Once-weekly single-tablet HIV regimen matches daily therapy in phase 3 switch trial

Switching virologically suppressed adults with HIV-1 to a once-weekly single tablet combining islatravir and lenacapavir was non-inferior to continuing daily standard-of-care antiretroviral therapy at 48 weeks. The result comes from ISLEND-2, published in The Lancet on 29 August 2026, whose first author is Amy E. Colson of the Zinberg Clinic at Cambridge Health Alliance and the Community Resource Initiative in Boston. A weekly tablet would reduce dosing from about 365 doses a year to 52.

ISLEND-2, registered on ClinicalTrials.gov as NCT06630299, was a randomised, open-label, active-controlled, phase 3 non-inferiority trial conducted at 100 sites in 14 countries and territories. Eligible participants were adults aged 18 or over with HIV-1 who had been virologically suppressed on daily oral standard-of-care treatment for at least six months and had no previous virological failure. Randomisation was 1:1, stratified by geographical region, antiretroviral class and CD4 T-cell count, either to switch to a once-weekly single-tablet regimen of islatravir 2 mg plus lenacapavir 300 mg or to continue daily oral standard of care, in both cases for at least 96 weeks.

Between 8 October 2024 and 30 April 2025, 727 people were screened, 647 were eligible, 634 were randomised and 626 received treatment: 314 on islatravir-lenacapavir and 312 on standard of care.

The trial population was unusually representative for HIV research. Of the 626 participants who received treatment, 211 (34 per cent) were female, 193 (31 per cent) were Black, 119 (19 per cent) were Asian, 123 (20 per cent) were Hispanic or Latine, and 89 (14 per cent) were aged 65 or older. At baseline, 552 (88 per cent) were already taking a single-tablet regimen and 478 (76 per cent) were receiving integrase strand transfer inhibitor-based therapy.

The primary endpoint was the proportion of participants with HIV-1 RNA of 50 copies per mL or higher at week 48, measured by the US Food and Drug Administration snapshot algorithm, against a non-inferiority margin of 4 per cent. One of 314 participants (0.3 per cent) on the weekly tablet met that threshold, against 4 of 312 (1.3 per cent) on standard of care, a difference of minus 1.0 per cent with a 95.002 per cent confidence interval of minus 3.0 to 1.1. Non-inferiority was met.

Treatment-related adverse events occurred in 58 of 314 participants (18 per cent) on islatravir-lenacapavir and in 1 of 312 (under 1 per cent) on standard of care. Grade 3 or higher adverse events occurred in 24 (8 per cent) against 28 (9 per cent), and serious adverse events in 22 (7 per cent) against 27 (9 per cent). Two participants on the weekly tablet and one on standard of care discontinued because of adverse events. Three deaths occurred, one in the weekly-tablet group and two in the standard-of-care group, none of them considered treatment-related.

The trial was funded by Gilead Sciences and Merck Sharp and Dohme. Co-authors include Princy N. Kumar of the Division of Infectious Diseases and Tropical Medicine at Georgetown University Hospital, Ploenchan Chetchotisakd of Srinagarind Hospital at Khon Kaen University in Thailand, Winai Ratanasuwan of Siriraj Hospital at Mahidol University in Bangkok, Afaaf Liberty of the Perinatal HIV Research Unit at Chris Hani Baragwanath Hospital in Johannesburg, and Alejandro Arenas-Pinto. The paper appears in The Lancet, volume 408, issue 10557, pages 821 to 832, with the digital object identifier 10.1016/S0140-6736(26)01442-X and the PubMed identifier 42586113.

The authors state that islatravir-lenacapavir “has potential to be the first once-weekly complete oral single-tablet regimen for HIV-1 treatment,” and note that longer-term safety data beyond week 48 are still required.

The same long-acting chemistry underpins twice-yearly injectable lenacapavir for HIV prevention. Open-label extension data from the PURPOSE 1 cohort of women in Uganda and South Africa, presented at AIDS 2026 in Rio de Janeiro in late July 2026, reported no new infections across 4,493 person-years.