This randomized controlled superiority study will be conducted during 2023-2025. The eligible participants are adult people living with HIV (PLWH) who are newly diagnosed with early syphilis. Participants will be randomized in a 1:1 ratio to receive single-dose benzathine penicillin G (BPG) (2.4 MU intramuscularly once) plus doxycycline (100 mg orally twice daily for 7 days) or single-dose BPG. The primary outcome is serologic response, defined as a decline of rapid plasma reagin (RPR) titer by 4-fold or greater, at week 24 and week 48; and the secondary outcomes include microbiologic response of syphilis and bacterial sexually transmitted infections (STIs) assessed by nucleic-acid amplification test (NAAT) at week 4.

Inclusion Criteria:

• People living with HIV (PLWH) aged ≥18 years with early syphilis
• Confirmed by a positive RPR titer with a reactive TPPA assay

Exclusion Criteria:

• PWH with RPR titers of <4
• Exposure to antibiotics with activity against T. pallidum within the preceding 4 weeks (penicillin, 3rd cephalosporin, doxycycline, macrolides)
• A known or suspected infection requiring additional treatment with an antimicrobial active against T. pallidum (penicillin, 3rd cephalosporin, doxycycline, macrolides)
• Testing positive for C. trachomatis and M. genitalium, for which doxycycline or macrolide was administered
• A history of intolerance to penicillin or doxycycline
• PLWH have already participated in this study
• Pregnancy