Does the literature support the use of doxycycline for post-exposure prophylaxis against sexually transmitted infections?

Background
Sexually transmitted infections (STIs) are a global public health concern, with chlamydia, gonorrhea, and syphilis being among the most common bacterial STIs.1 Despite significant efforts to control and prevent the spread of STIs, recent trends indicate that conventional approaches to mitigating the spread of infection are insufficient, signaling a need for new and effective approaches in this therapeutic area.2 From 2016 to 2020, cases of gonorrhea and syphilis in the United States increased by 45% and 52%, respectively. While reporting of syphilis grew steadily between 2012 and 2021, cases rose sharply by 25% from 2020 to 2021.3

Preventing STIs is critical to protecting individuals’ sexual health and overall well-being since these infections can cause a range of complications, including infertility, chronic pain, and increased risk of HIV transmission.4 The Centers for Disease Control and Prevention (CDC) updated their treatment guideline for STIs in 2021. While the majority of the guideline is focused on the treatment of suspected or confirmed infections, post-exposure prophylaxis (PEP) of STIs with antimicrobials is an active area of research that has led to the CDC publishing subsequent considerations for the use of doxycycline as post-exposure prophylaxis (PEP) in 2022.5

Doxy-PEP
Considerations for the use of doxycycline as PEP, commonly referred to as “Doxy-PEP,” are outlined in Box 1.5 The CDC published these considerations after interim findings from a multicenter, randomized, open-label trial demonstrated doxycycline’s effectiveness and tolerability against common STIs in MSM and transgender women (TGW) who have sex with men who are either living with HIV or using HIV pre-exposure prophylaxis (PrEP).5,6

Box 1. Considerations for Use of Doxy-PEP.5
  • Doxycycline 200 mg by mouth within 24 to 72 hours of condomless sex has demonstrated efficacy for the prevention of chlamydia, gonorrhea, and syphilis in gay and bisexual men and transgender women.
  • Antibiotics other than doxycycline should not be considered for PEP.
  • Patients who receive PEP with doxycycline should receive counseling about potential adverse side effects of therapy including phototoxicity, gastrointestinal symptoms, and esophageal ulceration.
  • Ongoing screening and testing for STIs per current guidelines should continue regardless of use of doxycycline as PEP or PrEP.
Abbreviations: Doxy-PEP, doxycycline as post-exposure prophylaxis; PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis; STI, sexually transmitted infection.

In 2019, a panel of experts in STI management convened in an effort to respond to several key questions surrounding adult syphilis management; responses would be used to inform the 2021 CDC guidelines for STI management.7 The following was one of the key questions addressed by the panel: Are there new interventions or new data on known interventions for preventing syphilis? Briefly, the expert panel stated that limited data suggest that prophylaxis with doxycycline may decrease syphilis incidence in MSM, but long-term data regarding their impact on antimicrobial resistance and the microbiome are lacking. Also mentioned are suboptimal screening rates for MSM populations at increased risk for syphilis.

Clinical Trials for Doxy-PEP
Doxycycline is the most studied agent in the arena of antimicrobial prophylaxis against bacterial STIs. Table 1 summarizes 2 key clinical trials assessing the efficacy of Doxy-PEP.6,8 Both studies included at-risk MSM and TGW who have sex with men and/or persons living with HIV (PLWH). Individuals enrolled in these studies had at least one of multiple risk factors that increase the risk for STI acquisition, including history of chlamydia, gonorrhea, or syphilis infection, living with HIV infection, and having condomless sex with multiple partners. Doxycycline was administered orally at a dose of 200 mg within 24 to 72 hours of condomless sex.

The results of studies evaluating Doxy-PEP generally support the efficacy of doxycycline as a prophylactic agent for bacterial STI prevention in at-risk populations. 6,8 Briefly, Doxy-PEP has been shown to reduce the overall STI risk by 43% to 66% in at-risk MSM or TGW taking HIV PrEP and by 62% in PLWH.6,8 The effectiveness of Doxy-PEP in reducing chlamydia and syphilis infections was more pronounced than its effectiveness in reducing gonorrhea infection, with one of the studies not reaching statistical significance in reducing gonorrhea infection. In both studies, Doxy-PEP was well tolerated with no unexpected safety events.6,8

