Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women

doi:10.1056/NEJMoa2101016

Randomized Controlled Trial

. 2021 Aug 12;385(7):595-608.

doi: 10.1056/NEJMoa2101016.

Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women

Raphael J Landovitz¹, Deborah Donnell¹, Meredith E Clement¹, Brett Hanscom¹, Leslie Cottle¹, Lara Coelho¹, Robinson Cabello¹, Suwat Chariyalertsak¹, Eileen F Dunne¹, Ian Frank¹, Jorge A Gallardo-Cartagena¹, Aditya H Gaur¹, Pedro Gonzales¹, Ha V Tran¹, Juan C Hinojosa¹, Esper G Kallas¹, Colleen F Kelley¹, Marcelo H Losso¹, J Valdez Madruga¹, Keren Middelkoop¹, Nittaya Phanuphak¹, Breno Santos¹, Omar Sued¹, Javier Valencia Huamaní¹, Edgar T Overton¹, Shobha Swaminathan¹, Carlos Del Rio¹, Roy M Gulick¹, Paul Richardson¹, Philip Sullivan¹, Estelle Piwowar-Manning¹, Mark Marzinke¹, Craig Hendrix¹, Maoji Li¹, Zhe Wang¹, Jeanne Marrazzo¹, Eric Daar¹, Aida Asmelash¹, Todd T Brown¹, Peter Anderson¹, Susan H Eshleman¹, Marcus Bryan¹, Cheryl Blanchette¹, Jonathan Lucas¹, Christina Psaros¹, Steven Safren¹, Jeremy Sugarman¹, Hyman Scott¹, Joseph J Eron¹, Sheldon D Fields¹, Nirupama D Sista¹, Kailazarid Gomez-Feliciano¹, Andrea Jennings¹, Ryan M Kofron¹, Timothy H Holtz¹, Katherine Shin¹, James F Rooney¹, Kimberly Y Smith¹, William Spreen¹, David Margolis¹, Alex Rinehart¹, Adeola Adeyeye¹, Myron S Cohen¹, Marybeth McCauley¹, Beatriz Grinsztejn¹; HPTN 083 Study Team

Collaborators, Affiliations

Collaborators

HPTN 083 Study Team:
Suwat Chariyalertsak, Eileen F Dunne, Nittaya Phanuphak, Tran Viet Ha, Omar Sued, Marcelo H Losso, Esper G Kallas, José Valdez Ramalho, Madruga Madruga, Breno Riegel Santos, Beatriz Grinsztejn, Juan Carlos Hinojosa Boyer, Javier Antonio Valencia Huamani, Jorge A Gallardo-Cartagena, Pedro Gonzales, Robinson Cabello, Keren Middelkoop, E Turner Overton, Temitope Oyedele, Albert Liu, Jessica Justman, Christopher Hurt, Daniel Reirden, Carl Fichtenbaum, Christopher Hall, Kenneth Mayer, Manya Magnus, Cornelius van Dam, Julie Franks, Colleen Kelley, Roberto C Arduino, Anne Rompalo, Shobha Swaminathan, Sue Ellen Abdalian, Hong Van Tieu, Jose Bazan, Ian Frank, Carlos Del Rio, Aditya Gaur, Raphael J Landovitz, Jesse Clark, Richard Novak, Rachel Presti, Roy Gulick

