392. Favorable Adherence and Safety of Twice-Yearly Subcutaneous Lenacapavir for PrEP Among PURPOSE 2 Participants Who Used Substances

Abstract Background Cisgender men and gender-diverse individuals with a high likelihood of HIV acquisition are disproportionately affected by substance use, which can affect HIV pre-exposure prophylaxis (PrEP) adherence. Twice-yearly subcutaneous (SC) lenacapavir (LEN) showed high efficacy and safety for PrEP in PURPOSE 2 (NCT04925752). We investigated the impact of substance use on LEN adherence and safety in PURPOSE 2. As LEN is an inhibitor of CYP3A, an enzyme involved in fentanyl metabolism, we developed a physiologically based pharmacokinetic (PBPK) model to evaluate this potential drug–drug interaction. Methods Substance use was defined as any self-reported drug use, stimulant use, and opioid use in the 12 weeks prior to baseline, and/or binge drinking (≥ 6 drinks on 1 occasion). Adherence (on-time injections) and safety (adverse events [AEs]) through the primary analysis were compared across participants reporting different types of substance use and those reporting no substance use. Prior in vitro, clinical, and published fentanyl PK data were used to develop a PBPK model to evaluate the impact of LEN on fentanyl concentrations. Results Of 2183 participants randomized to LEN, 767/2061 (37.2%) reported any drug use, 17/2092 (0.8%) injected drugs, 409/2058 (19.9%) used stimulants, 33/2086 (1.6%) used opioids, and 841/2074 (40.5%) had monthly or more binge-drinking episodes at baseline. LEN adherence was high and comparable across substance use types and to participants who did not report substance use (Figure). No substance use–related overdoses or study drug-related serious AEs were reported, and overall incidence of AEs was similar across groups (Table). The most common AEs (excluding injection-site reactions) were gonococcal, chlamydia, and upper respiratory tract infections. PBPK modeling indicated no clinically significant elevations in fentanyl PK with concomitant LEN. Conclusion In PURPOSE 2, a population with high rates of substance use, there was high adherence to twice-yearly SC LEN for PrEP and a favorable safety profile among participants who used drugs and alcohol. There were no substance use–related overdoses and no clinically significant impact of LEN on fentanyl concentrations was found. These data support twice-yearly SC LEN to prevent HIV in people who use substances. Disclosures Allison Agwu, MD, ScM, Gilead Biosciences: Grant/Research Support|Gilead Biosciences: Site PI of multi-site project & investigator-initiated grant (funds to institution) Jill Blumenthal, MD MAS, Clinical Care Options: speaking fees|Gilead Biosciences: Advisor/Consultant|Gilead Biosciences: Grant/Research Support