↑ 2 ↑ 1 – ? ? +/↑1 ↑ 1 + ? + + (↑)
1 Active level of the HIV drug increases!
2 Both active levels increase

When using -azoles during ART, the maximum dosage should be observed according to the specialist
information or checked via [Link].

Calcium antagonists (CCB)

DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Amlodipine ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Diltiazem ↑ ↑2 ↓ ↓ ↓ +/↑2 ↑2 + ↑ ↑2 + (↑)
Felodipine ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Lercanidipine –1 + ↓ ↓ ↓ +/+ + + -1 + + +
Nifedipine ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Verapamil ↑ ↑2 ↓ ↓ ↓ +/↑2 ↑2 + ↑ ↑2 + (↑)
1 Levels of calcium antagonists may rise sharply, especially in combination with boosted ART
(lercanidipine is contraindicated). Titrate cautiously, ECG monitoring if necessary.
2 Active level of the HIV drug increases!
676 Drugs

Immunosuppressants/cytostatics
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Azathioprine + + + + + +/+ + + + + + +
Carboplatin + + + + + +/+ + + + + + +
Ciclosporin ↑1 ↑2 ↓ ↓ ↓ +/↑2 ↑2 + ↑1 ↑2 + +
Cisplatin ↑ + + + + +/+ + + ↑ ? + +
Cyclophosphamide ? + ↓ ↓ ↓ +/+ + + ↓ + + +
Cytarabine + + + + + +/+ + + + + + +
Daunorubicin + + + + + +/+ + + + + + ↑
Docetaxel ↑ + ↓ ↓ ↓ +/? ? + ↑ + + ↑
Doxorubicin + + + + + +/+ + + + + + ↑
Etoposide ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Fluorouracil + + + + + +/+ + + ? ? + (↑)
Gemcitabine + + + + + +/+ + + + + + +
Irinotecan – + ↓ ↓ ↓ +/+ + + ↑ + + ↑
Methotrexate + + + + + ?/+ + + ↑ + + ↑
Mycophenolate ↓ + ↓ + + +/+ + + ↑ + + +
Oxaliplatin + + + + + +/+ + + + + + ?4
Paclitaxel ↑ ↓3 ↑ ↓ + ↓/↓3 ↓3 ↓3 ↑ ↓3 ↓3 ↑
Sirolimus – ↓ ↓ ↓ ↓ +/+ + + ↑ + + +
Tacrolimus ↑ ↓ ↓ ↓ ↓ +/+ + + ↑ + + ?4
Tamoxifen ↑ ↓3 ↓ ↓ ↓ +/↓3 ↓3 + ↑ ? + ↓4
Vinblastine ↑ ↓3 ↓ ↓ ↓ +/↓3 ↓3 ↓3 ↑ ↓3 ↓3 ↓
Vincristine ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
1 Active level of immunosuppressant increases; observe dose adjustment and maximum dose
(according to package insert)
2 Active level of the HIV drug increases!
3 Active level of the HIV drug decreases!
4 QT prolongation possible

Contraceptives
Particular caution is required when contraceptives are combined with protease
inhibitors or efavirenz. In contrast, concomitant use with rilpivirine, doravirine,
bictegravir, dolutegravir, cabotegravir, or raltegravir appears to be unproblematic.
Drug interactions 677

Malaria/Protozoan Therapy
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Artemisinin ↑ ↓1 ↓ ↓ ↓ +/↓1 ↓1 + ↑ ↓1 + (↑)
Atovaquone ? + ↓ ↓ ↓ +/+ + + + + + +
Chloroquine + + + + + +/+ + + + + + ?2
Doxycycline + + + + + +/+ + + + + + +
Lumefantrine ↑ + ↓ ↓ ↓ +/+ + + ↑ + + ?2
Mefloquine ↑ + ↓ ↓ ↓ +/+ + + ↑ + + ?2
Pentamidine + + + + + +/? + + + + + ↑2
Primaquine + + + + + +/+ + + + + + ?2
Proguanil ↓ + ↓ ↓ ↓ +/+ + + + + + +
Pyrimethamine + + + + + +/+ + + + + + +
1 Active level of the HIV drug decreases!
2 QT prolongation possible

Phosphodiesterase type 5 inhibitors

Combining PDE5 inhibitors with a boosted protease inhibitor sometimes leads to
strong increases in the PDE5 inhibitors. Therefore, they should always be given cau-
tiously and initially at half of the lowest dose maximum every 48 to 72 hours.
According to an FDA warning, sildenafil is contraindicated for treating PAH in com-
bination with boosted ART. Tadalafil should be adjusted for treating PAH when taken
concomitantly with PI. Also, be careful with EVG/c – this also significantly increases
levels of PDE5 inhibitors.
The combination of sildenafil (in PAH dose) + EVG/c is contraindicated, and simi-
larly, relevant interactions are also likely to exist for tadalafil and vardenafil. In com-
bination with EFV, NVP, and ETV, there are usually decreased levels of PDE5 inhibitor
activity. Concurrent use with DOR, RPV (caveat: QT time prolongation possible),
MVC, DTG, CAB, BIC, or RAL is possible.

Statins/lipid-lowering agents
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Atorvastatin ↑1 + ↓ ↓ ↓ +/+ + + ↑1 + + ↑
Clofibrate + + + + + +/+ + + + + + +
Ezetimibe ↑ + + + + +/+ + + + + + +
Fenofibrate + + + + + +/+ + + + + + +
Fluvastatin ↑ + ↑ ↑ + +/+ + + ↑ + + ↑
Gemfibrozil ? + + + + +/+ + + + + + +
Lovastatin – + ↓ ↓ ↓ +/+ + + – + + ↑
Pravastatin ↑ + ↓ ↓ + +/+ + + ↑ + + ↑
Rosuvastatin ↑1 + + + + +/+ + + ↑ + + ↑
Simvastatin – + ↓ ↓ ↓ +/+ + + – + + ↑
1 Always start with the lowest statin dose! Caution: rhabdomyolysis
678 Drugs

Substitution
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Buprenorphine ↑ + ↓ ↓ + +/+ + + + + + +
Codeine ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Methadone ? + ↓ ↑ ↓ ?/↓1 + + + + + ↑
Morphine ↓ + ↑ ↑ + +/+ + + ↑ + + +
1 Caution when combining methadone with RPV because of possible QT time prolongation