Affiliation

¹ From the Center for Clinical AIDS Research and Education, David Geffen School of Medicine, University of California, Los Angeles (R.J.L., R.M.K.), the Lundquist Institute at Harbor-UCLA Medical Center, Torrance (E.D.), the San Francisco Department of Public Health, San Francisco (H.S.), and Gilead Sciences, Foster City (J.F.R.) - all in California; the Fred Hutchinson Cancer Research Center, Seattle (D.D., B.H., L. Cottle, M.L., Z.W.); the Louisiana State University Health Sciences Center, New Orleans (M.E.C.); Instituto Nacional de Infectologia Evandro Chagas-Fiocruz, Rio de Janeiro (L. Coelho, B.G.), University of São Paulo (E.G.K.), and Centro de Referência e Treinamento DST-AIDS-SP (J.V.M.), São Paulo, and Hospital Nossa Senhora da Conceição, Porto Alegre (B.S.) - all in Brazil; Via Libre (R.C.), Universidad Nacional Mayor de San Marcos (J.A.G.-C.), and Asociacion Civil Impacta Salud y Educacion (P.G., J.V.H.), Lima, and Asociacion Civil Selva Amazonica, Iquitos (J.C.H.) - all in Peru; the Research Institute for Health Sciences, Chiang Mai University, Chiang Mai (S.C.), and the Institute of HIV Research and Innovation, Bangkok (N.P.) - both in Thailand; the Division of HIV-AIDS Prevention, Centers for Disease Control and Prevention (E.F.D.), the School of Medicine (C.F.K., C.R.), and Rollins School of Public Health (C.R.), Emory University - both in Atlanta; the Perelman School of Medicine, University of Pennsylvania, Philadelphia (I.F.), and Pennsylvania State University, State College (S.D.F.) - both in Pennsylvania; St. Jude Children's Research Hospital, Memphis, TN (A.H.G.); University of North Carolina at Chapel Hill, Chapel Hill (H.V.T., J.J.E., M.S.C.), FHI 360, Durham (A. Asmelash, M.B., C.B., J.L., N.D.S., K.G.-F., A.J., M.M.), and ViiV Healthcare, Research Triangle (K.Y.S., W.S., D.M., A.R.) - all in North Carolina; Hospital General de Agudos José María Ramos Mejia (M.H.L.) and Fundación Huésped (O.S.) - both in Buenos Aires; the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa (K.M.); University of Alabama at Birmingham, Birmingham (E.T.O., J.M.); Rutgers New Jersey Medical School, Newark (S. Swaminathan); Weill Cornell Medicine, New York (R.M.G.); Johns Hopkins University, Baltimore (P.R., P.S., E.P.-M., M.M., C.H., T.T.B., S.H.E., J.S.); University of Colorado Anschutz Medical Campus, Aurora (P.A.); Massachusetts General Hospital, Boston (C.P.); University of Miami, Coral Gables, FL (S. Safren); the Office of AIDS Research (T.H.H.) and Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD (K.S., A. Adeyeye).

PMID: 34379922
PMCID: PMC8448593
DOI: 10.1056/NEJMoa2101016

Randomized Controlled Trial

Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women

Raphael J Landovitz et al. N Engl J Med. 2021.

. 2021 Aug 12;385(7):595-608.

doi: 10.1056/NEJMoa2101016.

Authors

Collaborators

HPTN 083 Study Team:
Suwat Chariyalertsak, Eileen F Dunne, Nittaya Phanuphak, Tran Viet Ha, Omar Sued, Marcelo H Losso, Esper G Kallas, José Valdez Ramalho, Madruga Madruga, Breno Riegel Santos, Beatriz Grinsztejn, Juan Carlos Hinojosa Boyer, Javier Antonio Valencia Huamani, Jorge A Gallardo-Cartagena, Pedro Gonzales, Robinson Cabello, Keren Middelkoop, E Turner Overton, Temitope Oyedele, Albert Liu, Jessica Justman, Christopher Hurt, Daniel Reirden, Carl Fichtenbaum, Christopher Hall, Kenneth Mayer, Manya Magnus, Cornelius van Dam, Julie Franks, Colleen Kelley, Roberto C Arduino, Anne Rompalo, Shobha Swaminathan, Sue Ellen Abdalian, Hong Van Tieu, Jose Bazan, Ian Frank, Carlos Del Rio, Aditya Gaur, Raphael J Landovitz, Jesse Clark, Richard Novak, Rachel Presti, Roy Gulick

