Adherence, acceptability, preference and safety of placebo Long-Acting Pre-exposure Prophylaxis (LA-PrEP) injections and implants for HIV-Prevention in South African Men

BACKGROUND: Globally and in South Africa, cisgender men underutilize available effective HIV-prevention strategies. Early-stage research on emerging HIV prevention methods provide an opportunity to assess factors influencing the initiation and persistent use of novel drug delivery platforms for long-acting preexposure prophylaxis (LA-PrEP) among male users. METHODS: We conducted the SAMURAI randomized crossover study, where MSM and men who have sex only with women (MSW) in Cape Town and Johannesburg, South Africa, were administered placebo versions of bimonthly gluteal injections for six months and a six-month implant inserted in the inner upper arm in a randomized sequential order. We measured acceptability and defined adherence as the initiation and continued use of each product. We further monitored adverse events, serious adverse events (SAEs), injection/implant site reactions (ISRs), and social harms throughout the study and assessed LA-PrEP preference at study exit. FINDINGS: From July 2022 to June 2024, 184 cisgender men (n = 84 MSM, n = 100 MSW) were enrolled and retained with an 86% retention rate. More participants initiated injections than implants (97.8 vs. 91.3%, P = 0.007). Of those, 80.6% persisted with injections. For implants, 91.1% persisted (median 6.0 months, range 2.3-14.6), with 9% requesting early removal. Persistent use was significantly higher for implants (aRR 1.17, 95% CI: 1.07-1.27, P < 0.001). User satisfaction was high (injectables: 8.6, implants: 8.4; P = 0.44), with similar likelihood for future use (8.9 vs. 8.7; P = 0.28). Among those who tried both methods, 48.4% preferred injections and 47.7% preferred implants. All reported adverse events were unrelated to product use, 83 ISRs (most implant) documented, and 2% cited study-related SH. INTERPRETATION: Men in South Africa expressed strong interest in LA-PrEP, with these two novel drug delivery platforms rated highly acceptable. Following user experience with both placebo options, preferences for injections or implants were nearly equivalent, reinforcing heterogeneity of preferences and the importance of PrEP choice. Significant differences between product initiation and persistence suggested that delivery form familiarity and visit frequency tied to clinic burden influenced men's behavior, with implications for persistence in future LA-PrEP method use.