Virustatics/antivirals
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Acyclovir + + + + + +/+ + + ? + + +
Adefovir ?1 ?1 + + + +/+ + + – – + +
Cidofovir + + + + + +/+ + + ? + + +
Entecavir + + + + + +/+ + + + + + +
Famciclovir + + + + + +/+ + + + + + +
Foscarnet + + + + + +/+ + + ? + + +
Ganciclovir + + + + + +/+ + + ? + + +
Oseltamivir + + + + + +/+ + + + + + +
Ribavirin + + + + + +/+ + + + + + +
Valacyclovir + + + + + +/+ + + ? + + +
Valganciclovir + + + + + +/+ + + ? + + +
Glecaprevir/Pibrentasvir – + – – – +/+ + + + ? + (↑)
Elbasvir/Grazoprevir – + – – – +/+ + + – + + –
Sofosbuvir/Velpatasvir + + – – – +/+ + + + + + (↑)
1 No combination of adefovir with Symtuza® or Delstrigo®.
Drug interactions 679

Other
Here are listed alphabetically some more commonly used drugs that have not been
assigned to individual categories.
DRV DOR EFV ETV NVP CAB/ MVC DTG EVG/c BIC RAL FTR
RPV
Alendronate + + + + + +/+ + + + + + +
Allopurinol + + + + + +/+ + + + + + +
Budesonide – + ↓ ↓ ↓ +/+ + + – + + +
Celecoxib + + ↑ ↑ + +/+ + + + + + +
Colecalciferol + + + + + +/+ + + + + + ?
Dexamethasone4 ?1 ↓2 ↓2 ↓2 ↓2 ?/– ↓2 + ?1 ↓2 + +
Diclofenac + + ↑ ↑ + +/+ + + ?3 + + +
Ibandronate + + + + + +/+ + + + + + +
Ibuprofen + + ↑ ↑ + +/+ + + ?3 + + +
Naproxen + + ↑ ↑ + +/+ + + ?3 + + +
Paracetamol + + + + + +/+ + + + + + +
Prednisone ↑ + ↓ ↓ ↓ +/+ + + ↑ + + +
Theophylline ↓ + + + + +/+ + + + + + +
Torasemide + + ? ? + +/+ + + ? + + +
1 Dexamethasone level increases and active level of HIV drug decreases!
2 Active level of the HIV drug decreases
3 Caution: Check kidney values in combination with TDF
4 No combination of CAB/RPV as injection with dexamethasone!

Literature and links

Bartlett JG; Pocket Guide Adult HIV/AIDS Treatment 2008-09. [Link].
Fachinformationen: Atripla®, Biktarvy®, Celsentri®, Delstrigo®, Descovy®, Emtriva®, Edurant®, Epivir®, Eviplera®,
Genvoya®, Intelence®, Isentress®, Kivexa®, Norvir®, Odefsey®, Prezista®, Rekambys®, Retrovir®, Rukobia®, Stribild®,
Sustiva®, Symtuza®, Tivicay®, Triumeq®, Trizivir®, Truvada®, Tybost®, Viramune®, Viread®, Vocabria®, Ziagen®.
[Link] (Lexi-Comp Online™ Interaction Lookup).
[Link].
680

37. ART – alternative administrations

SARAH FISCHER, MARKUS UNNEWEHR

This chapter provides a brief overview of the options for ART via feeding tubes, in
case of difficulties swallowing, and via parenteral administration.

Pharmaceutical aspects
Drugs must be crushed, suspended, or dissolved to facilitate ingestion in case of
difficulties swallowing or for administration via a feeding tube. The manufacturer
has often not studied cutting, crushing, and dissolving ART, which is not recom-
mended. In this case, the use is off-label and constantly on a case-by-case medical
decision. Whether a drug is suitable for crushing and tube administration depends
on the active ingredient properties and the pharmaceutical manufacturing method.
Particular attention must be paid to active ingredient stability, bioavailability, osmo-
larity, and interactions with food components.
The active substance’s pharmacological location and absorption site must not be
affected by the type and position of the feeding tube. In this case, parameters such
as the pH value of the resorption site are relevant. Acid-sensitive active ingredients
protected by an enteric coating must not be crushed in an acidic gastric environ-
ment; conversely, jejunal administration is possible.
Environmental influences such as light, oxidation, and moisture affect the chemical
stability of the drug substance and limit its shelf life. Therefore, the medication must
be applied immediately after comminution. In addition, film-coating components
can swell rapidly and clog a feeding tube.
Liquid antiretroviral drugs available on the market are primarily designed for
pediatrics. Adults must, therefore, take large volumes due to the low concentration
of active ingredients. As a result, there is a risk of excipients accumulating and
relatively high sugar and sorbitol levels, leading to increased osmolarity and causing
gastrointestinal discomfort. This is why oral solutions should be diluted before
application. Depending on the type and width of the tube, maximum applicable
volumes must be noted.
The pharmacological processing into the solid drug form defines the possibility of
crushing. In particular, in the case of sustained-release tablets, there are various ways
to incorporate the drug substance and delay its release. Mechanical comminution
can release too large amounts of active ingredients in too short a time. This can lead
to dose-dependent side effects and insufficient duration of action.
Most hard gelatin capsules can be opened, and the content can be suspended. Some
dosage forms, such as lingual tablets or soft capsules, are less suitable for crushing,
division, or suspension because of their nature, shape, and release of active
ingredients. In principle, the method of taking a drug should not be changed.
Simultaneous food intake may affect absorption. However, this is necessary with
some antiretroviral agents to achieve adequate exposure because specific dietary
components (especially fat) are required, or a delayed intestinal transit time is needed.
For others, this is not necessary.
Caution is advised in using magnesium- or aluminum-containing antacids or iron-
and calcium-containing supplements. Complex formation can significantly reduce
drug exposure.
ART – alternative administrations 681

ART administration via feeding tubes

In general, the following applies to drug administration via a feeding tube:
• There is a risk that the desired clinical effect fails due to the active ingredient becom-
ing ineffective, the feeding tube becoming blocked, and the drug irritating the
mucous membranes.
• The preparation must be finely crushed and dissolved or suspended in water. Direct
dissolution in a syringe filled with water is preferable to avoid loss of the substance.
• Mortar and suspend medications only immediately before use.
• Each drug should be administered separately and not simultaneously with other
medications or enteral nutrition to avoid (chemical) incompatibilities.
• If fasting ART is required, enteral nutrition boluses are preferable to continuous
feeding. If continuous feeding is mandatory, it must be interrupted to administer
the solubilized drug after gastric emptying.
• Rinse the feeding tube with water before and after drug administration.

