Bacterial sexually transmitted infections (STIs) including gonorrhea, chlamydia and syphilis continue to occur at an alarming rate with an estimated 370 million annually worldwide.¹ The success of HIV pre and post exposure prophylaxis (PREP and PEP respectively) may in fact contribute to the practice of condomless sexual intercourse and result in the transmission of bacterial STIs. An attempt to piggyback on the success of HIV PREP and PEP with doxycycline, an agent active against the major causes of bacterial STIs, has been underway. In a recently accepted manuscript in Clinical Infectious Disease, Hazra and colleagues nicely outlined the evidence to date regarding doxycycline PEP (dPEP) and the remaining questions to be answered.²

The authors initiated their piece by reviewing the clinical trial data to date. The main studies that are focused on are the French IPERGAY study and the US DOXY-PEP study.^3,4 In both studies, doxycycline at a dosage of 200mg taken orally by cisgender men and transgender women within 72 hours of condomless sexual intercourse led to a statistically significant reduction in bacterial STIs compared with placebo. The magnitude of the effect was similar with relative risk reductions of 73% and 66% respectively. A major difference in the trial results was the absence of a statistically significant reduction in gonococcal infections in the French study where there is a greater incidence of doxycycline-resistant Neisseria gonorrhoeae. Additionally, the magnitude of the protective effect was greater for chlamydia and syphilis than for the gonococcus. The authors also importantly review the doxy-PEP clinical trial in cisgender women (assigned as female at birth) where doxycycline PEP was not associated with a reduction in bacterial STIs.⁵

After reviewing the evidence, the authors proceeded to discuss the potential challenges in the implementation of widescale use of doxycycline post-exposure prophylaxis. The authors first focused appropriately on safety. They noted increased partner violence for those on dPEP. They reference a meta-analysis of sixty-seven studies involving long term use of doxycycline to support its safety.⁶ Werner and colleagues in a German position paper on the subject review five clinical trials and indicate that gastrointestinal complaints including diarrhea, vomiting and gastroesophageal reflux were not uncommon.⁷ Additional potential safety concerns with widescale rollout could include photosensitivity in those not using sunscreen and esophageal ulceration especially in those who do not take the medication with water and are recumbent soon after administration. Important potential safety concerns due to drug interactions are increased bleeding in those on coumadin as well as intracranial hypertension in those on isotretinoin for cystic acne.

Foremost in the minds of Hazra and colleagues in their review and in the literature on doxy-PEP for STI prevention is the development of antimicrobial resistance (AMR). As mentioned previously the incidence of N gonnorheae resistant in France was already high at 56%. More N gonnorheae isolates developed resistance over time in the US study while MICs for N gonnorheae isolates increased in the doxycycline-treated group in the French study. Increased resistance of chlamydia and syphilis was not noted. Of potential importance also is the ‘bystander effect” of doxycycline on resistance to other antimicrobials. For example, an increase in the number of S aureus isolates was seen at 12 months in the doxycycline group as was resistance to the workhorse parenteral antimicrobial Ceftriaxone. The authors appropriately noted that robust surveillance programs will need to be put into place to monitor for resistance to doxycycline and other agents as doxy-PEP programs get introduced.

Given the unanswered questions regarding antimicrobial resistance and safety of doxy-PEP, the authors turn to modeling to assist in guiding who to treat. They cited the elegant study by Traeger and colleagues where they examined the prevention of bacterial STIs in 10 different models of doxy-PEP use in 10,546 LGBTQ individuals treated at the Fenway Health Center in Boston from 2105-2020.⁸ They found that if all individuals received doxy-PEP this would prevent 71% of infections with a number needed to treat (NNT) of 3.9 to prevent 1 infection. If doxy-PEP were confined to individuals with a bacterial STI in the last 12 months, doxycycline use could be decreased to 38% of this population while still averting 39% of STIs with a lower NNT range of (1.3-2.4). This data likely influences both the current national agency consideration and local and state health agency recommendations which confine doxy-PEP to this population.

The authors completed their review of the topic by discussing the prominent issues of disparities in the use of doxy-PEP for prevention of bacterial STIs. Most of the patient enrolled in these studies were White males in the US and Europe while bacterial STIs disproportionally affect Black and Hispanic patients and those in lower income countries who are less likely to have access to doxy-PEP. Additionally, no option is currently available for those assigned as female at birth including cisgender, transgender men, and non-binary individuals. The dPEP study was flawed by the low adherence rate to doxy-PEP making it entirely possible that this strategy may be effective in females. Additional studies will be needed to address this large population.

In summary, the current data supports the use of doxy-PEP in cisgender MSM and transgender women to prevent bacterial STIs. Critical issues about safety and antimicrobial resistance still need to be answered. A reasonable approach in the interim is to confine doxy-PEP to those with a bacterial STI in the last 12 months while gathering more data. Additional studies in women, low-income countries, and in the Black and Hispanic population are needed.

References

1. World Health Organization (WHO), Sexually transmitted infections (STIs), World Health Organization (WHOO), 20222 Available at https://www.who.int/news-room/fact-sheet/detail/sexually-transmitted infections-(stis). Accessed 2/15/2024.
2. Hazra A, McNulty MC, Pyra M, et al. Filling in the Gaps: Updates on Doxycycline Prophylaxis for Bacterial Sexually Transmitted Infections. Clin Infect Dis. 2024 Feb 9: ciae062. doi: 10.1093/cid/ciae062. Epub ahead of print.
3. 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 Mar;18(3):308-317. doi: 10.1016/S1473-3099(17)30725-9.
4. Luetkemeyer AF, Donnell D, Dombrowski JC, et al. Postexposure Doxycycline to Prevent Bacterial Sexually Transmitted Infections. N Engl J Med. 2023 Apr 6;388(14):1296-1306. doi: 10.1056/NEJMoa2211934.
5. Stewart J, Oware K, Donnell D, et al. Doxycycline Prophylaxis to Prevent Sexually Transmitted Infections in Women. N Engl J Med. 2023 Dec 21;389(25):2331-2340. doi: 10.1056/NEJMoa2304007.
6. Chan PA, Le Brazidec DL, Becasen JS, et al. Safety of Longer-Term Doxycycline Use: A Systematic Review and Meta-Analysis With Implications for Bacterial Sexually Transmitted Infection Chemoprophylaxis. Sex Transm Dis. 2023 Nov 1;50(11):701-712. doi: 10.1097/OLQ.0000000000001865.
7. Werner RN, Schmidt AJ, Potthoff A, Spornraft-Ragaller P, Brockmeyer NH; German STI Society (DSTIG). Position statement of the German STI Society on the prophylactic use of doxycycline to prevent STIs (Doxy-PEP, Doxy-PrEP). J Dtsch Dermatol Ges. 2023 Dec 20. doi: 10.1111/ddg.15282. Epub ahead of print.
8. Traeger MW, Mayer KH, Krakower DS, et al. Potential impact of doxycycline post-exposure prophylaxis prescribing strategies on incidence of bacterial sexually transmitted infections. Clin Infect Dis. 2023 Aug 18:ciad488. doi: 10.1093/cid/ciad488. Epub ahead of print.