Extending Daily Medication to Once Weekly: Two-Drug HIV Regimen Passes Phase 3 Trial Test

Antiretroviral therapy can now suppress HIV over the long term, but taking medication day after day may still bring the burdens of being reminded of the disease, missed doses, and arranging daily life around treatment. Two Phase 3 trials announced by Gilead Sciences and Merck show that reducing dosing frequency to once weekly may offer some people with stable disease an option between daily tablets and long-acting injections without sacrificing viral control.

This investigational single-tablet regimen combines 2 mg of islatravir with 300 mg of lenacapavir. The former is a nucleoside analog that acts on HIV reverse transcriptase, while the latter inhibits the viral capsid and disrupts multiple stages of the viral life cycle. The potency and persistence of the two drugs in the body make weekly dosing possible.

In the double-blind ISLEND-1 trial, among adults whose viral load was already suppressed on once-daily Biktarvy and who switched to the weekly regimen, no participant had at least 50 copies of HIV-1 RNA per milliliter at week 48. The proportion among those who continued taking Biktarvy was 0.3%. Under the trial’s prespecified criteria, the weekly regimen was noninferior to daily therapy in maintaining viral suppression.

The open-label ISLEND-2 trial enrolled adults who had been taking other stable daily antiviral combinations. At week 48, 0.3% of the weekly-regimen group reached the viral-load threshold described above, compared with 1.3% of those who continued standard treatment, likewise meeting the criterion for noninferiority. Both studies tested a “switch” strategy, and their findings cannot be directly extrapolated to people who are treatment-naive, whose viral load is uncontrolled, or who have complex drug resistance.

The companies described the overall safety profile as broadly similar to that of the comparator groups. Neither trial identified new safety signals, and CD4-positive T-cell and lymphocyte counts also remained stable. However, in ISLEND-2, adverse events considered treatment-related occurred in 18% of the weekly-regimen group and in less than 1% of the standard-treatment group. Common events included headache, nausea, and diarrhea. The trial was not blinded, which may have affected symptom attribution and reporting, but the disparity still requires clarification through the full conference data and subsequent review.

Participants who switched to weekly medication also reported greater treatment satisfaction and a lower burden, but these were only exploratory findings from ISLEND-2 and may likewise have been affected by the open-label design. The two companies plan to use the 48-week data to support regulatory applications. If approved, it could become the first complete once-weekly oral HIV treatment. However, the trials will continue through 96 weeks, and longer-term viral suppression, drug resistance, the consequences of missing a weekly dose, and adherence in real-world healthcare settings remain important questions in determining its clinical role.