Table 1
Active Trade name To take on Form2 Crushing Note
ingredient(s) an empty possible?3
stomach
Abacavir Ziagen® no matter FCT yes Solution
FTC Emtriva® no matter HC no Crushing not possible,
suspension possible (solution)
3TC Epivir® no matter FCT yes Solution
TDF Viread® no FCT yes Granulate
AZT Retrovir® no matter HC no Crushing not possible,
suspension possible, solution
ABC/3TC Kivexa® no matter FCT no
TAF/FTC Descovy® no matter FCT yes
TDF/FTC Truvada® no FCT yes
Dolutegravir Tivicay® no matter FCT yes Tablets for the preparation of
a suspension
Raltegravir Isentress® no matter FCT no Granulate, 400 mg, 600 mg
Raltegravir Isentress® no matter CT yes Granulate, 25 mg, 100 mg
Atazanavir Generic no HC no Crushing not possible,
suspension possible
Darunavir Prezista® no FCT yes Suspension
Lopinavir/r Kaletra® no matter FCT no Solution: Rinse with milk
Tipranavir Aptivus® no SC no
Efavirenz Sustiva® no FCT yes (crush before suspending)
Etravirine Intelence® no TAB no Crushing not possible, suspension
see product information
Nevirapine Viramune® no matter TAB yes Suspension, 200 mg
682 Drugs

Table 1: Continuation
Active Trade name To take on Form2 Crushing Note
ingredient(s) an empty possible?3
stomach
Nevirapine Viramune no matter SRT no 400 mg
RETARD®
Rilpivirine Edurant® no FCT no Barely soluble in
water, bitter taste
Doravirine Pifeltro® no matter FCT no
Maraviroc Celsentri® no matter FCT yes
Fostemsavir Rukobia® no matter SRT no
Efavirenz/FTC/TDF Generics yes FCT no
previously Atripla®
Bictegravir/FTC/TAF Biktarvy® no matter FCT yes Results of SOLUBIC
study pending; BIC
insoluble in water
Doravirin/3TC/TDF Delstrigo® no matter FCT no DOR is poorly
soluble in water
Dolutegravir/3TC Dovato® no matter FCT yes
Rilpivirine/FTC/TDF Eviplera® no FCT no altered resorption
Dolutegravir/Rilpivirine Juluca® no FCT yes
Rilpivirine/FTC/TAF Odefsey® no FCT no
Elvitegravir/c/FTC/TAF Genvoya® no FCT no Case Report
Elvitegravir/c/FTC/TDF Stribild® no FCT yes
Darunavir/c/FTC/TAF Symtuza® no FCT yes
Dolutegravir/Abacavir/3TC Triumeq® no matter FCT yes
Abacavir/3TC/AZT Trizivir® no matter FCT no
Cobicistat Tybost® no FCT no
Ritonavir Norvir® no FCT no Dilute suspension
with milk; precipit-
ate with water
1 Fasting = time interval between drug and food administration (1 h before or 2 h after a meal).
2 Dosage form: FCT – film-coated tablet, HC – hard capsule, CT – chewable tablet, TAB – tablet, SRT –
sustained-release tablet, SC – soft capsule.
3 “Crushing possible” – due to its nature, the drug can be crushed in a mortar from a pharmaceutical
point of view without any altered clinical effect. This is independent of the approved method of use.
Depending on the manufacturer and formulation, the indication may differ.
4 “Suspension possible” – the previously comminuted drug, the intact drug, or the capsule contents
can be dissolved or suspended in a liquid medium (including water juice) due to its nature from a
pharmaceutical point of view, without an expected altered clinical effect. This is independent of the
approved way of administration. Depending on the manufacturer and formulation, the indication
may differ.
ART – alternative administrations 683

Parenteral administration
If enteral drug administration is not possible in the context of, for example, intensive
care treatment, ART becomes problematic. This is because the number of parenterally
administrable agents currently approved is very limited:

Table 2: Preparations for parenteral ART.

Active ingredient Trade name Administration Dosage
Rilpivirine Rekambys® 900 mg/3 mL IM 900 mg every 2 months
Cabotegravir Vocabria® 600 mg/3 mL IM 600 mg every 2 months
Enfuvirtide Fuzeon® 90 mg/1 mL SC 90 mg every 12h
Zidovudine Retrovir IV® 200 mg/20 mL IV 1–2 mg/kg BW every 4h
Lenacapvir Sunlenca® 463.5 mg/1.5 mL SC 927 mg every 6 months
Ibalizumab Trogarzo® 200 mg/1.33 mL IV 2000 mg (initial dose),
maintenance dose 800 mg
every 2 weeks
IM = intramuscular, SC = subcutaneous, IV = intravenous after dilution

The two long-acting substances, rilpivirine and cabotegravir, are administered

simultaneously at monthly or bimonthly injection intervals. This combination is
not suitable as an acute treatment.
Intravenous AZT is a component of obstetrics in HIV-positive women.
Injectable antiretroviral therapies have not yet been adequately tested in studies on
intensive care patients. Considering the significantly altered pharmacokinetics and
pharmacodynamics under intensive care conditions, they are, at most, a therapeutic
alternative in justified individual cases (Berruti 2021).

Literature
Berruti M, Riccardi N, Canetti D, et al. Injectable Antiretroviral Drugs: Back to the Future. Viruses 2021, 13, 228.
Fuchs C, Radziwill R. Arzneimittelgabe über Ernährungssonden. Enterale Ernährung, Braun, 2005.
Liverpool Drug Interactions Group, University of Liverpool, [Link]. [Link]
[Link]/prescribing_resources/pdfs/000/000/011/original/ARV_Swallowing_2018_Oct.pdf?1540
371581
San C, Lê MP, Matheron S, et al. Management of oral antiretroviral administration in patients with swallowing
disorders or with an enteral feeding tube. Médecine et Maladies Infectieuses 2020, 50, 537-44.
Tseng A, Foisy M, Hughes C. Crushing and Liquid ART Formulations. [Link]/main/drugs_extra_files/
Crushing %20and %20Liquid %20ARV %[Link]
Clinical Images
686 Clinical Images

