Optimizing the Use of Cabotegravir Plus Rilpivirine Long-acting Therapy in HIV Care: Evidence, Implementation, and Unanswered Questions

Anna Maria Geretti^{1

2

3}, Marta Boffito⁴, Stefano Bonora⁵, Patrick Braun^{6

7}, Charlotte Charpentier^{8

9}, Federico Garcia^{10

11

12}, Jade Ghosn^{13

14}, Perpetua Gomes^{15

16}, Anne-Geneviève Marcelin¹⁷, Thibault Mesplède¹⁸, Milosz Parczewski¹⁹, Kyle Ring^{20

21}, Maria Mercedes Santoro²², Caroline Solas^{23

24}, Eva Wolf^{25

26}, Chloe Orkin^{20

21}

Affiliations

¹ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
² Department of Infection, Royal Free London NHS Foundation Trust-North Mid, London, UK.
³ School of Immunity & Microbial Sciences, King's College London, London, UK.
⁴ St Stephens and Department of Infectious Diseases, Chelsea and Westminster Hospital and Imperial College London, London, UK.
⁵ Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.
⁶ PZB Aachen, Laboratory Knechten, Aachen, Germany.
⁷ InXFo GmbH, Hamburg, Germany.
⁸ Service de Virologie, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.
⁹ Université Paris Cité, INSERM UMR 1137 IAME, Paris, France.
¹⁰ Servicio de Microbiología Clínica, Hospital Universitario Clínico San Cecilio Granada, Spain.
¹¹ Ciber de Enfermedades Infecciosas, CIBERINFEC, Madrid, Spain.
¹² Instituto de Investigación Biosanitaria Ibs.GRANADA, Granada, Spain.
¹³ Assistance Publique-Hôpitaux de Paris.Nord, Hôpital Bichat Claude Bernard, Service des Maladies Infectieuses et Tropicales, Paris, France.
¹⁴ Université paris Cité, INSERM UMR 1137 IAME, Faculté de Médecine site Bichat, Paris, France.
¹⁵ Laboratório de Biologia Molecular (LMCBM, SPC, HEM, ULS-LO) Lisboa, Portugal.
¹⁶ Egas Moniz Center for Interdisciplinary Research (CiiEM), Egas Moniz School of Health & Science, Caparica, Almada, Portugal.
¹⁷ Sorbonne Université, INSERM, UMR_S 1136 Pierre Louis Institute of Epidemiology and Public Health, AP-HP, Hôpital Pitié Salpêtrière, Laboratoire de Virologie, Paris, France.
¹⁸ Viroscience Department, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹⁹ Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, Szczecin, Poland.
²⁰ SHARE Collaborative, Blizard Institute, Queen Mary University of London, London, UK.
²¹ Department of Sexual Health, Barts Health NHS Trust, London, UK.
²² Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.
²³ Laboratoire de Pharmacocinétique et Toxicologie, AP-HM, Hôpital La Timone, Marseille, France.
²⁴ Unité des Virus Émergents (UVE: Aix-Marseille Univ, Università di Corsica, IRD 190, Inserm 1207, IRBA), Marseille, France.
²⁵ Clinical Research, MUC Research GmbH, Eurofins, Munich, Germany.
²⁶ Clinical Research, MVZ München am Goetheplatz, Munich, Germany.

PMID: 40735332
PMCID: PMC12304414
DOI: 10.1093/ofid/ofaf368

Review

Optimizing the Use of Cabotegravir Plus Rilpivirine Long-acting Therapy in HIV Care: Evidence, Implementation, and Unanswered Questions

Anna Maria Geretti et al. Open Forum Infect Dis. 2025.

. 2025 Jul 3;12(7):ofaf368.

doi: 10.1093/ofid/ofaf368. eCollection 2025 Jul.

