Once-weekly oral islatravir-lenacapavir is noninferior to daily HIV therapy

1. In this phase 3 randomized controlled trial, switching to once-weekly oral islatravir-lenacapavir maintained HIV-1 suppression as effectively as continuing once-daily bictegravir-emtricitabine-tenofovir alafenamide.

2. Rates of serious and grade 3 or higher adverse events were similar between groups. CD4+ T-cell and lymphocyte counts remained stable, and no resistance to islatravir or lenacapavir emerged through 48 weeks.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Once-daily, single-tablet antiretroviral regimens are highly effective for treating human immunodeficiency virus type 1 (HIV-1), but lifelong daily dosing may contribute to pill fatigue and adherence challenges. Islatravir is a nucleoside reverse-transcriptase translocation inhibitor, while lenacapavir inhibits HIV-1 capsid function. The pharmacokinetic properties of both drugs support once-weekly oral administration.

The ISLEND-1 trial evaluated whether adults with virologically suppressed HIV-1 could switch from once-daily bictegravir-emtricitabine-tenofovir alafenamide (B/F/TAF) to once-weekly islatravir-lenacapavir (ISL/LEN) without losing viral suppression. At week 48, no participants receiving ISL/LEN and one participant receiving B/F/TAF had an HIV-1 RNA level of 50 copies/mL or higher. This result met the prespecified criterion for noninferiority. The proportion with an HIV-1 RNA level below 50 copies/mL was also similar between groups, at 93.4% with ISL/LEN and 92.4% with B/F/TAF.

Overall adverse event rates were comparable, as were rates of serious events, grade 3 or higher events, and treatment discontinuation. CD4+ T-cell and lymphocyte counts remained stable, addressing earlier concerns about lymphocyte reductions with higher daily doses of islatravir. No resistance to either component of the weekly regimen developed during the first 48 weeks.

Strengths of the study included its randomized, double-blind, double-dummy design, use of an active standard-of-care comparator, and enrollment across 106 sites in 12 countries. However, all participants entered the trial with virologically suppressed HIV-1 while receiving B/F/TAF, making this a selected population with demonstrated treatment adherence. Because every participant took both weekly and daily tablets, with placebo used for the alternative regimen, the trial could not determine whether weekly treatment improves adherence or reduces pill fatigue in clinical practice. The results also do not apply to people initiating treatment, those with unsuppressed HIV-1 or previous virologic failure, or those with active hepatitis B virus infection. Longer-term efficacy and safety data from the ongoing 96-week trial remain necessary. Gilead Sciences and Merck Sharp and Dohme funded the trial and participated in its design, data collection, and analysis.

Click to read the study in NEJM

Relevant Reading: Weekly islatravir plus lenacapavir maintains HIV virologic suppression

In-Depth [randomized controlled trial]: ISLEND-1 was a phase 3, double-blind, active-controlled noninferiority trial conducted at 106 sites in 12 countries. Eligible participants were adults with an HIV-1 RNA level below 50 copies/mL for at least six months while receiving B/F/TAF. Participants with previous virologic failure, previous exposure to islatravir or lenacapavir, or active hepatitis B virus infection were excluded.

A total of 607 treated participants were included in the primary analysis. Of these, 304 switched to once-weekly oral ISL/LEN at a maintenance dose of 2 mg/300 mg, and 303 continued once-daily B/F/TAF. Both groups received matching placebo for the alternative regimen. The median participant age was 49 years, 20.6% were assigned female at birth, 31.1% were Black, 26.4% were Hispanic or Latine, and 15.2% were at least 65 years old.

The primary outcome was the proportion of participants with an HIV-1 RNA level of 50 copies/mL or higher at week 48, assessed using the Food and Drug Administration snapshot algorithm. The prespecified noninferiority margin was four percentage points. This outcome occurred in 0 of 304 participants receiving ISL/LEN and 1 of 303 participants receiving B/F/TAF, corresponding to a difference of -0.3 percentage points (95.002% confidence interval [CI], -1.4 to 0.8). ISL/LEN therefore met the criterion for noninferiority. An HIV-1 RNA level below 50 copies/mL was documented in 284 participants receiving ISL/LEN (93.4%) and 280 receiving B/F/TAF (92.4%; difference, 1.0 percentage point; 95% CI, -3.2 to 5.2). No resistance to islatravir or lenacapavir emerged.

The mean change in CD4+ T-cell count at week 48 was -10 cells/microliter with ISL/LEN and -18 cells/microliter with B/F/TAF. Adverse events occurred in 79.3% and 78.5% of participants, respectively. Grade 3 or higher adverse events occurred in 7.2% and 7.3%, serious adverse events in 5.3% and 4.6%, and treatment discontinuation due to adverse events in 2.0% and 1.7%. No deaths occurred. These findings indicate that once-weekly oral ISL/LEN can maintain viral suppression for 48 weeks in adults who are already virologically suppressed on daily B/F/TAF.

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