Safety and Tolerability of Oral Islatravir Once Monthly as Pre-exposure Prophylaxis in Cisgender Men and Transgender Women Who Have an Elevated Likelihood of HIV-1 Exposure: Results From the IMPOWER-24 Randomized Phase 3 Study

Landovitz R.J.; Pinedo Y.; Hinestrosa F.; Crofoot G.E.; Brinson C.; Buchbinder S.; Molina J.-M.; Gravett R.M.; Brock J.B.; Ramgopal M.N.; Lina Rosengren A.; Ofotokun I.; Valdez Madruga J.; Liegeon G.; Panchia R.; Supparatpinyo K.; Avihingsanon A.; Creticos C.; Swaminathan S.; Doblecki-Lewis S.; Rodriguez J.; Siegel M.; Oka S.; Puthanakit T.; Grinsztejn B.; Sanders E.J.; Lama J.R.; Lombaard J.; Ndlovu N.; Hwang P.; Du J.; Jackson B.; Homony B.; Evans B.; Sklar P.; Robertson M.N.; Plank R.M. · Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (2026) · DOI: 10.1093/cid/ciag171

Resumen

BACKGROUND: Islatravir once monthly (qm), a nucleoside reverse transcriptase translocation inhibitor with a long half-life, was evaluated for safety and tolerability in cisgender men and transgender women who have sex with men and are at increased likelihood of HIV-1 (HIV) exposure. METHODS: IMPOWER-24 (NCT04652700) was a double-blind, Phase 3 study. Participants were randomized 2:1 to islatravir 60 mg oral qm or emtricitabine (FTC; 200 mg) coformulated with either tenofovir disoproxil (245 mg) or tenofovir alafenamide (TAF; 25 mg) once daily (qd). After ∼9 months, blinded islatravir was discontinued due to lymphocyte reductions; participants were offered open-label comparator for 20 months. RESULTS: In total, 494 participants were enrolled (328 islatravir; 166 comparator): 91.5% were cisgender men, 41.7% were White, and median age was 27 years. Mean blinded dosing duration was 4.7 months (islatravir) versus 4.3 months (comparator). Overall, 211 participants (64.3%) in the islatravir group and 128 (77.1%) in the comparator group had ≥1 adverse event (AE). Most AEs were mild or moderate, with 1 AE leading to product discontinuation (islatravir; gastroesophageal reflux). Serious AEs occurred in <2%; none were related to study product. Change in total lymphocytes in the islatravir group at Month 3 was -7.4%; a trend toward recovery was observed after islatravir was stopped. Mean total lymphocytes remained within normal range. No HIV infections occurred in either group during the double-blind phase. CONCLUSIONS: Islatravir qm was generally well tolerated; decreases in total lymphocytes were observed with islatravir. Original primary efficacy objectives were not assessed due to early study stoppage. © The Author(s) 2026. Published by Oxford University Press on behalf of Infectious Diseases Society of America.