Virologic Outcomes With Lenacapavir in People With Human Immunodeficiency Virus: A Multicenter Real-World Study

Background Lenacapavir (LEN), a first-in-class long-acting human immunodeficiency virus type 1 (HIV-1) capsid inhibitor, has demonstrated potent antiviral activity in heavily treatment-experienced (HTE) people with HIV (PWH) in clinical trials, but real-world data remain limited. We describe outcomes from 6 US HIV clinics using LEN-based regimens in a largely HTE cohort of PWH to assess virologic response, regimen potency, and tolerability. Methods We conducted a multicenter retrospective cohort study of adults with HIV who initiated LEN between November 2020 and June 2025 at 6 clinics in Chicago, Illinois and Pittsburgh, Pennsylvania. Demographic, clinical, and genotypic data were abstracted from electronic health records. Virologic suppression was defined as HIV viral load <200 copies/mL. Stanford genotypic susceptibility scores (S-GSS) were calculated to assess regimen potency. Wilcoxon signed-rank tests compared antiretroviral therapy pill burden and regimen potency before and after LEN initiation. Results Seventy PWH initiated LEN. Median follow-up was 12 months. At baseline, 18 (26%) PWH with available genotypes had multidrug-resistant HIV, and 54% had unsuppressed virus. Among 38 PWH with unsuppressed virus, 34 (89%) achieved viral suppression, and none of the PWH with suppressed HIV experienced rebound. LEN significantly improved regimen potency (P < .00005) and reduced daily pill burden from 2 tablets to 1 tablet (P < .00005). Injection site reactions occurred in 30% and led to discontinuation in 1 person. Conclusions In this real-world cohort, LEN-based regimens achieved high rates of virologic suppression, improved regimen activity, and reduced pill burden with good tolerability. LEN represents a promising salvage therapy for PWH, warranting equitable and implementation-focused integration into HIV care.