Clinical Images Credits

TAFEL 1: 1 JR, 2 MO, 3 CH, 4 JR, 5 MO
TAFEL 2: 1+2 CH, 3+4 HJS, 5–7 CH
TAFEL 3: 1 JR, 2–6 MO, 7+8 CH, 9+10 MO
TAFEL 4: 1 CH, 2 SU, 3+4 CH, 5 HJS, 6 CH, 7 JR, 8 MO
TAFEL 5: 1+2 CL, 3 JR, 4 HJS, 5 CH, 6 SU, 7–9 MO
TAFEL 6: 1 JR, 2+3 MO, 4 SU, 5+6 GH, 7 CH, 8 HJS, 9 MO
TAFEL 7: 1+2 CH, 3 HJS, 4 CE, 5–9 CH
TAFEL 8: 1+2 CH, 3 JT, 4 CH, 5+6 HJS, 7 CH, 8 MS, 9 HJS, 10+11 MO
TAFEL 9: 1–8 CH, 9+10 CG
TAFEL 10: 1–8 CH, 9 MO, 10 JR
TAFEL 11: 1+2 CH, 3 HJS, 4 CH, 5 HJS, 6+7 CH
TAFEL 12: 1 JR, 2 HJS, 3 CH, 4 TB, 5 SH
TAFEL 13: 1 CH, 2 JJ, 3 MO, 4–10 CH, 11 KS, 12 CH
TAFEL 14: 1 MO, 2 HJS, 3+4 RJ, 5 MO, 6–10 RJ
TAFEL 15: 1 SE, 2 MO, 3+4 SE, 5–7 JJ, 8+9 MO
TAFEL 16: 1–3 JJ, 4+5 CH, 6–9 JJ
TAFEL 17: 1+2+4 CH, 3 KS, 5+6 MS, 7–9 CH
TAFEL 18: 1–4 GS, 5–8 SF
Clinical Images 687

1 2

4 5
1. Pneumocystis pneumonia
1 Chest X-ray with interstitial infiltrates. The patient is intubated and ventilated.
2 Pneumocystis pneumonia, confirmed in BAL.
3 Chest X-ray before and three weeks after cotrimoxazole therapy.
4 CT chest in PCP.
5 CT chest, multiple Kaposi's sarcomas simultaneously (in the setting of IRIS).
688 Clinical Images

1 2 3

4 5 6

2. Cerebral toxoplasmosis
1/2 MRI scan of the same patient, two planes. Multiple, small lesions.
3 Solitary lesion with typical ring-shaped contrast enhancement (CCT).
4 CCT with large, solitary lasing and extensive edema.
5/6 Large occipital lesion in two planes.
7 Typical ring-shaped contrast enhancement.
Clinical Images 689

1 2 3

4 5 6

7 8 9

3. Herpes diseases (CMV, HSV)

1 Typical funduscopic findings, CMV retinitis.
2 Large CMV ulcer on the tongue, severe immunodeficiency.
3 CMV-associated gastric ulcer.
4 CMV ulcers in the esophagus.
5 CMV colitis.
6 CMV proctitis.
7/8 Herpes simplex infection in a patient with massive
immunodeficiency, refractory to acyclovir, resolving with
foscarnet therapy.
9 Herpes simplex esophagitis.
10 10 Large HSV-associated ulcer.
690 Clinical Images

1 2 3

4 5 6

7 8

4. Herpes zoster infections and candidosis

1 Herpes zoster at the right arm, hemorrhagic.
2 Zoster ophtalmicus.
3/4 Herpes zoster before treatment and three weeks later.

Candidosis
5/6 Oral candidiasis (oral thrush).
7/8 Esophageal candidiasis, endoscopic images
Clinical Images 691

1 2 3

4 5 6

7 8

5. Tuberculosis, various manifestations

1 Tuberculosis pleuritis with right-sided
pleural effusion. Left-sided "Tree-in-bud"
phenomenon as seen in the bronchial
spread of tuberculosis.
2 Tuberculosis cavities in the left upper
lobe. Miliar nodules on the right.
3 Tuberculosis with splenic involvement.
4–6 Lymph node tuberculosis, abscessing,
in the context of an IRIS.
7–9 Miliary tuberculosis. Chest X-ray and
9 CT findings.
692 Clinical Images

1 2 3

4 5 6

7 8 9

6. Atypical mycobacterial infections and mycoses

1 CT scan of the abdomen with multiple lymph nodes, infection with M. avium intracellulare
(MAI) infection.
2/3 Intestinal MAI infection (coloscopy)
4 Abscess, detection of M. xenopi (manifestation as IRIS)
5/6 Cutaneous infection with Talaromyces marneffii (not AIDS-defining, but common in
Southeast Asia!).
7 Cryptococcosis, CT findings.
8 Cryptococcosis, pulmonary cryptococcoma.
9 Aspergilloma (and CMV pneumonia, both microbiologically confirmed).
Clinical Images 693

1 2 3

4 5 6

7 8 9
7. PML and HAND
1 MRI scan with a relatively small PML lesion (arrow). JCV was detected in CSF.
2 Cerebellar involvement of PML
3 Extensive PML lesions on MRI.
4 Axial T2-weighted MRI of a 60-year-old patient with HAND. Moderate atrophy, hyperintense
lesions at the rostral and caudal end of the cella media of lateral ventricles (typical but not
specific for HAND)
5/6 PML, MRI findings before and six months after initiation of ART. Partial regression
(T2-weighted scan).
7–9 PML during ART. On the left, manifestation of occipital lesion two months after starting ART,
then maximum manifestation two months later. On the right, regression, a further three
months later. No specific PML therapy was given.
694 Clinical Images

1 2 3

4 5 6

7a 7b 8

9 10 11

8. Kaposi's sarcoma (KS)

1–5 Miscellaneous cutaneous findings.
6 Plate-like involvement in the groin, often with accompanying lymphodema of the affected
extremity.
7a/b Mucocutaneous involvement of the hard palate before and after four cycles of
chemotherapy.
8 Penile lesion.
9 Conjunctival lesions.
10 Visceral disease.
11 Pulmonary KS.
Clinical Images 695

1 2 3

4 5 6

7 8 9
9. Malignant lymphomas
1 Burkitt's lymphoma, rapidly growing, cervical location.
2 Diffuse large B cell lymphoma, destructive of the nasal area.
3 Plasmablastic lymphoma of the oral cavity (rare subtype,
almost exclusively occurring in PLWH).
4–6 Primary CNS lymphoma. On the left, a large solitary lesion
with contrast enhancement. In the middle, the same
patient, complete remission after radiotherapy. On the right,
the same patient, almost three years later. Marked atrophy
10 due to radiotherapy (clinical dementia)
7/8 Hodgkin's disease with typical cervical manifestation before
and after chemotherapy (complete remission).
9 Multicentric Castleman's disease (MCD) with
hepatosplenomegaly on CT abdomen.
10 MCD, large spleen (autopsy finding).
11 MCD, characteristic histological findings, germinal center
with a typical “onion-skin” pattern

11
696 Clinical Images

1 2

3 4 5

6 7 8
10. Lipodystrophy
1/2 Buffalo Hump.
3–5 Extended abdominal fat
accumulation.
6 Facial lipoatrophy.
7 Lipoatrophy. Due to the
subcutaneous fat loss,
a Port-a-Cath system
(used for CMV treatment)
is visible
8/9 Subcutaneous fat loss at
the lower extremities with
bulging veins, occurring
after years of NRTI therapy
(“D-drugs”, DDI, and D4T)
10 Classic wasting syndrome.

