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. 2025 May 6:jiaf222.
doi: 10.1093/infdis/jiaf222. Online ahead of print.

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

Sharon L Hillier  1   2 , Linda-Gail Bekker  3 , Sharon A Riddler  2 , Craig W Hendrix  4 , Sharlaa Badal-Faesen  5 , Pippa Macdonald  3 , Gonasagrie Nair  3 , Johannes Lombaard  6 , Yoseph Caraco  7 , Avivit Peer  8 , Munjal Patel  9 , Ryan Vargo  9 , Brenda Homony  9 , Katherine Nedrow  9 , Barbara Evans  9 , Prachi Wickremasingha  9 , Yun-Ping Zhou  9 , Valerie Teal  9 , Peggy Hwang  9 , Ciaran McMullan  9 , Keith D Kaufman  9 , Michael N Robertson  9 , Rebeca M Plank  9
Affiliations

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

Sharon L Hillier et al. J Infect Dis. .

Abstract

Background: Islatravir, a nucleoside reverse transcriptase translocation inhibitor, exhibits high potency against 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, 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 islatravir (60-mg: 68.0%; 120-mg: 64.9%) and placebo arms (75.0%). AEs were generally mild-moderate, with infection-related AEs comparable across arms. Lymphocyte count decreased in the islatravir arms, with mean percent changes of -21.3±20.1% (60-mg) and -35.6±22.8% (120-mg) vs +4.4±25.9% (placebo) at week 24. Median intracellular PBMC islatravir-triphosphate concentrations remained above the prespecified pharmacokinetics 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 islatravir-triphosphate exposure levels projected to be effective for once-monthly oral HIV-1 pre-exposure prophylaxis.

Clinical trials registration: www.clinicaltrials.gov, NCT04003103.

Keywords: PrEP; islatravir; long-acting; nucleoside reverse transcriptase translocation inhibition; pre-exposure prophylaxis.

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