BACKGROUND: In the USA, post-exposure prophylaxis (PEP) with doxycycline within 72 h after sex is recommended to prevent chlamydia, gonorrhoea, and syphilis in men who have sex with men (MSM) and transgender women. However, concerns surround potential expansion of Neisseria gonorrhoeae lineages harbouring antimicrobial resistance (AMR) in settings that implement doxycycline PEP. We aimed to assess the real-world effectiveness of doxycycline PEP in preventing sexually transmitted infections, and whether effectiveness against N gonorrhoeae infection was durable following doxycycline PEP implementation. METHODS: We conducted a retrospective, test-negative, observational study in individuals receiving care from the Kaiser Permanente Southern California integrated health-care system. Eligible participants were assigned male at birth and living with HIV or receiving HIV pre-exposure prophylaxis or PEP at any time between July 1, 2021, and June 30, 2025.
The primary outcomes were laboratory-confirmed chlamydia, gonorrhoea, and syphilis infections in eligible cohort members. Primary analyses used a test-negative design; we fit logistic regression models to estimate protective effectiveness of doxycycline PEP by comparing history of doxycycline PEP prescription fills 90 days or less before positive or negative tests for infection with Chlamydia trachomatis, N gonorrhoeae, and Treponema pallidum. In analyses defining doxycycline PEP effectiveness as a time-varying parameter, we assessed how effectiveness against gonorrhoea infection varied throughout the study period and in association with the proportion of local N gonorrhoeae isolates harbouring tetM, a plasmid-borne gene conferring high-level tetracycline resistance. FINDINGS: 33 118 individuals met eligibility criteria, of whom 26 582 had one or more sexually transmitted infection tests between Jan 1, 2023, and June 30, 2025, and were thus included in the primary analyses. 2262 (8· 5%) of 26 582 participants received one or more doxycycline PEP fills.
Doxycycline PEP fills occurred 90 days or less before 39 (0· 8%) of 4659 positive and 3288 (2· 5%) of 130 138 negative C trachomatis tests; 212 (3· %) of 6539 positive and 3112 (2· 4%) of 128 238 negative N gonorrhoeae tests; and 11 (0· 5%) of 2169 positive and 794 (3· 0%) of 26 913 negative T pallidum tests. Throughout the study period, preventive effectiveness of doxycycline PEP against chlamydia was 66· 5% (95% CI 53· 6 to 75· 9), against gonorrhoea was -1· 8% (-18· 5 to 12· 5), and against syphilis was 60· 7% (28· 3 to 78· 5). Effectiveness against gonorrhoea decreased from 42· 3% (2· 7 to 65· 8) before statewide doxycycline PEP implementation to -15· 0% (-51· 1 to 11· 4) between January and June, 2025, in association with a rapid increase of tetM prevalence in circulating N gonorrhoeae lineages. Effectiveness during periods with tetM detected in 20· 0-29· 9% of N gonorrhoeae isolates was 47· 2% (4· 1 to 70· 3), decreasing to -8· 5% (-33· 2 to 11· 2) during periods with tetM detected in 50% or more of isolates. INTERPRETATION: We report rapid loss of doxycycline PEP effectiveness against gonorrhoea within the first year after doxycycline PEP implementation in MSM and transgender women in southern California, associated with expansion of high-level tetracycline resistance in N gonorrhoeae.
Whereas we report sustained doxycycline PEP effectiveness against chlamydia and syphilis more than 2 years after doxycycline PEP implementation, our findings suggest protection against gonorrhoea might not be durable. Risk-benefit considerations for doxycycline PEP implementation strategies should assume limited or transient benefits associated with gonorrhoea prevention, and address potential consequences of AMR expansion in N gonorrhoeae. FUNDING: US Centers for Disease Control and Prevention.