Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083 randomised controlled trial

Raphael J. Landovitz, Center for Clinical AIDS Research and Education, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: rlandovitz@mednet.ucla.edu.
Brett S. Hanscom, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Meredith E. Clement, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
Ha V. Tran, Department of Health Behavior, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Esper G. Kallas, Department of Parasitic and Infectious Diseases, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
Manya Magnus, Department of Epidemiology, Milken Institute School of Public Health, George Washington University, Washington, DC, USA.
Omar Sued, Fundación Huésped, Buenos Aires, Argentina.
Jorge Sanchez, Centro de Investigaciones Tecnologicas, Biomedicas y Medioambientales, Universidad Nacional Mayor de San Marcos, Lima, Peru.
Hyman Scott, San Francisco Department of Public Health, San Francisco, CA, USA.
Joe J. Eron, Department of Health Behavior, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Carlos Del Rio, Emory University School of Medicine and Grady Health System, Atlanta, GA, USA.
Sheldon D. Fields, Ross and Carol Nese College of Nursing, Pennsylvania State University, University Park, PA, USA.
Mark A. Marzinke, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Susan H. Eshleman, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Deborah Donnell, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Matthew A. Spinelli, Division of HIV, Infectious Diseases, and Global Medicine, University of California San Francisco, San Francisco, CA, USA.
Ryan M. Kofron, Center for Clinical AIDS Research and Education, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Richard Berman, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Estelle M. Piwowar-Manning, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Paul A. Richardson, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Philip A. Sullivan, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jonathan P. Lucas, FHI 360, Durham, NC, USA.
Peter L. Anderson, Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO, USA.
Craig W. Hendrix, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Adeola Adeyeye, Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
James F. Rooney, Gilead Sciences, Foster City, CA, USA.
Alex R. Rinehart, ViiV Healthcare, Research Triangle Park, NC, USA.
Myron S. Cohen, Department of Health Behavior, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Marybeth McCauley, FHI 360, Durham, NC, USA.
Beatriz Grinsztejn, Instituto Nacional de Infectologia Evandro Chagas-Fiocruz, Rio de Janeiro, Brazil.

Document Type

Journal Article

Publication Date

12-1-2023

Journal

The lancet. HIV

Volume

10

Issue

12

DOI

10.1016/S2352-3018(23)00261-8

Abstract

BACKGROUND: Injectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study. METHODS: The HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094. FINDINGS: Of the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation. INTERPRETATION: Long-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance. FUNDING: Division of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

Department

Epidemiology

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