People living with HIV (PWH) may soon benefit from a once-weekly treatment regimen instead of the standard daily antiretroviral therapy to manage their condition. Two recent phase III trials, ISLEND-1 and -2, have shown the efficacy of islatravir/lenacapavir (ISL/LEN) vs bictegravir/emtricitabine/tenofovir/alafenamide (B/F/TAF) or standard of care (SOC).
“ISL/LEN was noninferior to B/F/TAF, with no virologic failures at week 48, and was well tolerated,” said ISLEND-1 lead author Dr Jürgen K Rockstroh, University Hospital Bonn, Bonn, Germany.
More than 1,200 PWH were included in the two trials and randomized to receive either ISL/LEN or SOC (ISLEND-1: n=607, median age 49 years; ISL/LEN: n=304; B/F/TAF: n=303; ISLEND-2: n=626, median age 52 years; ISL/LEN: n=314; SOC: n=312). [AIDS 2026, abstracts OAB1406LB and OAX1106LB]
Among the participants in ISLEND-1, 21 percent were female, 31 percent were Black PWH, and 26 percent were Hispanic or Latine. In ISLEND-2, the corresponding proportions were 34 percent, 31 percent, and 20 percent.
ISLEND-1
The baseline CD4+ T-cell count in ISLEND-1 was 739 cells/µL in the ISL/LEN group and 745 cells/µL in the B/F/TAF group. [https://programme.aids2026.org/Abstract/Abstract/?abstractid=12349]
At week 48, none of the PWH in the ISL/LEN group had HIV-1 RNA ≥50 copies/mL compared with one (0.3 percent) in the B/F/TAF group (difference, ‒0.3 percent, 95 percent confidence interval [CI], ‒1.4 to 0.8). This result showed that ISL/LEN is noninferior to B/F/TAF.
The majority of PWH in both groups had HIV-1 RNA <50 copies/mL: 284 (93.4 percent) in ISL/LEN and 280 (92.4 percent) in B/F/TAF (difference, 1.0 percent, 95 percent CI, ‒3.2 to 5.2). At week 48, the mean change in CD4+ T-cell count was ‒10 and ‒18 cells/µL, respectively (least-squares mean difference, 12, 95 percent CI, ‒16 to 39).
“In this phase III trial, the once-weekly, single-tablet, oral ISL/LEN regimen showed noninferior efficacy to guideline-recommended, once-daily, oral B/F/TAF, with virologic suppression occurring in a high percentage of participants at week 48,” wrote Rockstroh and colleagues.
“Likewise, in the open-label phase III ISLEND-2 trial, switching to ISL/LEN was noninferior to continuing the current standard regimen, with virologic suppression being maintained with ISL/LEN in 95.2 percent of the participants at week 48,” they added.
ISLEND-2
In ISLEND-2, one PWH (0.3 percent) in the ISL/LEN group and four (1.3 percent) in the SOC group had HIV-1 RNA ≥50 copies/mL (difference, ‒1.0 percent, 95 percent CI, ‒3.0 to 1.1) at week 48, also demonstrating noninferiority. [https://programme.aids2026.org/Abstract/Abstract/?abstractid=12363]
Most of the participants in both treatment groups achieved HIV-1 RNA <50 copies/mL: 299 (95.2 percent in ISL/LEN and 298 (95.5 percent) in SOC (difference, ‒0.3 percent, 95 percent CI, ‒3.9 to 3.2).
At week 48, the mean change in CD4+ T-cell count was ‒45 cells/µL with ISL/LEN and ‒8 cells/µL with SOC (least-squares mean difference, ‒31, 95 percent CI, ‒58 to ‒4). This result potentially indicated higher mean baseline counts in the ISL/LEN group (795 vs 761 cells/µL), with a conjunction at 12 months (750 cells/µL in both groups).
Furthermore, the two treatment groups demonstrated a comparable mean percentage change in CD4+ T-cell counts at week 48, with overlapping CIs (ISL/LEN: ‒0.2 percent, 95 percent CI, ‒4.2 to 3.9; SOC: 2.4 percent, 95 percent CI, ‒0.8 to 5.6).
“ISL/LEN … has the potential to be the first complete once-weekly oral single-tablet treatment regimen for HIV-1,” said ISLEND-2 lead author Dr Amy E Colson, Community Resource Initiative, Boston, US.
Tolerability
Lymphocyte counts did not significantly differ between the two groups at week 48 in both ISLEND-1 and -2 trials. Likewise, none of the PWH in the two studies discontinued treatment due to reductions in CD4+ T-cells or lymphocyte counts. ISL/LEN was also well tolerated. However, one participant (0.3 percent) stopped treatment due to hepatitis B (incident infection in an unvaccinated individual).
The most common adverse events (AEs) of any grade among participants were upper respiratory tract infection (ISLEND-1: n=36; ISLEND-2: n=37), headache (ISLEND-1: n=20; ISLEND-2: n=30), and nasopharyngitis (ISLEND-1: n=23; ISLEND-2: n=25).
Grade ≥3 AEs were similar between ISLEND-1 and -2, occurring in 22 (7.2 percent) and 24 (7.6 percent) PWH, respectively. Serious AEs occurred in 16 (5.3 percent) and 22 participants (7.0 percent), respectively. None of the participants in the ISLEND-1 trial died, but one in ISLEND-2 did, which was deemed unrelated to the study drug (road traffic accident).
Adherence
In ISLEND-1, participants had virologically suppressed HIV-1 at baseline, “which implies high adherence to their existing B/F/TAF treatment, [so] this group of participants may not be fully representative of the real-world population, in which adherence challenges are common,” Rockstroh and colleagues said. [Lancet HIV 2025;12:e587-e595]
“Unlike long-acting injectable agents, a once-weekly oral treatment is not conducive to direct monitoring of adherence through clinic visits; nevertheless, it may be amenable to structured adherence support, which has been shown to improve adherence,” they added. [AIDS Behav 2016;20:2629-2638; AIDS 2011;25:825-834]
At present, long-acting injectable combinations are either approved or under development for the treatment of HIV-1. However, not all PWH prefer injections, and the use of injectable agents requires clinic-based administration, presenting challenges to adherence and demands on health system capacity. [Adv Drug Deliv Rev 2023;200:115009-115009; Open Forum Infect Dis 2025;12:ofaf368-ofaf368]
“Weekly oral therapy may offer an alternative long-acting approach for persons who prefer oral administration or face barriers to injectable therapy,” wrote Rockstroh and colleagues. [J Int AIDS Soc 2023;26(suppl 2):e26099-e26099]
“Although we could not assess preference in our blinded trial, this variable was evaluated as an exploratory patient-reported outcome in the ISLEND-2 trial,” they added. [N Engl J Med 2026;doi:10.1056/NEJMoa2607973]
ISLEND-1 and -2 are global, multicentre, randomized phase III noninferiority trials of virologically suppressed adults with HIV-1, with no prior virologic failure.
In ISLEND-1, participants were randomly assigned to receive ISL/LEN 2/300 mg or continue once-daily B/F/TAF, plus matching placebos. In ISLEND-2, PWH were randomized to switch to once-weekly oral ISL/LEN or continue daily SOC. All treatments lasted for 96 weeks.
Islatravir is a nucleoside reverse-transcriptase translocation inhibitor used in combination with doravirine for the treatment of HIV-1 infection. Lenacapavir is a first-in-class selective inhibitor of HIV-1 capsid function. [Lancet HIV 2020;7:e164-e172; Clin Transl Sci 2021;14:1935-1944; N Engl J Med 2022;386:1793-1803; Nature 2020;584:614-618]