Affiliation

¹ From the Center for Clinical AIDS Research and Education, David Geffen School of Medicine, University of California, Los Angeles (R.J.L., R.M.K.), the Lundquist Institute at Harbor-UCLA Medical Center, Torrance (E.D.), the San Francisco Department of Public Health, San Francisco (H.S.), and Gilead Sciences, Foster City (J.F.R.) - all in California; the Fred Hutchinson Cancer Research Center, Seattle (D.D., B.H., L. Cottle, M.L., Z.W.); the Louisiana State University Health Sciences Center, New Orleans (M.E.C.); Instituto Nacional de Infectologia Evandro Chagas-Fiocruz, Rio de Janeiro (L. Coelho, B.G.), University of São Paulo (E.G.K.), and Centro de Referência e Treinamento DST-AIDS-SP (J.V.M.), São Paulo, and Hospital Nossa Senhora da Conceição, Porto Alegre (B.S.) - all in Brazil; Via Libre (R.C.), Universidad Nacional Mayor de San Marcos (J.A.G.-C.), and Asociacion Civil Impacta Salud y Educacion (P.G., J.V.H.), Lima, and Asociacion Civil Selva Amazonica, Iquitos (J.C.H.) - all in Peru; the Research Institute for Health Sciences, Chiang Mai University, Chiang Mai (S.C.), and the Institute of HIV Research and Innovation, Bangkok (N.P.) - both in Thailand; the Division of HIV-AIDS Prevention, Centers for Disease Control and Prevention (E.F.D.), the School of Medicine (C.F.K., C.R.), and Rollins School of Public Health (C.R.), Emory University - both in Atlanta; the Perelman School of Medicine, University of Pennsylvania, Philadelphia (I.F.), and Pennsylvania State University, State College (S.D.F.) - both in Pennsylvania; St. Jude Children's Research Hospital, Memphis, TN (A.H.G.); University of North Carolina at Chapel Hill, Chapel Hill (H.V.T., J.J.E., M.S.C.), FHI 360, Durham (A. Asmelash, M.B., C.B., J.L., N.D.S., K.G.-F., A.J., M.M.), and ViiV Healthcare, Research Triangle (K.Y.S., W.S., D.M., A.R.) - all in North Carolina; Hospital General de Agudos José María Ramos Mejia (M.H.L.) and Fundación Huésped (O.S.) - both in Buenos Aires; the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa (K.M.); University of Alabama at Birmingham, Birmingham (E.T.O., J.M.); Rutgers New Jersey Medical School, Newark (S. Swaminathan); Weill Cornell Medicine, New York (R.M.G.); Johns Hopkins University, Baltimore (P.R., P.S., E.P.-M., M.M., C.H., T.T.B., S.H.E., J.S.); University of Colorado Anschutz Medical Campus, Aurora (P.A.); Massachusetts General Hospital, Boston (C.P.); University of Miami, Coral Gables, FL (S. Safren); the Office of AIDS Research (T.H.H.) and Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD (K.S., A. Adeyeye).

PMID: 34379922
PMCID: PMC8448593
DOI: 10.1056/NEJMoa2101016

Abstract

Background: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection.

Methods: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection.

Results: The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified.

Conclusions: CAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.).

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Figures

**Figure 1.. Trial Design, Screening, Randomization, and Follow-up.**
CAB denotes cabotegravir, CAB-LA long-acting injectable CAB, HIV human immunodeficiency virus, PK pharmacokinetic, and TDF–FTC tenofovir disoproxil fumarate–emtricitabine.

**Figure 2.. Incident HIV infection.**
Panel A shows Kaplan–Meier estimates of incident HIV infection. The inset shows the same data on an enlarged y axis. Panel B shows hazard ratios for incident HIV infection in the prespecified subgroups. Race was reported by the participant. MSM denotes men who have sex with men, and PY person-years.

