One Dose versus Three Doses of Benzathine Penicillin G in Early Syphilis in People Living with HIV: A Systematic Review and Meta-Analysis

Despite the current recommendations of the CDC and IUSTI, controversy persists regarding the adequate dose and duration of benzathine penicillin G (BPG) for early syphilis in people living with HIV (PLWH). PubMed, Embase, and Cochrane were searched from inception to October 2025 for studies comparing a single-dose versus a 3-dose BPG regimen in PLWH with early syphilis. A random-effects meta-analysis was performed using risk ratios (RRs) with 95% confidence intervals (CIs). The primary outcome included serologic cure, defined as a ≥4-fold (2-dilution) decline from baseline in antibody titers measured by nontreponemal (lipoidal antigen) tests, including rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) tests, at 6 and 12 months. A total of 8 studies, including 2randomized controlled trials (RCTs) and 6observational studies, were included. Pooled analysis showed no significant difference in serologic cure between a single-dose versus 3-dose BPG at 6months (RR 1.00; 95% CI 0.93 to 1.07; P = 0.95) or 12 months (RR 0.98; 95% CI 0.92 to 1.04; P = 0.46). Overall, our pooled results did not show a significant difference between single-dose and 3-dose BPG. However, our study did not evaluate selected high-risk subgroups, particularly individuals with advanced immunosuppression or untreated HIV infection. Thus, a potential benefit of enhanced therapy in these specific populations cannot be entirely ruled out, underscoring the need for future RCTs focused on these subgroups and designed to stratify or adjust for key disease-modifying factors.