Authors

Affiliations

¹ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
² Department of Infection, Royal Free London NHS Foundation Trust-North Mid, London, UK.
³ School of Immunity & Microbial Sciences, King's College London, London, UK.
⁴ St Stephens and Department of Infectious Diseases, Chelsea and Westminster Hospital and Imperial College London, London, UK.
⁵ Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.
⁶ PZB Aachen, Laboratory Knechten, Aachen, Germany.
⁷ InXFo GmbH, Hamburg, Germany.
⁸ Service de Virologie, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France.
⁹ Université Paris Cité, INSERM UMR 1137 IAME, Paris, France.
¹⁰ Servicio de Microbiología Clínica, Hospital Universitario Clínico San Cecilio Granada, Spain.
¹¹ Ciber de Enfermedades Infecciosas, CIBERINFEC, Madrid, Spain.
¹² Instituto de Investigación Biosanitaria Ibs.GRANADA, Granada, Spain.
¹³ Assistance Publique-Hôpitaux de Paris.Nord, Hôpital Bichat Claude Bernard, Service des Maladies Infectieuses et Tropicales, Paris, France.
¹⁴ Université paris Cité, INSERM UMR 1137 IAME, Faculté de Médecine site Bichat, Paris, France.
¹⁵ Laboratório de Biologia Molecular (LMCBM, SPC, HEM, ULS-LO) Lisboa, Portugal.
¹⁶ Egas Moniz Center for Interdisciplinary Research (CiiEM), Egas Moniz School of Health & Science, Caparica, Almada, Portugal.
¹⁷ Sorbonne Université, INSERM, UMR_S 1136 Pierre Louis Institute of Epidemiology and Public Health, AP-HP, Hôpital Pitié Salpêtrière, Laboratoire de Virologie, Paris, France.
¹⁸ Viroscience Department, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹⁹ Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, Szczecin, Poland.
²⁰ SHARE Collaborative, Blizard Institute, Queen Mary University of London, London, UK.
²¹ Department of Sexual Health, Barts Health NHS Trust, London, UK.
²² Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.
²³ Laboratoire de Pharmacocinétique et Toxicologie, AP-HM, Hôpital La Timone, Marseille, France.
²⁴ Unité des Virus Émergents (UVE: Aix-Marseille Univ, Università di Corsica, IRD 190, Inserm 1207, IRBA), Marseille, France.
²⁵ Clinical Research, MUC Research GmbH, Eurofins, Munich, Germany.
²⁶ Clinical Research, MVZ München am Goetheplatz, Munich, Germany.

PMID: 40735332
PMCID: PMC12304414
DOI: 10.1093/ofid/ofaf368

Erratum in

Correction to: Optimizing the Use of Cabotegravir Plus Rilpivirine Long-acting Therapy in HIV Care: Evidence, Implementation, and Unanswered Questions.
[No authors listed] [No authors listed] Open Forum Infect Dis. 2026 Feb 18;13(2):ofag066. doi: 10.1093/ofid/ofag066. eCollection 2026 Feb. Open Forum Infect Dis. 2026. PMID: 41716679 Free PMC article.

Abstract

Cabotegravir plus rilpivirine long-acting (CAB + RPV-LA) injectable therapy marks a major milestone in HIV care, offering an efficacious, well-tolerated alternative to daily oral antiretroviral treatment. This article reviews data from pivotal trials and observational studies of CAB + RPV-LA, addressing emerging questions and highlighting key research priorities. We examine factors influencing virological outcomes, including issues related to HIV subtype, archived drug resistance, body mass index, and pharmacokinetics, and discuss challenges related to hepatitis B virus immunity and infection, pregnancy, and adherence. We outline strategies to address barriers to implementation, advocating for a tailored approach to maximize the potential of CAB + RPV-LA in improving outcomes across diverse populations with HIV.

Keywords: HBV; long-acting; pharmacokinetics; resistance; subtype.

PubMed Disclaimer

Conflict of interest statement

Potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of potential conflicts of interest.

Figures

**Figure 1.**
Cases of confirmed virological failure among FLAIR, ATLAS, and ATLAS-2M trial participants according to the presence of baseline and post-baseline factors. The figure was compiled from data published by Orkin et al in reference 8, including the Supplementary material. Abbreviations: BL, baseline; BMI, body mass index; CAB, cabotegravir; C_trough, trough plasma concentration; CVF, confirmed virologic failure; RAM, resistance-associated mutation; RPV, rilpivirine.

**Figure 2.**
Proposed algorithm for managing the results of HBV serological testing. Abbreviations: +ve, positive; -ve, negative; anti-HBc, hepatitis B core antibody; anti-HBe, antibody to hepatitis B e-antigen; anti-HBs, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

See this image and copyright information in PMC

References

1. Swindells S, Lutz T, Van Zyl L, et al. Week 96 extension results of a Phase 3 study evaluating long-acting cabotegravir with rilpivirine for HIV-1 treatment. AIDS 2022; 36:185–94. - PMC - PubMed
1. Orkin C, Bernal Morell E, et al. Initiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label phase 3 FLAIR study. Lancet HIV 2021; 8:e668–78. - PubMed
1. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with human immunodeficiency virus 1 type 1 infection: 152-week results from ATLAS-2 M, a randomized, open-label, phase 3b, noninferiority study. Clin Infect Dis 2023; 76:1646–54. - PMC - PubMed
1. Gandhi RT, Bedimo R, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2022 recommendations of the International Antiviral Society–USA Panel. JAMA 2023; 329:63–84. - PubMed
1. Sax PE, Thompson MA, Saag MS. IAS-USA treatment guidelines panel. Updated treatment recommendation on use of cabotegravir and rilpivirine for people with HIV from the IAS-USA Guidelines Panel. JAMA 2024; 331:1060–1. - PubMed

Publication types

Actions

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Optimizing the Use of Cabotegravir Plus Rilpivirine Long-acting Therapy in HIV Care: Evidence, Implementation, and Unanswered Questions

Affiliations

Optimizing the Use of Cabotegravir Plus Rilpivirine Long-acting Therapy in HIV Care: Evidence, Implementation, and Unanswered Questions

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

LinkOut - more resources

Full Text Sources