9 10
Clinical Images 697

1 2

3 4

5 6 7

11. Other side effects of antiretroviral therapies.

1 Avascular necrosis of the humerus (possibly due to PI therapy)
2 Serum sample from a patient with hypertriglyceridemia> 3,000 mg/dl, caused by PI-based
therapy with saquinavir/r (resolved after switching to PI-free regimens).
3 Gangrenous ergotism: finger necrosis occurring under the combination of lopinavir/r and
ergotamine.
4,5,7 NNRTI rash in patients treated with nevirapine (1–3 weeks after onset).
6 Exanthema, occurring with darunavir (clinically indistinguishable from NNRTI rash).
698 Clinical Images

3 4

12. Various cutaneous manifestations in PLWH

1 Macular exanthema in acute HIV infection.
2 Seborrheic exanthema (indicator disease!).
3 Cutaneous porphyria (extrahepatic manifestation of hepatitis C, resolving after HCV treatment).
4 Scabies infection.
5 Multiple abscesses after chemsex (mephedrone) in an HIV-infected MSM.
Clinical Images 699

1 2 3

4 5 6

7 8 9

10 11 12
13. Sexually transmitted diseases (Syphilis and LGV)
1–4 Primary syphilis.
5 Painful ulcer caused by chlamydia L3, lymphogranuloma venerum (LGV), swollen lymph
nodes (arrow).
6 LGV ulcer.
7–12 Various findings (no pain, no pruritus!) in lues II.
700 Clinical Images

1 2 3

4 5 6

7 8 9
14. Oral manifestations in PLWH (thrush see candidiasis)
1/2 Oral hairy leukoplakia (OHL), typical plaques which cannot
be scraped off
3 Solitary oral warts on the tongue
4 Solitary oral warts on the oral mucosa
5 “Plaque muqueuses” (oral manifestation of syphilis)
6 Necrotizing ulcerative periodontitis at teeth 33 and 35.
7 Linear gingival erythema on the vestibular gingiva.
8 Generalized chronic periodontosis.
9 Disseminated oral warts on the vestibular gingiva.
10 Oral vestibular ulcers at tooth 37.
10
Clinical Images 701

1 2 3

4 5 6

7 8 9

15. HPV-associated diseases

1/2 Anal condylomata acuminata.
3 Genital condyloma.
4 Bowenoid papulosis.
5 Perianal infection with molluscum contagiosum virus (not HPV-related!).
6 Anal intraepithelial neoplasia (AIN) III.
7 AIN III with the transition to anal carcinoma (green Siton drainage of a fistula).
8 Anal dysplasia (yellow areas).
9 Anal dysplasia, FICE technique (red areas).
702 Clinical Images

1 2 3

4 5

7 8 9

16. Anal carcinomas and differential diagnoses

1 HIV-positive woman presenting with "hemorrhoids". Diagnosis: Invasive anal carcinoma
(stage T2).
2 Verrucous anal carcinoma, prolapsing from the anal canal.
3 HIV-positive man with a three-week history of a growing tumor. Chlamydial proctitis was
initially misdiagnosed as anal carcinoma.
4/5 Painful ulcer due to lymphogranuloma venerum (LGV), initially misinterpreted as anal
carcinoma, resolving after three weeks of doxycycline.

Inflammatory proctological findings

6 Anal CMV infection with extremely painful ulcers.
7 Anal HSV infection, also painful ulcers.
8 Purulent (purulent!) gonococcal proctitis.
9 Painful purulent proctitis with induration (detection of gonococci and chlamydia L3 serotype).
Clinical Images 703

1 2

3 4

5 6

7 8 9
17. Mpox
1/2 Isolated necrotic lesion on the penis. On the right, five weeks later (of note, still positive
MPXV PCR).
3 Genital lesion with edema.
4 Very painful perianal lesions; hospitalization required (analgesia).
5/6 Isolated lesions on fingers, genital, note the central necrosis.
7 Isolated lesion on upper extremity.
8 Unusual, painless, flat-like lesion temporal.
9 Extremely painful pharyngeal ulcer.
704 Clinical Images

1 2

3 4

5 6

7 8

18. Mpox, changes over time

1–4 Pubic lesions at different stages, resolving over 21 days without therapy (MPXV PCR positive
at all stages).
5–8 Pubic lesions, rapid progression over seven days with hemorrhages.
705

