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Cabotegravir for the prevention of HIV-1 in women:
results from HPTN 084, a phase 3, randomised clinical trial
  April 01, 2022
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40 HIV infections met the primary endpoint definition and were included in the ITT analysis. 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]; table 2). Participants in the cabotegravir group had an 88% lower risk of HIV infection compared with those in the TDF-FTC group (HR 0⋅12 [0⋅05-0⋅31]; p<0⋅0001), after adjusting for site and the group-sequential design (figure 3). Analysis of treatment effect across the pre-specified subgroups of age, contraceptive use, and BMI at baseline were consistent with the primary outcome (table 2). The absolute risk difference between the cabotegravir and TDF-FTC groups was -1⋅6% (-1⋅0% to -2⋅3%).
Two of four participants in the cabotegravir group with incident HIV infection had no evidence of recent cabotegravir exposure on history and did not receive any cabotegravir injections; cabotegravir concentrations were unquantifiable at the first HIV-positive visit in both people (participants B1 and B2; figure 4). In the third participant, HIV infection was detected at the study site during the injection phase and was initially classified as an incident infection; however, retrospective testing at the HPTN Laboratory Center indicated that this participant had HIV infection at study enrolment. This case was subsequently re-classified as a baseline infection (participant A1). The fourth infection occurred during the injection phase of the study in a participant with delayed injection visits (participant DX). This participant had cabotegravir concentrations of less than four times the protein-adjusted concentration required for 90% viral inhibition at the first HIV-positive visit; her last injection occurred 16⋅1 weeks before this visit.
Very few HIV infections were observed in the cabotegravir group during the injection phase of the study. In one of four cases, retrospective post-hoc testing revealed that the participant had HIV infection at enrolment. Detection of HIV infection at study sites was delayed in several participants in both this trial and in HPTN 083.12, 17 These instances illustrate the challenge of using conventional testing approaches to screen for HIV infection in studies using potent, long-acting, PrEP agents. More data are needed to establish the optimal approach for detection of HIV infection in people using cabotegravir and other long-acting agents for PrEP. In HPTN 083, five participants receiving cabotegravir had integrase strand transfer inhibitor resistance mutations detected with an ultrasensitive clinical assay that were ascribed to cabotegravir exposure; no integrase strand transfer inhibitor resistance mutations were detected in HPTN 084.10, 12, 32 Viral load testing might be a substantial barrier to implementation of cabotegravir in many settings in low-income and middle-income countries. More data are needed to understand potential differences in risk of breakthrough infection in cisgender women compared with cisgender men and transgender women who have sex with men, as well as subsequent resistance and response to dolutegravir-based treatment regimens that are widely used in sub-Saharan Africa.

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.
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.
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.
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.
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.
No major integrase strand transfer inhibitor resistance mutations were detected in any of the four HIV infections observed in the cabotegravir group. One participant in the TDF-FTC group (E32) had a nucleoside reverse transcriptase inhibitor resistance mutation (M184V) detected. This participant had documented poor adherence to TDF-FTC before infection. Several participants in the TDF-FTC group also had non-nucleoside reverse transcriptase inhibitor resistance mutations detected (mainly K103N).

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