Is 3 Really What We Need? Relative Effectiveness of Benzathine Penicillin G and Doxycycline Treatment Regimens for Late or Unknown Duration Syphilis in 6 US Jurisdictions, 2016–2021

BACKGROUND: Little evidence supports the need for 3 weekly benzathine penicillin G (BPG) injections to treat late or unknown duration syphilis, and completion of the regimen may be difficult. We compared treatment effectiveness of 1 versus 3 doses of BPG and doxycycline. METHODS: We conducted a retrospective cohort study using surveillance data for cases diagnosed with late or unknown duration syphilis between 2016 and 2021 from 6 jurisdictions. We categorized BPG and doxycycline treatment based on the recorded number and timing of doses received. We defined treatment effectiveness as a 4-fold decrease in nontreponemal serum titer by 24 months posttreatment and compared treatment effectiveness using log binomial regression. RESULTS: Among 18 027 cases eligible for inclusion, over half had 3 doses of BPG recorded (11 342, 63%); relatively few had only 1 dose recorded (1928, 11%) or received at least 28 days of doxycycline (3017, 17%). Fourfold titer decreases were observed for 75% and 80% of cases given 3 doses and 1 dose of BPG, respectively, and for the 74% given doxycycline. Treatment effectiveness was similar across all treatment dose/interval categories and remained comparable when stratified by baseline titer, pregnancy status, and human immunodeficiency virus (HIV) infection. CONCLUSIONS: We did not observe a difference in treatment effectiveness between 1 and 3 doses of BPG, or between 3 doses of BPG and doxycycline, for late or unknown duration syphilis. Additional observational and clinical studies with more complete treatment and serologic response information are needed to confirm these findings and inform practice recommendations.