Editor’s Note:
Recently, the U.S. Centers for Disease Control and Prevention (CDC) released an important clinical guideline offering new guidance on the prevention of bacterial sexually transmitted infections (STIs). The “Clinical Guidelines for the Use of Doxycycline Post-Exposure Prophylaxis (Doxy PEP) for Bacterial STIs” marks a significant addition to current STI prevention strategies, particularly for high-risk populations. The guideline also emphasizes the importance of ongoing monitoring and data collection to assess its long-term effectiveness and potential impact. This new guideline not only provides a new strategy for sexual health protection but also lays the foundation for future preventive measures.
01 Overview of Doxycycline Post-Exposure Prophylaxis
Doxycycline is a broad-spectrum tetracycline antibiotic known for its good absorption and tolerability, with a half-life of approximately 12 hours. It is the recommended treatment for chlamydia infections and serves as an alternative treatment for non-pregnant syphilis patients who are severely allergic to penicillin or unable to use penicillin. Doxycycline also exhibits some antibacterial activity against Neisseria gonorrhoeae.
Doxycycline Post-Exposure Prophylaxis (Doxy PEP) is a preventive measure against bacterial STIs, primarily used among men who have sex with men (MSM). This prevention strategy involves taking doxycycline immediately after sexual activity to reduce the risk of bacterial STIs, particularly syphilis, chlamydia, or gonorrhea.
02 Effectiveness of Doxy PEP
French IPERGAY Study
- Study Population: 232 HIV-negative MSM and transgender women (TGW) using tenofovir and emtricitabine (TDF/FTC) as HIV pre-exposure prophylaxis (PrEP).
- Methodology: Participants were randomly assigned to either (1) a single oral dose of 200 mg doxycycline, preferably within 24 hours after unprotected sex, and no later than 72 hours, up to three times a week; or (2) no prophylaxis. The primary endpoint was the first occurrence of bacterial STIs (syphilis, chlamydia, and gonorrhea) during 10 months of follow-up.
- Results: The risk of contracting syphilis and chlamydia was reduced by 70% (HR 0.30, 95% CI: 0.13–0.70) and 73% (HR 0.27, 95% CI: 0.07–0.98) respectively in the Doxy PEP group, with no significant difference in gonorrhea infections.
U.S. DoxyPEP Study
- Study Population: 501 MSM and TGW who were either HIV-positive or on HIV PrEP, with a history of unsafe sex and STI within the past 12 months.
- Methodology: Self-administered 200 mg doxycycline within 24 hours after unprotected sex, and no later than 72 hours.
- Results: The relative risk (RR) of bacterial STIs, including gonorrhea (RR 0.45, 95% CI: 0.34–0.65), chlamydia (RR 0.12, 95% CI: 0.05–0.25), and syphilis (RR 0.13, 95% CI: 0.03–0.59) in the HIV PrEP cohort (n=327) and the HIV-positive cohort (n=174) was significantly reduced.
French ANRS DOXYVAC Study
- Study Population: MSM on HIV PrEP for at least 6 months, with at least one STI in the past 12 months.
- Methodology: Participants were randomly assigned to (1) Doxy PEP group (n=332), taking doxycycline within 24–72 hours after sex; (2) no Doxy PEP group (n=170); (3) 4CMenB vaccine group (n=257); or (4) no vaccine group (n=245).
- Results: Doxy PEP significantly reduced the incidence of gonorrhea (aHR 0.49, 95% CI: 0.32–0.76), chlamydia (aHR 0.11, 95% CI: 0.04–0.30), and syphilis (aHR 0.21, 95% CI: 0.09–0.47).
Trial for Cisgender Women
- Study Population: 449 cisgender women in Kenya.
- Methodology: 200 mg doxycycline within 72 hours after sex, compared with standard care.
- Results: No significant reduction in bacterial STIs (RR 0.88, 95% CI: 0.60–1.29), chlamydia (RR 0.73, 95% CI: 0.47–1.13), or gonorrhea (RR 1.64, 95% CI: 0.78–3.47) was observed. Due to only two early syphilis cases during the study period, the effectiveness against syphilis could not be evaluated. Despite 78% of Doxy PEP users reporting event-driven dose coverage weekly, only 58 out of 200 hair samples (29.0%) from 50 randomly selected participants in the Doxy PEP group tested positive for doxycycline, indicating non-adherence as a possible reason for reduced efficacy. Other factors contributing to reduced efficacy, such as biological differences, require further exploration.
03 Potential Risks of Doxycycline Use
Clinical Adverse Events in Doxy PEP Trials
- In the IPERGAY study, gastrointestinal side effects were more common in the Doxy PEP group (53% vs. 41%; P=0.05).
- In the DoxyPEP study, five participants in the Doxy PEP group discontinued due to intolerance or patient preference.
- In the ANRS DOXYVAC study, three participants (0.9%) discontinued due to gastrointestinal adverse reactions (n=2) or concerns about adverse effects (n=1).
Adverse Events in Other Clinical Uses of Doxycycline
- Systematic reviews and meta-analyses found that long-term daily use of doxycycline (≥8 weeks) may increase the risk of gastrointestinal or dermatological adverse events.
- Compared to the placebo group, participants using doxycycline were more likely to withdraw from clinical trials due to adverse events.
Promotion of Antimicrobial Resistance
- Doxy PEP may promote antimicrobial resistance (AMR) in bacterial STIs and other common bacterial pathogens, such as Staphylococcus aureus.
- A study found that after 12 months of follow-up, the proportion of doxycycline-resistant Staphylococcus aureus in nasal isolates from the Doxy PEP group increased from 5% to 13%.
- There is limited research on the relationship between doxycycline and AMR in non-STI pathogens. Existing data indicate no significant association between daily doxycycline use and resistance in Propionibacterium acnes, Staphylococcus epidermidis, or gastrointestinal pathogens causing diarrhea, although the doses of doxycycline used in these studies were lower.
- No studies have been conducted on the long-term, intermittent use of doxycycline and its effects on the microbiome. As the guideline is implemented, the potential risks related to resistance development and microbiome changes need to be monitored.
04 Key Points from the CDC Guidelines
Population, Usage, and Dosage
Supporting Clinical Services for Doxy PEP
- When providing Doxy PEP, it should be integrated into a comprehensive sexual health approach, including risk reduction counseling, STI screening and treatment, recommended vaccinations, and connections to HIV PrEP, HIV care, or other appropriate services. Individuals receiving Doxy PEP should undergo bacterial STI testing at exposure sites at baseline and every 3–6 months thereafter. HIV-negative MSM and TGW should be screened for HIV according to current recommendations.