An additional abstract published in 2023 further describes Doxy-PEP in 720 MSM receiving HIV PrEP who had an STI within the last 12 months.9 In this randomized, open-label, factorial trial, participants received Doxy-PEP or no Doxy-PEP (2:1) and 2 doses of meningococcal B vaccine or no vaccine (1:1). Interim results in August 2022 demonstrated that DoxyPEP reduced the rate of new STIs by 65% (approximately 80% for chlamydia and syphilis and approximately 55% for gonorrhea). Thereafter, the Data and Safety Monitoring Board recommended stopping trial enrollment and offering the preventive interventions to all participants through a final visit in January 2023. Additional clinical studies evaluating Doxy-PEP in similar at-risk populations as well as heterosexual cis-gender women are ongoing.4,10

Table 1: Clinical Trials of Doxy-PEP for STI Prevention in At-Risk Individuals.6,8
Citation
Design
Population
Treatment groups
Overall STI Risk for Doxy-PEP vs control
Individual STI risk for Doxy-PEP vs control
Luetkemeyer et al (2023)6
 
 
R, OL in the US
 
 
Two cohorts
1) MSM or TGW taking HIV PrEP who had an STI within the last 12 months and a history of condomless sex within the last 12 months (n=327)
 
2) PLWH who had an STI within the last 12 months and a history of condomless sex within the last 12 months (n= 174)
Doxy-PEP: doxycycline hyclate 200 mg within 24 to 72 hours of condomless sex 
 
Control: standard care
MSM or TGW on PrEP: RR, 0.34 (95% CI, 0.24 to 0.46)
 
PLWH: RR, 0.38 (95% CI, 0.24 to 0.60)
 
MSM or TGW on PrEP
Chlamydia: RR, 0.12 (95% CI, 0.05 to 0.25)
Gonorrhea: RR, 0.45 (95% CI, 0.32 to 0.65)
Early syphilis: RR, 0.13 (95% CI, 0.03 to 0.59)
 
PLWH
Chlamydia: RR, 0.26 (95% CI, 0.12 to 0.57)
Gonorrhea: RR, 0.43 (95% CI, 0.26 to 0.71)
Early syphilis: RR, 0.23 (95% CI, 0.04 to 1.29)
Molina et al (2018)8
 
Substudy of the ANRS IPERGAY trial
 
R, OL in France
 
 
Median follow up, 8.7 months
MSM or TGW taking oral HIV PrEP who had a history of condomless sex within the last 6 months (n=232)
Doxy-PEP: doxycycline hyclate 200 mg within 24 to 72 hours of condomless sex; max 3 times weekly
 
Control: standard care
 
Both groups were receiving risk-reduction and adherence counselling on PrEP and free condoms and gel
First occurrence: HR, 0.53 (95% CI, 0.33 to 0.85)
 
All occurrence during follow-up: HR, 0.57 (95% CI, 0.13 to 0.62)
Chlamydia first occurrence: HR, 0.30 (95% CI, 0.13 to 0.70)
Gonorrhea first occurrence: HR, 0.83 (95% CI, 0.47 to 1.47)
Syphilis first occurrence: HR, 0.27 (95% CI, 0.07 to 0.98)
Abbreviations: ANRS IPERGAY, National Agency of Research on AIDS and Viral Hepatitis– On Demand Antiretroviral Pre-exposure Prophylaxis for HIV Infection in Men Who Have Sex With Men; CI, confidence interval; HIV, human immunodeficiency virus; HR, hazard ratio; MSM, men who have sex with men, OL, open label; PEP, post-exposure prophylaxis; PLWH, persons living with HIV; PrEP, pre-exposure prophylaxis; R, randomized; RR, relative risk; STI, sexually transmitted infection; TGW, transgender women; US, United States.

Discussion
Doxycycline is a tetracycline antibiotic that is commonly used as first-line therapy for chlamydia infection in adults and adolescents who are not pregnant.4 Doxycycline is typically administered at an oral dose of 100 mg twice daily for 7 to 21 days, and common side effects include gastrointestinal upset, photosensitivity, and tooth discoloration. Doxycycline should be avoided in pregnancy as tetracyclines can accumulate in long tubular bones and developing teeth, which may lead to permanent discoloration of teeth.

Two published randomized trials as well as a published abstract of a third randomized trial support updated considerations from the CDC regarding the use of doxycycline 200 mg orally as PEP following unprotected sex in MSM and TGW who have sex with men who are either living with HIV or using HIV PrEP.6,8,9 Reductions in the risk of chlamydia and syphilis appear more pronounced when compared to the reduction in gonorrhea. Experts predict that this is likely due to differences in prevalence of gonococcal resistance to doxycycline in the US vs internationally.11 For example, in the US, prevalence of gonococcal resistance to doxycycline ranges from 20% to 30%, whereas resistance rates are upwards of 50% in France.

