By Jake Scott, MD
Clinical Assistant Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley
SYNOPSIS: In an open-label, randomized study involving men who have sex with men and transgender women, the use of doxycycline within 72 hours of condomless sex was associated with a two-thirds reduction in the incidence of bacterial sexually transmitted infections as compared with those who received standard care.
SOURCE: Luetkemeyer AF, Donnell D, Dombrowski JC, et al. Postexposure doxycycline to prevent bacterial sexually transmitted infections. N Engl J Med 2023;388:1296-1306.
Luetkemeyer and colleagues conducted an open-label, randomized study that evaluated the effectiveness of 200 mg of oral doxycycline taken as postexposure prophylaxis for the prevention of bacterial sexually transmitted infections (STIs) when used within 72 hours of condomless sex.1 The study enrolled adult men who have sex with men (MSM) and transgender women from human immunodeficiency virus (HIV) clinics and sexual health clinics in San Francisco and Seattle from Aug. 19, 2020, through May 13, 2022. All participants had been diagnosed with gonorrhea, chlamydia, or early syphilis in the previous year and were considered to be at high risk for bacterial STIs. The study included two cohorts: people taking preexposure prophylaxis (PrEP) against HIV infection (PrEP cohort) and people living with HIV infection (persons living with HIV infection [PLWH] cohort). Participants were assigned randomly in a 2:1 ratio to take doxycycline postexposure prophylaxis (doxy-PEP) or receive standard care without doxy-PEP. Those in the doxy-PEP group were instructed to take a one-time dose of 200 mg of doxycycline as soon as possible — preferably within 24 hours and no later than 72 hours — after any condomless anogenital, vaginal, or oral sex, and not to take more than 200 mg every 24 hours.
Participants were asked to complete computer-assisted surveys to report their sexual activity and any symptoms. Regular assessments of doxycycline adherence and side effects were conducted during quarterly visits over a 12-month period. Quarterly STI screenings were performed with nucleic acid amplification testing of specimens obtained from the urine, pharynx, and rectum for gonorrhea and chlamydia and serologic testing for syphilis. Participants who tested positive for Neisseria gonorrhea were asked to return for swabs for gonococcal culture prior to treatment to have phenotypic tetracycline resistance testing performed. (Tetracycline resistance was used as a surrogate for doxycycline resistance.) All participants had swabs obtained from the anterior nares and oropharynx at baseline, six months, and 12 months for Staphylococcus aureus culture and doxycycline resistance testing. The primary end point of the study was the incidence of at least one bacterial STI per quarter. Antimicrobial resistance among N. gonorrhea and S. aureus isolates at baseline was compared with organisms isolated at study follow-up. Secondary end points included the incidence of each individual bacterial STI, as well as safety, adverse events, and acceptability.
The study included 501 participants in the modified intention-to-treat population and found that doxy-PEP was associated with a roughly two-thirds reduction in the incidence of bacterial STIs. Among participants in the PrEP cohort, at least one bacterial STI was diagnosed in 61 of 570 quarterly visits (10.7%) in the doxycycline group as compared with 82 of 257 (31.9%) in the standard-care group (absolute difference, -21.2 percentage points; relative risk, 0.34; 95% confidence interval [CI], 0.24 to 0.46; P < 0.001). Among those in the PLWH cohort, at least one STI was diagnosed in 36 of 305 quarterly visits (11.8%) in the doxycycline group and 39 of 128 (30.5%) in the standard-care group (absolute difference, -18.7 percentage points; relative risk, 0.38; 95% CI, 0.24 to 0.60; P < 0.001). The number needed to treat to prevent at least one STI per quarter in this population was 4.7 in the PrEP cohort and 5.3 in the PLWH cohort.
Among the three STIs tested, gonorrhea was the most frequently diagnosed. The incidence of gonorrhea at all anatomical sites was significantly lower in the participants who took doxy-PEP. In the PrEP cohort, the quarterly incidence of gonorrhea was 9.1% (52 of 570 quarters) in the doxycycline group vs. 20.2% (52 of 257 quarters) in the standard-care group (relative risk, 0.45; 95% CI, 0.32 to 0.65). In the PLWH cohort, the incidence was 8.9% (27 of 305) and 20.3% (26 of 128), respectively (relative risk, 0.43; 95% CI, 0.26 to 0.71).
