Background. Italian oral pre-exposure prophylaxis (PrEP) implementation faced challenges until the drug reimbursement approval in 2023. National real-life data on effectiveness are lacking. This study aimed to report incidence rates (IR) of HIV and other sexually transmitted infections (STIs), along with probabilities and predictors of poor adherence and PrEP discontinuation. Methods. Prospective national cohort study (ItaPrEP) on oral PrEP users (PrUs) in eight Italian centers (September 2017–November 2023) that could partially provide free drug supplies. IRs of HIV and STIs, and Kaplan–Meier estimated probabilities of poor adherence and discontinuation were evaluated. Mixed-effect logistic models with random intercept on the center were used to explore the association between risk factors and poor adherence and discontinuation. Results. About 1758 PrUs were included, 98% MSM; five HIV seroconversions were observed with an IR 0.187/100 person-year follow-up (PYFU; 95% CI: 0.061–0.436). IR/100 PYFU were 13.1 (95%CI:11.7–14.5) for syphilis, 23.8 (95% CI: 22–25.7) for chlamydia, and 24.2 (95% CI: 22.4–26.1) for gonorrhea. The 2-year probability of poor adherence and discontinuation was 57.9% (95% CI: 54.8–61.0) and 37.1% (95% CI: 34.3–40.1), respectively. Chemsex and switching schedule were associated with poor adherence, unlike a high educational level. Age >40 years, free drug supplies, and laboratory monitoring were associated with a lower risk of discontinuation, while chemsex was associated with a higher risk. Conclusions. In this Italian oral PrEP program, the HIV incidence was lower than that observed in pivotal clinical trials in high-risk populations and close to that of observational real-life studies. Identifying fragile groups (youngest, low educational level, and chemsex users) and addressing barriers (free drugs and monitoring) are key to targeting strategies to improve oral PrEP implementation.
