Switch to Once-Weekly, Single-Tablet Islatravir-Lenacapavir from Daily Standard of Care for HIV-1 (ISLEND-2): a Multicentre, Randomised, Open-Label, Active-Controlled, Phase 3 Non-Inferiority Trial.

BACKGROUND:Antiretroviral therapies with long dosing intervals have the potential to improve virological outcomes and treatment satisfaction for people with HIV-1. We report the primary endpoint results from week 48 of ISLEND-2, a phase 3 trial evaluating the efficacy and safety of switching to once-weekly oral islatravir-lenacapavir from daily oral standard of care in virologically suppressed adults with HIV-1. METHODS:This randomised, open-label, active-controlled, phase 3 non-inferiority trial was conducted at 100 sites in 14 countries and territories. Eligible participants were adults (aged ≥18 years) with HIV-1 who had been virologically suppressed on daily oral standard-of-care treatment for at least 6 months and had no previous virological failure. Participants were randomly assigned (1:1), using interactive response technology and stratified by geographical region, antiretroviral class, and CD4+ T-cell count, to switch to the once-weekly, single-tablet oral regimen of islatravir (2 mg)-lenacapavir (300 mg) or to continue daily oral standard of care for at least 96 weeks. The primary endpoint was the proportion of participants with an HIV-1 RNA viral load of 50 copies per mL or higher at week 48 (as per the US Food and Drug Administration-defined Snapshot algorithm), with a non-inferiority margin of 4%, assessed in all randomly assigned participants who received any dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT06630299, and is active but closed to new participants. FINDINGS:From Oct 8, 2024, to April 30, 2025, 727 participants were screened, of whom 647 were eligible for the study, 634 were randomly assigned, and 626 received treatment: 314 with islatravir-lenacapavir and 312 with standard of care. Of 626 participants, 211 (34%) were female, 193 (31%) were Black, 119 (19%) were Asian, 123 (20%) were Hispanic or Latine, and 89 (14%) were aged 65 years or older. At baseline, 552 (88%) were on a single-tablet antiretroviral regimen and 478 (76%) were receiving regimens containing integrase strand transfer inhibitors. At week 48, one (0·3%) of 314 participants in the islatravir-lenacapavir group and four (1·3%) of 312 participants in the standard-of-care group had an HIV-1 RNA viral load of 50 copies per mL or higher (difference -1·0% [95·002% CI -3·0 to 1·1]), meeting the non-inferiority criteria. Treatment-related adverse events occurred in 58 (18%) of 314 participants in the islatravir-lenacapavir group and one (<1%) of 312 participants in the standard-of-care group. Two (1%) of 314 participants in the islatravir-lenacapavir group and one (<1%) of 312 participants in the standard-of-care group discontinued the study owing to adverse events, with adverse events of grade 3 or higher occurring in 24 (8%) and 28 (9%) participants and serious adverse events in 22 (7%) and 27 (9%) participants in the islatravir-lenacapavir group and standard-of-care group, respectively. There were three deaths: one in the islatravir-lenacapavir group and two in the standard-of-care group, none of which were considered treatment-related. INTERPRETATION:Once-weekly islatravir-lenacapavir showed non-inferior efficacy to the standard of care and was generally well tolerated. Longer-term safety data will provide further valuable insights beyond the week 48 data presented here. Islatravir-lenacapavir has potential to be the first once-weekly complete oral single-tablet regimen for HIV-1 treatment. FUNDING:Gilead Sciences and Merck Sharp & Dohme.