Safety, Tolerability, and Pharmacokinetics of Once-Monthly Oral Islatravir: A Phase 2a Study in Participants at Low Risk for Acquiring Human Immunodeficiency Virus Type 1

Abstract

Background. Islatravir, a nucleoside reverse transcriptase translocation inhibitor, exhibits high potency against human immunodeficiency virus type 1 (HIV-1), with a long intracellular half-life. The safety, tolerability, and pharmacokinetics of once-monthly oral islatravir were evaluated in adults at low risk of acquiring HIV-1. Methods. In this double-blind, placebo-controlled trial, participants were randomized 2:2:1 to receive 6 once-monthly doses of islatravir 60 mg, islatravir 120 mg, or placebo. Objectives included assessing safety, tolerability, and pharmacokinetic profiles of islatravir in plasma and its active metabolite, islatravir triphosphate (ISL-TP), in peripheral blood mononuclear cells (PBMCs). Results. Of 242 participants (islatravir 60 mg, n = 97; islatravir 120 mg, n = 97; placebo, n = 48), most were aged ≤45 years (90.1%), female (67.4%), and White (52.9%). Proportions of participants experiencing ≥1 adverse event (AE) were similar in the islatravir (60 mg: 68.0%; 120 mg: 64.9%) and placebo (75.0%) arms. AEs were generally mild to moderate, with infection-related AEs comparable across arms. Lymphocyte count decreased in the islatravir arms, with mean percentage changes of −21.3% ± 20.1% (60 mg) and −35.6% ± 22.8% (120 mg) versus +4.4% ± 25.9% (placebo) at week 24. Median intracellular PBMC ISL-TP concentrations remained above the prespecified pharmacokinetic threshold for HIV-1 prophylaxis (0.050 pmol/106 cells) through 4 weeks after the first dose and ≥8 weeks after the last dose. Conclusions. Oral islatravir 60 mg and 120 mg once monthly demonstrated similar tolerability and AE profiles to placebo, except for dose-dependent decreases in total lymphocyte counts. A partial recovery in total lymphocyte counts was observed. In most participants, both islatravir doses achieved PBMC ISL-TP exposure levels projected to be effective for once-monthly oral HIV-1 preexposure prophylaxis. Clinical Trials Registration NCT04003103.