Abstract
Introduction: Bacterial sexually transmitted infections (STIs) remain a significant burden among populations at high risk, including people living with HIV (PLWH) and HIV-negative individuals receiving HIV pre-exposure prophylaxis (PrEP). This study evaluated the efficacy and safety of doxycycline pre- and post-exposure prophylaxis for preventing bacterial STIs among people with or without HIV. Methods: This systematic review followed PRISMA 2020 guidelines and was prospectively registered in PROSPERO (CRD420251171815). We conducted comprehensive searches in PubMed, Embase, and Cochrane CENTRAL through October 2025. We included randomized controlled trials evaluating doxycycline prophylaxis versus standard care. Meta-analysis was performed using random-effects models in RevMan 5.4. Results: Seven randomized controlled trials (2,091 participants) were included. Doxycycline prophylaxis significantly reduced bacterial STI incidence by 57% (pooled RR 0.43, 95% CI 0.35–0.53; p < 0.00001; I² = 42%). In the subgroup analysis of HIV-positive participants, doxycycline achieved a 62% reduction (RR 0.38; 95% CI 0.28–0.52). Pathogen-specific analysis showed a 72% reduction for chlamydia (RR 0.28), a 72% reduction for syphilis (RR 0.28), and a 44% reduction for gonorrhea (RR 0.56). Safety outcomes were summarized descriptively, with gastrointestinal symptoms most frequently reported; no pooled adverse-event or discontinuation estimate was calculated. The number needed to treat calculated from pooled event counts was approximately 4. Conclusion: Doxycycline prophylaxis reduced bacterial STI incidence in high-risk populations with and without HIV. These findings support considering doxycycline prophylaxis as a prevention strategy, while emphasizing limitations in regimen-specific evidence and the need for ongoing safety and antimicrobial-resistance monitoring.