**Figure 3.. Pharmacologic and Virologic Data for HIV Infections in the Cabotegravir Group.**
Panels A through D show the timing of key events for the 16 infections that occurred in the cabotegravir group. These infections were classified into four groups: group A (Panel A) includes infections that occurred before enrollment; group B (Panel B) includes infections that occurred with no recent exposure to cabotegravir; group C (Panel C) includes infections that occurred before cabotegravir injection; and group D (Panel D) includes infections that occurred in participants with appropriately timed CAB-LA doses and expected plasma cabotegravir concentrations. The “first HIV-positive visit” refers to the first visit at which the participant was determined to be HIV positive. The “first site-positive visit” refers to the first visit at which evidence of HIV infection was identified at the trial site. HIV genotyping results are shown to the right of each horizontal bar. Major resistance mutations are shown for nucleoside or nucleotide reverse-transcriptase inhibitors (K65R and M184V) and nonnucleoside reverse-transcriptase inhibitors (L100I, K103N, Y181C, H221Y, and P225H). All integrase strand-transfer inhibitor (INSTI) resistance mutations are shown (L74I, E138K or E138E/K, E138A, G140A, G140G/S, Q148R or Q148K, and R263K); major INSTI mutations are shown in bold text. Genotyping results are shown for the first visit at which the viral load was 500 copies or more per milliliter and for follow-up visits at which such a viral load occurred, denoted as one dot or two dots, respectively. The number of days between the first HIV-positive visit and the visit with additional mutations was 60 days for case A2, 10 days for case C1, and 112 days for case D3. NA indicates that the genotyping result was not available (either no visit occurred at which viremia was found to be sufficient for performance of the genotyping assay or the assay failed to produce a genotyping result). BLQ denotes below the limit of quantification, LLOQ lower limit of quantification, PA-IC90 protein-adjusted 90% cabotegravir inhib itory concentration, and WT wild type.

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Comment in

Enhancing HIV Prevention with Injectable Preexposure Prophylaxis.
Abdool Karim Q. Abdool Karim Q. N Engl J Med. 2021 Aug 12;385(7):652-653. doi: 10.1056/NEJMe2110665. N Engl J Med. 2021. PMID: 34379927 No abstract available.
Injectable PrEP superior to oral PrEP.
Thomas T. Thomas T. Nat Rev Urol. 2021 Oct;18(10):576. doi: 10.1038/s41585-021-00515-8. Nat Rev Urol. 2021. PMID: 34453152 No abstract available.

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References

1. 2020 global AIDS update — seizing the moment — tackling entrenched inequalities to end epidemics. Geneva: Joint United Nations Programme on HIV/AIDS, July6, 2020. (https://www.unaids.org/en/resources/documents/2020/global-aids-report).
1. Mayer KH, Molina J-M, Thompson MA, et al.Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet 2020;396239–54. - PMC - PubMed
1. Molina JM, Capitant C, Spire B, et al.On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med 2015;373:2237–46. - PubMed
1. Grant RM, Lama JR, Anderson PL, et al.Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587–99. - PMC - PubMed
1. Baeten JM, Donnell D, Ndase P, et al.Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367:399–410. - PMC - PubMed

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[1] 2020 global AIDS update — seizing the moment — tackling entrenched inequalities to end epidemics. Geneva: Joint United Nations Programme on HIV/AIDS, July6, 2020. (https://www.unaids.org/en/resources/documents/2020/global-aids-report).

[2] 2020 global AIDS update — seizing the moment — tackling entrenched inequalities to end epidemics. Geneva: Joint United Nations Programme on HIV/AIDS, July6, 2020. (https://www.unaids.org/en/resources/documents/2020/global-aids-report).

[3] Mayer KH, Molina J-M, Thompson MA, et al.Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet 2020;396239–54. - PMC - PubMed

[4] Mayer KH, Molina J-M, Thompson MA, et al.Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet 2020;396239–54. - PMC - PubMed

[5] Molina JM, Capitant C, Spire B, et al.On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med 2015;373:2237–46. - PubMed

[6] Molina JM, Capitant C, Spire B, et al.On-demand preexposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med 2015;373:2237–46. - PubMed

[7] Grant RM, Lama JR, Anderson PL, et al.Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587–99. - PMC - PubMed

[8] Grant RM, Lama JR, Anderson PL, et al.Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363:2587–99. - PMC - PubMed

[9] Baeten JM, Donnell D, Ndase P, et al.Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367:399–410. - PMC - PubMed

[10] Baeten JM, Donnell D, Ndase P, et al.Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012;367:399–410. - PMC - PubMed

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Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women

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Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women

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