Index
3 Bevirimat ...........................................116
3TC see lamivudine Bictegravir ...........................74, 174, 633
Bictegravir, resistance ........................271
A Biktarvy see bictegravir
Blips ...................................................123
Abacavir.......................................49, 628
Boosting PIs .........................................67
Abacavir, HSR ....................................191
Brand names........................................45
Acute HIV infection ............................31
Brecanavir ..........................................101
Acyclovir....................................264, 629
Broadly neutralizing antibodies ........109
Adaptive immunity .............................26
BST-2 ....................................................25
Addictive disorders ............................575
Budding ...............................................24
Adefovir ...............................................99
Burkitt’s lymphoma...........................366
Adherence..........................................159
AIC 292..............................................101
AIDP...................................................562 C
AIDS dissidents ..................................162 Cabenuva...........................202, 634, 657
AIN.....................................................383 Cabotegravir ........................75, 202, 634
Albuvirtide...................................95, 105 Cabotegravir, resistance ....................271
Aldesleukin ........................................119 Caelyx see doxorubicin
Allergic reactions.......................190, 544 Caesarian section...............................485
ALLINIs ..............................................103 Calanolide A ......................................101
Alovudine ............................................99 Candidiasis ........................................302
Amphotericin B .................................630 Cannabinoids ....................................119
Amprenavir..........................................70 Capravirine ........................................101
Anal carcinoma .................................383 Capsid inhibitors...........................92, 95
Ancriviroc ..........................................107 CARD8 .................................................25
Aplaviroc ...........................................107 Cardiac arrythmias ............................517
APOBEC3G ..........................................25 Cardiomyopathy ...............................516
Apretude see cabotegravir Cardiopulmonary diseases ................511
Apricitabine .........................................97 Cardiovascular diseases .....................516
Aptivus see tipranavir Cardiovascular events .......................191
ART, overview......................................43 CAR-T-cells.........................................367
ART, perspective ..................................40 CCR5 receptor .....................................22
ART, side effects.................................281 CD4 receptor .......................................22
Aspergillosis .......................................344 CD4 T-cells ..........................27, 127, 237
Assembly..............................................24 CD8 T-cells...........................................27
Atazanavir ...........................68, 173, 630 CDC classification .................................7
Atevirdine ..........................................101 Celsenti see maraviroc
Atovaquone .......................................631 Cenicriviroc .......................................105
Atripla........................................172, 632 Censavudine ........................................97
Attachment inhibitors.........................83 Cerebral toxoplasmosis .....................294
Atypical mycobacteriosis...................316 Cervical dysplasia ..............................472
Azithromycin.....................................632 Chancroid..........................................421
AZT ..............................................49, 633 Checkpoint inhibitors.......................118
Chemokines.........................................22
B Chemsex....................................165, 587
Babesia ...............................................452 Children ............................................493
Bacillary angiomatosis ......................345 Chlamydia infection .........................418
Bacterial pneumonia .........................328 Cholera vaccine.................................448
Bartonella quintana...........................345 Cidofovir............................................634
706 Index

CIDP ..................................................562 Dialysis ..............................................527

Circumcision .............................262, 608 Didanosine ..........................................50
Clarithomycin ...................................635 DILS ...................................................562
Clindamycin......................................635 Directly administered therapy ..........160
CMV IRIS ...........................................338 Directly observed therapy .................160
CMV retinitis.....................................298 Discordant response ..........................126
CNS penetration effectiveness score 557 Dolutegravir ................................76, 640
Cobicistat.....................................67, 636 Dolutegravir, resistance .....................269
Coccidioidomycosis ..........................347 Dolutegravir-LA ...................................94
Combinectin......................................105 Doravirine ...................................60, 641
Combivir .....................................56, 637 Doravirine, resistance........................266
Complera ...........................................646 DOT (directly observed therapy) ......160
Compliance .......................................159 Dovato ...............................177, 201, 641
Concurrent illnesses ..........................163 Doxil see Doxorubicin
Condylomata acuminata ..........383, 422 Doxorubicin (liposomal) ...................642
Contraception ...................................473 Doxorubicin, liposomal ....................356
COPD.................................................514 Doxy-PEP ...........................................609
Coreceptor antagonists .................83, 85 Drug Interactions ..............................670
Coronary heart disease......................516 Dry skin .............................................549
Corticosteroids ..................................118 DSSP...................................................564
Costs ....................................................46 Dual therapies in first-line ................177
Cotrimoxazole ...................................637 Dual therapy......................................200
COVID-19 ..........................................403 Duesbergians .....................................162
CPE score ...........................................557 Dyslipidemia......................................188
Crixivan see indinavir
Cryptococcal IRIS ..............................339
Cryptococcosis ..................................333 E
Cryptosporidiosis ..............................331 Edurant see rilpivirine
Cure ...................................................136 Efavirenz ......................................61, 642
CXCR4 antagonists ...........................106 EKAF paper ........................................261
CXCR4 receptor...................................22 Elipovimab ........................................111
Cyclosporine A ..................................118 Elite controllers ...........................24, 138
Cystoisosporiasis ...............................347 Elpida.................................................101
Elvitegravir ..........................77, 176, 643
Elvitegravir, resistance.......................268
D Elvucitabine.........................................97
D4T ......................................................50 Emivirine ...........................................102
Dapivirine..........................................102 Emtricitabine ...............................51, 643
Dapsone.............................................638 Emtriva see FTC
Darunavir ....................................69, 638 Enfuvirtide...........................................88
Darunavir, resistance .........................267 Enterocytozoon bieneusi...................350
Daunorubicin, liposomal ..........356, 639 Entry inhibitors ...................................83
DDC .....................................................50 Epclusa...............................................644
DDI ......................................................50 Epidemiology ....................................2, 9
Delavirdine ..........................................60 Epivir see lamivudine
Delstrigo ....................................171, 639 Epzicom .............................................652
Dendritic cells......................................24 Eradication ........................................138
Dengue fever vaccine ........................449 Esulfavirine ........................................101
Depression .........................................571 Ethambutol........................................645
Descovy .............................................640 Etravirine .....................................62, 645
Dexelvucitabine...................................99 Etravirine, resistance .........................265
Diagnostic window .............................16 Eviplera......................................171, 646
Index 707

