ISLEND-2 trial - switch to once-weekly, single-tablet islatravir–lenacapavir from daily standard of care for HIV-1

Switch to once-weekly, single-tablet islatravir–lenacapavir from daily standard of care for HIV-1 (ISLEND-2 trial)

Overview

• ISLEND-2 is a phase 3, multicentre, randomised, open-label, active-controlled trial evaluating the efficacy and safety of switching virologically suppressed adults with HIV-1 to a once-weekly, single-tablet regimen of islatravir (2 mg) plus lenacapavir (300 mg) versus continuing daily standard-of-care (SOC) oral antiretroviral therapy (ART)
• key finding: switching to once-weekly oral ISL/LEN demonstrated non-inferiority in maintaining virologic suppression at Week 48 compared to daily SOC, offering a novel long-acting oral alternative to daily pills

Study design & methods

• design: phase 3, randomised (1:1), open-label, active-controlled, non-inferiority trial conducted across 13 countries
• population: 626 adults living with HIV-1 who were virologically suppressed (HIV-1 RNA <50 copies/mL for ≥6 months) on stable, guideline-recommended daily SOC oral ART (INSTI-, NNRTI-, or boosted PI-based regimens)
• intervention group: switched to once-weekly single-tablet islatravir 2 mg / lenacapavir 300 mg (ISL/LEN)
• control group: continued current daily standard-of-care oral ART
• primary endpoint: proportion of participants with HIV-1 RNA ≥50 copies/mL at Week 48 (FDA snapshot algorithm, non-inferiority margin 4%)

Key results

1. Efficacy (Week 48)

• virologic failure (HIV-1 RNA ≥50 copies/mL): met criteria for non-inferiority (virologic failure rates were extremely low: 0.3% in the ISL/LEN group vs control)
• maintenance of virologic suppression (<50 copies/mL): high rates of viral suppression were maintained in both study arms (~93–94%)
• resistance: no emergent resistance to islatravir or lenacapavir was detected among participants experiencing protocol-defined virologic failure

2. Safety & tolerability

• overall safety: the once-weekly regimen was generally safe and well-tolerated
• adverse events (AEs):
  • treatment-related AEs occurred in 18% of the ISL/LEN group vs <1% in the open-label SOC group (driven primarily by open-label reporting bias for new treatments)
  • common mild-to-moderate side effects in the ISL/LEN group included headache (5%), diarrhoea (3%), and nausea (3%)
• discontinuations: discontinuations due to AEs were very low in both groups (<1%)
• laboratory & physical parameters: total lymphocyte and CD4+ T-cell counts remained stable; no clinically meaningful weight changes were observed

3. Patient-reported outcomes (PROs)

• over 75% of participants who switched to once-weekly ISL/LEN reported being more or much more satisfied with the weekly pill compared to their previous daily regimen
• nearly two-thirds reported that daily dosing was more burdensome, compared to only 1% for weekly dosing

Practical implications for primary care & HIV specialists

1. long-acting oral option: provides a middle ground for patients who desire long-acting treatment without the need for intramuscular injections (e.g. cabotegravir/rilpivirine)
2. mechanism complementarity: combines islatravir (a nucleoside reverse transcriptase translocation inhibitor / NRTTI) and lenacapavir (a first-in-class HIV capsid inhibitor), delivering high potency and long half-lives that support weekly dosing
3. adherence & flexibility: may improve adherence and quality of life for patients experiencing daily pill fatigue, travel burdens, or privacy concerns associated with daily regimens

Reference:

1. Colson A et al. Switch to once-weekly, single-tablet islatravir–lenacapavir from daily standard of care for HIV-1 (ISLEND-2): a multicentre, randomised, open-label, active-controlled, phase 3 non-inferiority trial. The Lancet, 2026