Landovitz RJ, Hanscom BS, Clement ME, Tran HV, Kallas EG, Magnus M, Sued O, Sanchez J, Scott H, Eron JJ, Del Rio C, Fields SD, Marzinke MA, Eshleman SH, Donnell D, Spinelli MA, Kofron RM, Berman R, Piwowar-Manning EM, Richardson PA, Sullivan PA, Lucas JP, Anderson PL, Hendrix CW, Adeyeye A, Rooney JF, Rinehart AR, Cohen MS, McCauley M, and Grinsztejn B
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., Competing Interests: Declaration of interests RJL reports receiving consulting fees from Gilead Sciences, Merck, and ViiV Healthcare; and receiving travel support from Merck. MEC reports receiving grants from ViiV Healthcare, Gilead Sciences, and Janssen; and receiving consulting fees from ViiV Healthcare. MMa reports receiving royalties from Jones & Barlett Learning; receiving consulting fees from the National Institutes of Health; and participating on several data and safety monitoring boards for R-series, investigator-initiated HIV prevention studies. OS reports receiving travel support from the International AIDS Society. JS reports receiving consulting fees from Gilead Sciences. JJE reports receiving grants from ViiV Healthcare, Gilead Sciences, and Janssen; receiving consulting fees from ViiV Healthcare, Gilead Sciences, and Merck; and participating on the data and safety monitoring board for TaiMed Biologics. CdR reports being the President of the Infectious Diseases Society of America; and being a board member for the International AIDS Society. SDF reports receiving payment from Gilead Sciences. MAM reports receiving grants from ViiV Healthcare and Gilead Sciences; receiving royalties from Elsevier; and receiving consulting fees and honoraria from Bio-Rad. MAS reports receiving grants from Gilead Sciences; and receiving payment as the Editor for Johns Hopkins eHIV CME Review. PLA reports receiving grants from Gilead Sciences; receiving consulting fees from Gilead Sciences, Merck, and ViiV Healthcare; and having a patent USA 18/175,418 pending. CWH reports receiving grants from Merck and Gilead Sciences; receiving honoraria from the Association of Nurses in AIDS Care and Association of Reproductive Immunology; holding patents USA 10,092,509 and 10,646,434; and being the founder of Prionde Biopharma. JFR reports being an employee of and holding stock interest in Gilead Sciences. ARR reports being an employee of and holding stock interest in ViiV Healthcare. MSC reports receiving consulting fees from Aerium and Atea; receiving honoraria from NY Course, MJH Life Sciences, Clinical Care Solutions, Virology Education, Amgen, Medscape, UpToDate, and AstraZeneca; receiving travel support from GSK; and being the co-chair of HPTN and CoVPN. All other authors declare no competing interests., (Copyright © 2023 Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)