Comparative Effectiveness of Three Benzathine Penicillin G-Based Regimens in People with HIV Who Presented with Early Syphilis.

OBJECTIVES: To compare 12-month serologic responses to three benzathine penicillin G (BPG)-based regimens among people with HIV (PWH) and early syphilis. METHODS: We retrospectively included syphilis episodes treated with BPG, BPG plus 7-day doxycycline (BPG/doxycycline), or BPG/doxycycline plus single-dose ceftriaxone during 2018-2024. Episodes with baseline rapid plasma reagin (RPR) titers <1:4 or exposure to other Treponema pallidum-active antibiotics were excluded. Serologic response was defined as a ≥4-fold RPR decline at 12 months. Intention-to-treat (ITT) with last-observation-carried-forward and per-protocol analyses were performed. RESULTS: Among 1,077 episodes in 762 PWH, 453 received BPG, 570 BPG/doxycycline, and 54 BPG/doxycycline/ceftriaxone. ITT response rates were 74.6%, 83.2%, and 88.9%, respectively (P < .001); per-protocol rates were 74.4%, 83.4%, and 89.8% (P < .001). Higher baseline RPR titers and doxycycline-containing regimens were independently associated with response. In analyses directly comparing BPG/doxycycline with and without ceftriaxone, adding ceftriaxone to BPG/doxycycline was not significantly associated with a higher serologic response. CONCLUSIONS: BPG/doxycycline was associated with a higher likelihood of 12-month serologic response. The incremental association of ceftriaxone remained uncertain because of the small number of ceftriaxone-treated episodes.