Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial

Abstract

Background: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women.

Methods: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564.

Findings: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -1·6% [-1·0% to -2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported.

Interpretation: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women.

Funding: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support.

Conflict of interest statement

Declaration of interests PLA has received fees from Merck, ViiV Healthcare, and Gilead Sciences, and research support from Gilead Sciences paid to his institution. AR, WRS, and KS are employees of ViiV Healthcare. JFR is an employee of Gilead Sciences. All other authors declare no competing interests.

Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial design TDF-FTC=tenofovir disoproxil fumarate plus emtricitabine.

Figure 2

Trial profile TDF-FTC=tenofovir disoproxil fumarate plus emtricitabine. *One person could have had more than one reason for exclusion.

Figure 3

Cumulative HIV incidence by study group Kaplan-Meier estimates of HIV infection are shown. Four HIV infections were observed in the cabotegravir group (HIV incidence 0·20 per 100 person-years [95% CI 0·06–0·52]) and 36 in the TDF-FTC group (1·85 per 100 person-years [1·3–2·57]). Participants in the cabotegravir group had an 88% lower risk of HIV infection than those in the TDF-FTC group (hazard ratio 0·12 [0·05–0·31]; p

Figure 4

Pharmacological and virological data for HIV infections in the cabotegravir group The timing of key events for the four infections in the cabotegravir group are shown (participants A1, B1, B2, and DX). Group A includes infections that occurred before enrolment; group B includes infections that occurred with no recent exposure to cabotegravir; and group D includes infections that occurred in participants with appropriately timed cabotegravir injections. Participant DX acquired the infection during the step 2 injection phase but is called DX because three of nine injections were delayed. PA-IC90=protein-adjusted concentration required for 90% viral inhibition. LLoQ= lower limit of quantitation. BLQ=below the limit of quantitation.