F Histoplasmosis...................................346
Fanconi syndrome.............................524 HIV cure ............................................136
Festinavir .............................................97 HIV encephalopathy see HAND
Fiebig stages.........................................31 HIV PCR...............................................15
Fipravirimat (GSK-254) .....................116 HIV testing ..........................................13
First-line therapy ...............................157 HIV, vaccine.......................................614
Fluconazole........................................646 HIV-2 infection..................................456
Folliculitis ..........................................546 HIV-AN ..............................................521
Fosamprenavir .............................70, 647 HIV-associated myelopathy...............558
Foscarnet............................................647 HIV-associated nephropathy.............521
Fosdevirine ........................................102 HIV-associated neurocognitive disorder
Fostemsavir..........................83, 218, 647 see HAND
Fostemsavir, resistance ......................273 HIV-associated thrombocytopenia....538
Fozivudine ...........................................97 HIVE see HAND
FTC ..............................................51, 643 HLA system..................................26, 136
Fusion inhibitors .................................88 Hodgkin’s disease ..............................373
Fuzeon see enfuvirtide Hormone substitution.......................595
HPV vaccine ..............................438, 471
HTLV-I....................................................3
G
Human papillomavirus .....383, 422, 471
Gag polymorphisms ..........................116
Humoral response ...............................28
Ganciclovir ........................................648
Hydroxyurea......................................118
Gastrointestinal symptoms ...............188
Hyperlipidemia..................................188
G-CSF, GM-CSF..................................118
Hypersensitivity reaction (HSR) ........191
Generics ...............................................45
Genital ulcers ....................................418
Genotyping, resistance......................255 I
Genvoya see elvitegravir
Ibalizumab...........................84, 219, 649
Genvoya ............................................648
Immune modulators .........................118
Glecaprevir see Maviret
Immune reconstitution inflammatory
Global access to ART .........................245
syndrome see IRIS
Global fund ...............................247, 273
Immune reconstitution.............125, 238
Glomerulonephritis...........................522
Indinavir..............................................71
Gonorrhea .........................................416
Influenza vaccination........................437
Granuloma inguinale ........................422
Innate Immune System.......................24
GSK-254 .............................................116
INSTIs ..........................................74, 174
Guillan-Barré syndrome ....................562
Intelence see etravirine
Gynaecology......................................470
Intensification trials ..........................139
Interactions ...............................164, 670
H Interferon ..........................................650
Haemophilus ducreyi ........................421 Interferons for HIV............................119
HAND ................................................552 Interferons for KS ..............................357
Harvoni..............................................649 Interleukin-2......................................119
HCV co-infection ..............................392 Interleukin-7, -12, - 15 ......................119
HDAC inhibitors ...............................140 Invirase see saquinavir
Hepatitis B .........................................398 IRIS.....................................................338
Hepatitis C ........................................392 Isentress see raltegravir
Hepatitis vaccination ........................437 Islatravir.........................................94, 97
Hepatotoxicity...................................192 Islatravir, resistance ...........................273
Herpes simplex ..................................319 Isoniazid ............................................650
Herpes simplex, prevention ..............263 Isosporiasis.........................................347
Herpes zoster .....................................322 Itraconazole .......................................651
708 Index

J MDR-TB .............................................311
Japanese encephalitis ........................447 Measles vaccination ..........................438
JC virus ..............................................324 Measles ..............................................451
Juluca.........................................200, 651 Mega-ART ..........................................119
Meningococcal vaccine .............439, 447
K Menopause ................................466, 473
Kaletra see lopinavir Mephedrone ......................................590
Kaposi’s sarcoma................................354 Microbicides ..............................264, 609
Ketamine ...........................................590 Microsporidiosis ................................350
Kivexa ..........................................55, 652 Minor variants...................................262
Mississippi Baby ................................137
L MK-8507 ............................................101
Lactic acidosis....................................195 Molluscum contagiosum...................546
Lamivudine .................................50, 628 Monitoring ........................................234
Late presenters...................................150 Monkeypox .......................................431
Latency ................................................24 Monotherapies ..................................205
Latent reservoirs ................................139 Mozenavir..........................................102
Latent TB ...........................................308 Mpox vaccine ....................................440
LEDGINs ............................................103 Mpox .................................................431
Ledipasvir see Harvoni mRNA vaccines for HIV ....................618
Leishmaniasis ............................348, 451 Mucocutaneous diseases ...................543
Lenacapavir .........................92, 219, 652 Multicentric Castleman.....................375
Lenacapavir, resistance......................274 Multi-class resistance.........................219
Leronlimab ........................................106 Murabutide ........................................119
Lersivirine ..........................................102 Mycobacterial IRIS.............................338
Lexiva see fosamprenavir Mycobacterium avium complex .......316
LIP......................................................514 Mycophenolate..................................119
Lipodystrophy ...................................193 Mycoplasma infections .....................420
Lipovirtide .........................................106 Myopathy ..........................................569
Lobucavir .............................................99
Lodenosine ..........................................99 N
Long-acting drugs........................94, 202 Natural course of HIV ..........................6
Long-Term Non Progressors ................24 Natural course, HIV-2........................455
Long-term toxicity ............................184 Natural killer cells ...............................26
Lopinavir .....................................69, 653 Nelfinavir.....................................71, 655
Loviride..............................................102 Neonates, treatment..........................487
Low-level viremia ..............................122 Nephropathy .....................................519
Lues....................................................411 Neuromuscular diseases ....................562
Lung cancer .......................................386 Neuropsychiatric adverse events.......193
Lung diseases .....................................511 Neutralizing antibodies .....................109
Lymphogranuloma venereum ..........418 Nevirapine ...................................62, 655
Lymphoid interstitial pneumonia ....514 NNRTI hypersusceptibility ................222
NNRTIs ........................................60, 171
M Nocardiosis ........................................350
Malaria prophylaxis ..........................450 Non-AIDS-defining malignancies .....381
Malignant lymphomas......................361 Non-Hodgkin’s lymphoma ...............362
Maraviroc.....................................87, 653 Norvir see ritonavir
Maraviroc, resistance.........................272 NRTI Backbone ....................................53
Maturation inhibitors .......................116 NRTIs ...................................................48
Maviret ..............................................654 Nucleoside analogs..............................48
Mavorixafor (AMD 11070) ................106 Nuke Backbone....................................53
MCD ..................................................375 Nuke sparing in first-line ..................177
Index 709

O Pro-140 ..............................................106
Obefazimod .......................................116 Progression risk .................................145
Occupational exposure........................17 Protease inhibitors...............................67
Odefsey ......................................171, 655 Proteinuria.........................................520
OI treatment in renal insuffiency.....530 Proviral resistance testing .................256
Opportunistic infections ...................286 Prurigo nodularis...............................547
Oral hairy leukoplakia (OHL) ...302, 700 Pruritus ..............................................547
Osteomalacia .....................................192 Psoriasis vulgaris................................547
Osteoporosis ......................................191 Psychiatric diseases............................571
Pulmonary arterial hypertension......517
P Pyrimethamine..................................656
PAH ....................................................517
Papular dermatoses ...........................546 Q
Parenteral administration .................680
Quadruple nuke.................................179
Partner Study .....................................262
Quasispecies.........................................23
Party drugs.........................................165
QUATUOR trial..................................229
Pathogenesis ........................................20
PCP ....................................................288
PDE-5 inhibitors ................................585 R
Pediatric HIV .....................................493 Rabies vaccine ...................................446
Penicillium see Talaromycosis Racivir ..................................................98
Pentamidine ......................................656 Raltegravir ...........................78, 175, 657
PEP .....................................................621 Raltegravir, resistance ........................268
PEPFAR.......................................245, 273 Rapid start .........................................146
Pericardial effusion............................516 Rapid tests ...........................................16
Periconceptional ART ........................477 RDEA806............................................101
Perinatal infection.....................483, 493 Regulatory T cells ................................27
Phenotyping, resistance ....................254 Rekambys...........................................657
Phosphazide (Nicavir) .........................98 Remune..............................................119
Pibrentasvir see Maviret Renal adverse events with ART .........194
Pifeltro see doravirine Renal insufficiency ............................528
Pityriasis versicolor............................546 Replication cycle .................................22
Plasmablastic lymphoma ..................366 Rescriptor see delaviridine
Plerixafor ...........................................106 Resistance tables ................................275
PML IRIS ............................................339 Resistance testing ..............................253
PML....................................................324 Resistance, HIV-2...............................460
Pneumococcal vaccine ......................437 Restriction factors................................25
Pneumocystis pneumonia.................288 Retrovir see AZT
Polio vaccine .....................................447 Reverse transcriptase ...........................23
Polyneuropathy .................................562 Reverset................................................99
Polyradiculopathy .............................562 Reyataz see atazanavir
Post treatment controllers.................137 Rezolsta see darunavir
Post-exposure prophylaxis ................621 Rheumatology ...................................578
Pre-exposure prophylaxis..........365, 603 Rhodococcus......................................351
Pregnancy ..........................................477 Ribavirin ............................................658
PrEP ...........................................265, 603 Rifabutin ............................................659
Prevention .................................258, 600 Rifampicin .........................................659
Preventive HIV vaccine .....................614 Rilpivirine ....................................63, 660
Prezcobix see darunavir Rilpivirine, resistance ........................265
Prezista see darunavir Rilpivirine-LA ..............................94, 202
Primary CNS lymphoma ...................371 Ritonavir................................67, 70, 661
Primary effusion lymphoma .............366 Rituximab ..........................................365
710 Index

