Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women

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.).

Copyright © 2021 Massachusetts Medical Society.

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.