Doxycycline Post-Exposure Prophylaxis for Sexually Transmitted Infections: A Systematic Review and Meta-Analysis with Trial Sequential Analysis.

OBJECTIVES: To evaluate the efficacy of doxycycline post-exposure prophylaxis (DoxyPEP) for preventing bacterial sexually transmitted infections (STIs) and determine, using trial sequential analysis (TSA), whether the accumulated evidence was sufficient to support reliable conclusions. METHODS: In this systematic review and meta-analysis, we searched four databases through July 29, 2025 for randomized controlled trials (RCTs) comparing DoxyPEP with standard care in men who have sex with men (MSM) and transgender women (TGW) at high STI risk. Random-effects meta-analysis, RoB 2, and TSA were applied (OSF: z8ah6). RESULTS: Three RCTs involving 1,278 participants were included. DoxyPEP reduced any bacterial STI overall (pooled relative risk [RR] 0.41, 95% TSA-adjusted confidence interval [CI] 0.20-0.85), chlamydia (RR 0.22, 95% TSA-adjusted CI 0.12-0.39), syphilis (RR 0.24, 95% TSA-adjusted CI 0.13-0.44), and gonorrhea (RR 0.79, 95% TSA-adjusted CI 0.66-0.95). Pathogen-specific analyses crossed monitoring boundaries and reached the required information size. The composite crossed the boundary but not its heterogeneity-adjusted required information size (1,278/1,696); heterogeneity was substantial (I²=89.1%). CONCLUSIONS: In high-risk MSM and TGW, DoxyPEP reduced chlamydia and syphilis, with a smaller gonorrhea benefit. TSA supported the direction of pathogen-specific effects, while the composite estimate and long-term antimicrobial resistance remained uncertain.