Rovafovir .............................................98 Talaromycosis marneffei ...................351

RSV vaccine .......................................439 TAMs ..................................................264
Rukobia see fostemsavir TasP............................................258, 600
TB-IRIS .......................................313, 338
S TDF ..............................................52, 665
TDF, renal toxicity.............................526
Salmonella septicemia.......................337
Telzir see fosamprenavir
Salvage therapy .................................215
Tenofovir .....................................51, 665
Saquinavir....................................71, 662
Tenofovir, renal toxicity....................524
SARS-CoV-2 vaccination ...........405, 439
Teropavimab ......................................110
Scabies ...............................................548
Testicular tumors ...............................386
Schistosoma.......................................452
Testing .................................................13
Seborrheic dermatitis ........................548
Testosteron ........................................586
Self-testing ...........................................16
Tetanus vaccination ..........................436
Selzentry see maraviroc
THC ...................................................119
SERINC3 ..............................................26
Therapeutic drug monitoring ...........241
Sexual dysfunction ............................583
Thrombocytopenia............................538
Sexual transmission...............................4
Tick-borne encephalitis (TBE) ...........447
Sexually transmitted diseases............409
Tipranavir ....................................71, 666
Shigellosis ..........................................428
Tivicay see dolutegravir
Shock and kill....................................140
TLD ....................................................157
Side effects .........................................183
Trans*Medicine..................................593
Sildenafil............................................585
Transmission prophylaxis .................484
Simplification ....................................199
Transmission routes...............................3
Single tablet regime (STR) .................199
Transmitted resistance ..............162, 260
Skin diseases ......................................543
Traveling with HIV............................445
SMART Study .....................................230
Treatment as prevention ...........258, 600
Sofosbuvir ..........................................662
Treatment interruption .....................226
Sovaldi see sofosbuvir
Treatment start/initiation .................145
Staging of HIV infection .......................8
Tregs.....................................................27
START study.......................................149
Triple class resistance/failure.............215
Statins ................................................188
Triple nuke.........................................179
Stavudine .............................................50
Triumeq .....................................175, 666
Stem cell transplantation ..................367
Trizivir................................................667
Stilbenavir .................................103, 127
Trogarzo see ibalizumab
Stocrin see efavirenz
Tropism shift .......................................86
Strand transfer .....................................74
Tropism testing............................86, 257
Stribild see elvitegravir
Truvada ........................................53, 667
Strongyloides stercoralis....................452
Trypanosoma cruzi ............................352
Structured intermittent treatment ....229
Tuberculosis .......................................305
Sulfadiazine .......................................663
Typhoid fever ....................................446
Sunlenca see lenacapavir
Sustiva see efavirenz
U
Switch studies....................................187
UB-421 ...............................................106
Symtuza .....................................173, 664
Ulcus molle........................................421
Syphilis ..............................................411
UNAIDS .......................................10, 248
Universal testing................................259
T Ureaplasma urealyticum ...................420
T-20..............................................88, 664
Tadalafil .............................................585 V
TAF...............................................51, 665 Vaccinations ......................................435
TAF, renal toxicity .............................526 Vaginal delivery.................................485
Index 711

Valganciclovir ....................................667 W
Varicella vaccine................................439 Warts..................................................549
Vicriviroc ...........................................107 Wasting syndrome.............................342
Videx see ddI Weight gain .......................................189
Viracept see nelfinavir Western Blot ........................................13
Viral genome .......................................21 WHO HIV pediatric classification.....495
Viral kinetics......................................236
Viral load, methods...........................234 X
Viral load, monitoring ......................234
Xeroderma .........................................549
Viral setpoint .........................................8
Viral structure......................................20
Viramune see nevirapine Y
Viread see tenofovir Yellow fever vaccine ..........................446
Virip ...................................................107
Virological failure ......................121, 209 Z
Virological success.............................121 Zalcitabine ...........................................50
VISCONTI ..........................................137 Zepatier ..............................................669
Vitamins ............................................119 Zerit see d4T
Vocabria see cabotegravir Ziagen ..................................................49
Vosevi ................................................668 Zidovudine ..........................................49
VRC01................................................110 Zinlirvimab........................................111
712 Notes
Hoffmann | Rockstroh
Hoffmann | Rockstroh

HIV 2023/24
Hoffmann | Rockstroh HIV 2023/2024
HIV 2023/2024 [Link]

[Link]
What to start with? When to switch? How can a failing antiretroviral
drug combination be improved? How to treat pregnant women and
children, patients with tuberculosis or other AIDS events, with
hepatitis coinfections or with HIV-2? What about STDs, Mpox and
COVID-19? How should PrEP be taken and monitored?

To answer these and many more questions, HIV physicians need to

be constantly updating themselves. This textbook, also available at
[Link], will help them – with clear-cut recommendations
for everyday practice.

Medizin Fokus Verlag

ISBN 978-3-941727-30-4 Medizin Fokus Verlag