Efficacy and safety of long-acting lenacapavir for HIV treatment and prevention: A systematic review of randomized trials.

BACKGROUND

Lenacapavir is a first-in-class, long-acting HIV-1 capsid inhibitor enabling treatment and prevention with reduced reliance on daily oral adherence. Evidence from randomized trials across indications remains fragmented. We systematically synthesized trial data on its efficacy and safety in both treatment and pre-exposure prophylaxis (PrEP) settings.

METHODS

Following PRISMA 2020 (protocol registered at OSF), we reviewed phase 2-3 randomized controlled trials evaluating lenacapavir for HIV treatment or prevention, with searches conducted from database inception through 15 January 2026. Comparators included placebo or active antiretroviral regimens. Primary outcomes were virologic efficacy and safety (injection-site reactions [ISRs], serious adverse events [SAEs]); secondary outcomes included resistance and treatment discontinuation.

RESULTS

Five trials involving 9986 participants from 20 countries were included. In treatment trials, lenacapavir administered with optimized background regimens achieved viral suppression (<50 copies/mL) in 83-100% of participants through weeks 24-54, comparable to standard oral therapy. In PrEP trials, HIV incidence was reduced to 0.00-0.10 per 100 person-years versus 0.93-2.37 in controls (incidence-rate ratio 0.00-0.11; P<0.001). ISRs were the most frequent adverse events (≤1.2% discontinuation), with no treatment-related SAEs. Capsid resistance mutations were rare and often transient.

CONCLUSIONS

Lenacapavir provides durable efficacy and favorable safety across treatment and prevention, supporting its role as a transformative biannual injectable strategy to advance global HIV control.