Background:
Data from randomized clinical trials of long acting injectable treatment with cabotegravir and rilpivirine (LAI) are lacking for persons with HIV (PWH) and a history of adherence challenges.
Methods:
ACTG A5359 is a phase III, prospective, randomized, open-label trial comparing LAI vs. oral standard of care (SOC) ART in PWH in the U.S. with a history of suboptimal adherence (persistent HIV-1 RNA >200 c/mL or loss to follow-up). Enrolled participants received conditional cash incentives for viral suppression on SOC of up to 24 weeks (Step 1). Participants achieving HIV-1 RNA ≤200 c/mL in Step 1 were randomized to monthly LAI (with/without oral lead-in) vs. continuation of SOC ART for 52 weeks (Step 2). Primary composite endpoint was the earliest occurrence of virologic failure (VF, confirmed HIV-1 RNA>200 c/mL) or treatment discontinuation. Key secondary efficacy endpoints included VF, treatment-related failure (VF or discontinuation due to adverse events, AEs) and treatment discontinuation. On Feb 12, 2024 a pre-planned interim review by an independent Data and Safety Monitoring Board recommended to stop randomization and offer LAI to all eligible participants. We present the interim results on which the DSMB recommendation was made.
Results:
As of 3 Jan 2024, 434 eligible participants were enrolled in Step 1. Median age 40 years, 70% male, 64% Black/African American, 17% Hispanic, 5% transgender, 14% current/prior injection drug use, median CD4+ cells 270/mm3, and median HIV-1 RNA 3.55 log10 c/mL. 294 eligible participants were randomized in Step 2 (LAI n=146, SOC n=148). Cumulative probability of AEs was similar in both arms. Three participants on LAI had ≥ Grade 3 injection site reactions (ISR) and one discontinued due to ISR. All efficacy endpoints favored the LAI arm (Table). Although the primary endpoint did not meet the predefined stopping criterion for this interim analysis (nominal 98.75% confidence interval excluding zero), key secondary endpoints of VF and treatment related failure met this stringent criterion, demonstrating superiority of the LAI arm vs. SOC. Two confirmed VFs in each arm had new resistance associated mutations (RAMS) including ≥2 new integrase inhibitor RAMs in both LAI participants.
Conclusions:
When considering all endpoints together, long-acting CAB/RPV demonstrated superior efficacy compared to daily oral SOC in PWH with adherence challenges.