The quarterly incidence of chlamydia also was substantially lower in the doxycycline group. In the PrEP cohort, the incidence of chlamydia was 1.4% (8 of 570) in the doxycycline group as compared with 12.1% (31 of 257) in the standard-care group (relative risk, 0.12; 95% CI, 0.05 to 0.25). In the PLWH cohort, the incidence of chlamydia was 3.9% (12 of 305) and 14.8% (19 of 128), respectively (relative risk, 0.26; 95% CI, 0.12 to 0.57). The overall incidence of early syphilis was relatively low (diagnosed in 14 quarters total) but also was lower in the doxycycline group as compared with the standard-care group. In the PrEP cohort, the incidence of syphilis was 0.4% (2 of 570) vs. 2.7% (7 of 257), respectively (relative risk, 0.13; 95% CI, 0.03 to 0.59). In the PLWH cohort, the incidence was 0.7% (2 of 305) vs. 2.3% (3 of 128), respectively (relative risk, 0.23; 95% CI, 0.04 to 1.29). In a secondary analysis, time to first bacterial STI diagnosis was 66% lower in the doxycycline group in the PrEP cohort (hazard ratio, 0.34; 95% CI, 0.23 to 0.51) and 52% lower in the doxycycline group in the PLWH cohort (hazard ratio, 0.48; 95% CI, 0.28 to 0.83).
Adherence to doxycycline was high; 86% of participants in the doxy-PEP groups reported taking it consistently within 72 hours after condomless sex and 71% reported never missing a dose after condomless sex. No serious adverse events were attributed to doxycycline. One case of elevated transaminases and five grade 3 adverse events (three diarrheal events and two headaches or migraines) were attributed to doxycycline. Eighty-nine percent of participants in the doxy-PEP groups reported that taking doxy-PEP was acceptable or very acceptable. Tetracycline resistance was detected in four of 15 N. gonorrhea isolates (27%) at baseline. After enrollment, tetracycline resistance was found in five of 13 isolates (38%) in the doxycycline groups and two of 16 (12%) in the standard-care groups. Culture data were limited due to an inability to obtain cultures before treatment in half of the participants and due to a lack of culture growth in a number of specimens. S. aureus was isolated during baseline screening tests from 45% of study participants, 12% of which was doxycycline resistant. Twelve months after enrollment, S. aureus was isolated from 28% in the doxycycline groups and 47% in the standard-care groups (P = 0.03); doxycycline resistance was detected in 16% in the doxycycline groups and 8% in the standard-care groups.
COMMENTARY
Cases of gonorrhea, chlamydia, and syphilis have continued to rise in the United States. Between 2017 and 2021, overall reported STIs increased 7%, according to the latest surveillance data from the Centers for Disease Control and Prevention.2 Globally, more than 1 million STIs are acquired every day and most cases are initially asymptomatic.3 Broad and robust support for research into diagnostics, therapeutics, and vaccines for STIs is urgently needed, and interventions such as pre- and post-exposure prophylaxis for certain high-risk populations deserve serious consideration.
This study showed that doxy-PEP was highly effective at preventing bacterial STIs in MSM and transgender women who were either on HIV PrEP or living with HIV infection and that it was well tolerated and accepted. Similar findings were shown previously in the IPERGAY trial, which was a smaller, open-label randomized study conducted in France that included MSM participants on HIV PrEP and found that doxy-PEP was associated with an overall 47% relative reduction in the risk of developing a new bacterial STI.4 No significant reduction in incident gonorrhea was observed, however, potentially because of a higher prevalence of tetracycline resistance in France at that time.
The extent to which these findings can be generalized to cisgender women is unknown and requires further research. A randomized trial of doxy-PEP used among cisgender women in Kenya reportedly failed to show significant effectiveness in the prevention of bacterial STIs; this study has been presented only in abstract form and is not yet published.5 Additional research also is needed to further assess the potential impact of doxy-PEP on antimicrobial resistance and the gut microbiome.
REFERENCES
- Luetkemeyer AF, Donnell D, Dombrowski JC, et al. Postexposure doxycycline to prevent bacterial sexually transmitted infections. N Engl J Med 2023;388:1296-1306.
- Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance, 2021. Published April 11, 2023. https://www.cdc.gov/std/statistics/2021/default.htm
- World Health Organization. Sexually transmitted infections (STIs). https://www.who.int/news-room/fact-sheets/detail/sexually-transmitted-infections-(stis)
- Molina JM, Charreau I, Chidiac C, et al. Post-exposure prophylaxis with doxycycline to prevent sexually transmitted infections in men who have sex with men: An open-label randomised substudy of the ANRS IPERGAY trial. Lancet Infect Dis 2018;18:308-317.
- Stewart J, Oware K, Connell D, et al. Doxycycline postexposure prophylaxis for prevention of STIs among cisgender women. 30th CROI, Conference on Retroviruses and Opportunistic Infections, Feb. 19-22, 2023, Seattle.
In an open-label, randomized study involving men who have sex with men and transgender women, the use of doxycycline within 72 hours of condomless sex was associated with a two-thirds reduction in the incidence of bacterial sexually transmitted infections as compared with those who received standard care.
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