While the emerging data regarding the effectiveness of Doxy-PEP appear promising, medical societies have not yet adopted Doxy-PEP as standard care. As previously mentioned, the CDC only provides considerations for the use of Doxy-PEP, but does not specifically provide recommendations for or against use.4 In a 2022 publication, the USA International Antiviral Society stated that pending further data on doxycycline’s effect on antimicrobial resistance and the microbiome, the use of Doxy-PEP should be considered on a case-by-case basis for individuals at high risk of chlamydia, gonorrhea, and syphilis infection.12 Additionally, the British Association for Sexual Health and HIV and the UK Health Security Agency do not endorse the use of doxycycline taken as PEP or PrEP to prevent STIs.13 These organizations also note concerns regarding  doxycycline’s impact on antimicrobial resistance and the microbiome, as well as tetracycline-related safety concerns with more widespread use of doxycycline.

Conclusion
Evidence supporting the use of antimicrobials to prevent common STIs, including chlamydia, gonorrhea, and syphilis, is emerging.4,5 Notably, doxycycline 200 mg orally as PEP following unprotected sex in at-risk in MSM and TGW who have sex with men who are either living with HIV or using HIV PrEP has demonstrated significant reductions in STI acquisition.6,8,9 Patients who receive Doxy-PEP should receive counseling about potential adverse side effects of therapy, and ongoing screening and testing for STIs per current CDC guidelines should continue regardless of use of doxycycline prophylaxis. Since the long-term data regarding Doxy-PEP’s impact on antimicrobial resistance and the microbiome are lacking, clinicians should be vigilant when recommending Doxy-PEP, making sure to carefully weigh the potential benefits against the risks of therapy.10,11

References:

  1. Kreisel KM, Spicknall IH, Gargano JW, et al. Sexually transmitted infections among us women and men: prevalence and incidence estimates, 2018. Sex Transm Dis. 2021;48(4):208-214. doi:10.1097/olq.0000000000001355
  2. Centers for Disease Control and Prevention. Reported STDs in the United States, 2020. 2023. Accessed June 16, 2023. https://www.cdc.gov/nchhstp/newsroom/fact-sheets/std/std-us-2020.html
  3. Centers for Disease Control and Prevention. Preliminary 2021 STD Surveillance Data. 2022. Accessed June 16, 2023. https://www.cdc.gov/std/statistics/2021/default.htm
  4. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. Accessed June 16, 2023. https://www.cdc.gov/std/treatment-guidelines/toc.htm
  5. Centers for Disease Control and Prevention. CDC Resposne to Doxy-PEP data presented at 2022 International AIDS Conference. 2022. Accessed June 16, 2023. https://www.cdc.gov/nchhstp/newsroom/2022/Doxy-PEP-clinical-data-presented-at-2022-AIDS-Conference.html
  6. Leutkemeyer A, Donnell D, Dombrowski JC, et al. Postexposure doxycycline to prevent bacterial sexually transmitted infections. N Engl J Med. 2023;388(14):1296-1306. doi:10.1056/NEJMoa2211934
  7. Tuddenham S, Ghanem KG. Management of Adult Syphilis: Key Questions to Inform the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines. Clin Infect Dis. 2022;74(Suppl_2):S127-s133. doi:10.1093/cid/ciac060
  8. 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(3):308-317. doi:10.1016/s1473-3099(17)30725-9
  9. Molina JM, Bercot B, Assoumou L, et al. ANRS 174 DOXYVAC: an open-label randomized trial to prevent STIs in MSM on PrEP. Oral Abstract Session-03 presented at: 29th Conference on Retroviruses and Opportunistic Infections; February 19-22, 2023; Seattle, WA. Abstract number 119. Accessed June 16, 2023. Available at: https://www.natap.org/2023/CROI/croi_03.htm.
  10. Grant JS, Stafylis C, Celum C, et al. Doxycycline Prophylaxis for Bacterial Sexually Transmitted Infections. Clin Infect Dis. 2020;70(6):1247-1253. doi:10.1093/cid/ciz866
  11. Kong FYS, Kenyon C, Unemo M. Important considerations regarding the widespread use of doxycycline chemoprophylaxis against sexually transmitted infections. J Antimicrob Chemother. 2023;dkad129. doi:10.1093/jac/dkad129
  12. Gandhi RT, Bedimo R, Hoy JF, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2022 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2023;329(1):63-84. doi:10.1001/jama.2022.22246
  13. Saunders J, Kohli M, Medland N, Fifer H. Position statement on doxycycline as prophylaxis for sextually transmitted infections 2021 update. November 2, 2021. Accessed June 16, 2023. https://www.bashh.org/guidelines

Prepared by:
Katherine Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

July 2023

The information presented is current as of June 16, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.