Doxycycline Prophylaxis for Prevention of Sexually Transmitted Infections

Participants will be randomized to receive on-demand doxycycline post-exposure prophylaxis (doxyPEP), weekly doxycycline, or standard of care (SOC) and will be followed quarterly to assess the impact of doxycycline use on the quarterly incidence of STIs (gonorrhea \[GC\], chlamydia \[CT\], and early syphilis), and within the doxycycline arms adherence and acceptability of weekly versus on-demand dosing. Approximately 760 females will be randomized 1:1:1 to (1) on-demand doxyPEP (doxycycline 200 mg as soon as possible and within 72 hours after any condomless oral, vaginal, and/or anal sex), (2) weekly doxycycline (doxycycline 200 mg weekly regardless of sexual activity), or (3) SOC (quarterly STI testing/treatment and sexual health counseling). Participants will complete quarterly study visits over the course of 1 year during which they will receive STI testing (GC, CT, and syphilis), complete surveys, undergo safety monitoring, provide specimens for objective markers of doxycycline adherence and other laboratory assessments, and provide specimens (vaginal and rectal swabs \[participant self-collected or staff-collected if the participant prefers\]) for future testing, such as microbiome analysis. Resistance testing will be conducted on Staphylococcus (S.) aureus and Neisseria (N.) gonorrhoeae isolates to evaluate for doxycycline and tetracycline resistance, respectively. Participants will also complete weekly assessments of sexual activity and doxycycline adherence via the HealthMpowerment (HMP) application (app).