Longer dosing intervals for antiretroviral therapy may improve virological outcomes and treatment satisfaction for people living with HIV‑1. The ISLEND‑2 trial tested whether switching virologically suppressed adults from a daily oral standard‑of‑care regimen to a once‑weekly, single‑tablet oral combination of islatravir‑lenacapavir could maintain viral suppression while offering an alternative dosing schedule.
ISLEND‑2 was a randomised, open‑label, active‑controlled, phase 3 non‑inferiority trial conducted at 100 sites across 14 countries and territories. Adults aged 18 years or older with HIV‑1 who had been virologically suppressed on daily oral standard‑of‑care antiretroviral therapy for at least 6 months and with no prior virological failure were eligible.
Participants were randomly assigned 1:1 to either switch to the once‑weekly, single‑tablet regimen containing islatravir 2 mg and lenacapavir 300 mg or to continue their daily standard‑of‑care regimen. Randomisation used interactive response technology and was stratified by geographical region, antiretroviral class, and CD4+ T‑cell count. The planned treatment period was at least 96 weeks; the primary endpoint reported here is at week 48.
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 assessed by the US Food and Drug Administration‑defined Snapshot algorithm. The non‑inferiority margin was 4%. The primary analysis population comprised all randomly assigned participants who received any dose of the assigned treatment. The trial is registered with ClinicalTrials.gov (NCT06630299).
Between Oct 8, 2024, and April 30, 2025, 727 individuals were screened; 647 were eligible, 634 were randomised, and 626 received treatment. Of those who received treatment, 314 participants were assigned to the once‑weekly islatravir‑lenacapavir arm and 312 to the daily standard‑of‑care arm.
Baseline characteristics among the 626 treated participants included 211 (34%) female participants, 193 (31%) Black participants, 119 (19%) Asian participants, and 123 (20%) who identified as Hispanic or Latine. Eighty‑nine participants (14%) were aged 65 years or older. At baseline, 552 participants (88%) were on a single‑tablet antiretroviral regimen and 478 (76%) were receiving regimens that contained integrase strand transfer inhibitors (INSTIs).
At week 48, virological failure as defined by HIV‑1 RNA ≥50 copies per mL occurred in one (0.3%) of 314 participants in the islatravir‑lenacapavir group and four (1.3%) of 312 participants in the standard‑of‑care group. The between‑group difference was −1.0% with a 95.002% confidence interval of −3.0 to 1.1. This result met the predefined non‑inferiority criteria versus the 4% margin.
Treatment‑related adverse events were reported in 58 (18%) of 314 participants receiving islatravir‑lenacapavir compared with one (<1%) of 312 participants continuing standard‑of‑care. Adverse events of grade 3 or higher occurred in 24 (8%) participants in the islatravir‑lenacapavir group and 28 (9%) participants in the standard‑of‑care group. Serious adverse events were reported in 22 (7%) and 27 (9%) participants, respectively. Two (1%) participants in the islatravir‑lenacapavir group and one (<1%) participant in the standard‑of‑care group discontinued the study because of adverse events.
Across both arms there were three deaths (one in the islatravir‑lenacapavir group and two in the standard‑of‑care group); none were judged to be treatment‑related in the study report. The authors note that longer‑term safety data beyond week 48 will be important to further characterize the safety profile of once‑weekly islatravir‑lenacapavir.
The week 48 primary endpoint data from ISLEND‑2 indicate that switching virologically suppressed adults with HIV‑1 to a once‑weekly single‑tablet regimen of islatravir‑lenacapavir was non‑inferior to continuing daily standard of care for the proportion with HIV‑1 RNA ≥50 copies/mL. The regimen was generally well tolerated in the first 48 weeks, although treatment‑related adverse events were more frequently reported in the islatravir‑lenacapavir group than in the standard‑of‑care group.
These results suggest potential for a once‑weekly complete oral single‑tablet regimen as an alternative maintenance strategy for people with stable viral suppression. The study authors emphasize the need for ongoing follow‑up to provide longer‑term safety and durability data beyond week 48.
ISLEND‑2 is registered on ClinicalTrials.gov under identifier NCT06630299. The trial was funded by Gilead Sciences and Merck Sharp & Dohme. Declarations of interest and detailed conflict‑of‑interest statements are provided in the source report; several authors reported relationships with pharmaceutical companies, as described in the published disclosure section.