Effectiveness, safety, adherence and risk compensation of oral pre-exposure prophylaxis (PrEP) in men who have sex with men: a systematic review and meta-analysis

Objective This systematic review and meta-analysis evaluate the clinical effectiveness, safety and potential risk compensation associated with oral pre-exposure prophylaxis (PrEP) in men who have sex with men (MSM). Methods We systematically searched PubMed, Embase and the Cochrane Library up to 17 September 2025 for randomised controlled trials (RCTs) and observational studies. The primary outcomes were HIV incidence and sexually transmitted infections (STIs). Secondary outcomes included PrEP adherence and adverse events. Meta-analyses used random-effects models, presenting results as relative risks (RRs), risk differences and calculated absolute risk reduction/increase (ARR/ARI) and number needed to treat (NNT) where applicable. Results A total of 21 studies (7 RCTs and 14 observational) with 18 214 participants were included. PrEP use was associated with a 68% RR reduction in HIV acquisition (RR=0.32, 95% CI 0.19 to 0.53; ARR=1.14%, NNT=88). High adherence (≥80%) led to a 78% reduction in HIV risk (RR=0.22, 95% CI 0.09 to 0.54; ARR=1.51%, NNT=66), while lower adherence showed a non-significant 58% reduction (RR=0.42, 95% CI 0.16 to 1.09). Meta-regression indicated a 17% decrease in efficacy per 10% drop in adherence (β = –1.7, p=0.009). No significant differences were found in any adverse events (RR=1.02, 95% CI 0.88 to 1.18) or serious adverse events (RR=0.93, 95% CI 0.68 to 1.28; ARI=−0.00%). There was no significant increase in overall STIs (RR=1.05, 95% CI 0.95 to 1.17; ARI=0.05%) or syphilis incidence (RR=1.11, 95% CI 0.96 to 1.30; ARI=0.11%). Sexual behaviour outcomes were mixed, with no consistent evidence of increased risk-taking. Conclusion PrEP effectively reduces HIV incidence among MSM, particularly when adherence is high, without a significant increase in overall STIs risk. Adherence support and comprehensive sexual health counselling should be integral to PrEP programmes to maximise its effectiveness and mitigate potential risk compensation behaviours. PROSPERO registration number CRD42024593380.