islatravir–lenacapavir

Overview

• investigational once-weekly oral single-tablet antiretroviral regimen for the maintenance treatment of virologically suppressed HIV-1 in adults.
• developed jointly by Gilead Sciences and Merck & Co. as the first once-weekly oral option for HIV treatment.

Mechanism of action

• Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that blocks viral reverse transcriptase translocation, resulting in immediate and delayed chain termination.
• Lenacapavir (LEN) is a first-in-class HIV-1 capsid inhibitor that disrupts essential capsid-mediated steps throughout the viral replication cycle, including nuclear import, viral assembly, and capsid release.
• combination provides dual-target antiviral activity with non-overlapping resistance profiles.

Dosage and administration

• administered orally once weekly as a fixed-dose combination tablet containing 2 mg islatravir and 300 mg lenacapavir.
• lower dose of islatravir (2 mg) was selected following early trial findings to avoid total lymphocyte and CD4+ T-cell count drops seen at higher doses.

Efficacy and safety

• Phase 3 ISLEND-1 and ISLEND-2 trials demonstrated that switching to once-weekly ISL/LEN was non-inferior to continuing once-daily oral regimens (including Biktarvy) at maintaining HIV-1 RNA <50 copies/mL at week 48.
• CD4+ T-cell and total lymphocyte counts remained stable through week 48 without dose-limiting lymphopenia at the 2 mg dose.
• adverse event profile was comparable to standard daily oral therapy; most frequently reported events were mild headache and nausea.

Reference:

1. Colson A, et al. Phase 3 trial of weekly oral islatravir–lenacapavir for HIV-1 treatment (ISLEND-1). N Engl J Med / PubMed (NCT06630286).
2. Gilead Sciences & Merck & Co. Investigational once-weekly oral HIV treatment regimen of islatravir and lenacapavir maintained virological suppression in adults with HIV (Phase 3 ISLEND-1 and ISLEND-2 primary endpoint results).
3. Colson A, et al. Safety and efficacy of once-weekly oral islatravir plus lenacapavir in virologically suppressed adults with HIV-1: 48-week results. HIV Drug Therapy Glasgow Conference / International AIDS Conference