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
Year: 2025
Type: article
Study designs: Randomized Controlled Trial, Clinical Trial
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.
Authors: Sharon L Hillier, Linda-Gail Bekker, Sharon A Riddler, Craig W Hendrix, Sharlaa Badal-Faesen, Pippa Macdonald, Gonasagrie Nair, Johannes Lombaard, Yoseph Caraco, Avivit Peer, Munjal Patel, Ryan Vargo, Brenda Homony, Katherine Nedrow, Barbara Evans, Prachi Wickremasingha, Yun-Ping Zhou, Valerie Teal, Peggy Hwang, Ciaran McMullan, Keith D Kaufman, Michael N Robertson, Rebeca M Plank
Institutions: University of Pittsburgh, Magee-Womens Research Institute, University of Cape Town, Institute of Infectious Disease and Molecular Medicine, Johns Hopkins University, Johns Hopkins Hospital, University of the Witwatersrand, Hadassah Medical Center, Rambam Health Care Campus, Merck & Co., Inc., Rahway, NJ, USA (United States)
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,763
Funder: International AIDS Society
OpenAlex ID: W4410106413