DoxyPEP: Opportunities for Expansion

Abstract

Clinical trials show that doxycycline post-exposure prophylaxis (DoxyPEP) significantly reduces the risk of bacterial sexually transmitted infections (STIs), especially syphilis and chlamydia, in cisgender men who have sex with men and transgender women. Real-world data suggest DoxyPEP may be beneficial for other populations disproportionately affected by STIs. Given the ongoing STI epidemic we recommend discussing DoxyPEP with all eligible patients. We review clinical guidelines and practical considerations surrounding DoxyPEP, highlight areas for future research, and propose strategies for implementation.

Commentary

Up to half of reported sexually transmitted infections (STIs) are diagnosed in primary care clinics. ¹ Rates of bacterial STIs such as chlamydia, gonorrhea, and syphilis in the United States (US) increased by 90% from 2004 to 2023. ² In 2023, there were 1.6 million cases of chlamydia, 601 319 cases of gonorrhea, and 209 253 cases of syphilis, including 3882 cases of syphilis among newborns, a 106% increase since 2019. ³ This rise in STI rates is thought to be due to structural inequities affecting access to healthcare and prevention in marginalized communities, with delays in diagnosis and treatment exacerbated by the COVID-19 pandemic.^4,5 Like HIV, STIs disproportionately impact gay, bisexual, and other cisgender men who have sex with men; transgender women; adolescents and young adults; and racial/ethnic minorities, especially people who identify as Black or African American, American Indian or Alaska Native, and Native Hawaiian or other Pacific Islander.^3,6

Doxycycline post-exposure prophylaxis (DoxyPEP) is the use of doxycycline 200 mg within 72 h after oral, anal, or vaginal sex to prevent bacterial STIs. ⁷ In 2024 the Centers for Disease Control and Prevention (CDC) recommended discussing DoxyPEP with cisgender men who have sex with men and transgender women who have had a bacterial STI diagnosed in the past 12 months. ⁷ DoxyPEP can be used every day if needed and should not exceed more than 200 mg in 24 h. ⁷ In randomized open-label trials in men who have sex with men and transgender women, DoxyPEP was shown to reduce syphilis and chlamydia transmission by more than 70% and gonorrhea from 33% to 50%,^8-10 the latter reflecting regional differences in rates of doxycycline-resistant gonococcal strains. ¹¹

Little is currently known regarding the uptake of DoxyPEP in primary care, especially as endorsement of DoxyPEP varies by country. In the US, most early prescribers of DoxyPEP have been providers and health centers with experience in HIV prevention and care.^12-15 Only 13.9% of family medicine physicians and 8.1% of internal medicine physicians reported prescribing HIV pre-exposure prophylaxis (PrEP) in 2019, and a mere 1% of primary care providers reported providing care to people living with HIV in 2020.^16,17 DoxyPEP may thus be underutilized in US primary care settings where a significant portion of STI screening and diagnoses occur. ¹⁸

Providers should tailor DoxyPEP to the patient’s estimated frequency of use. In post-hoc analysis of one of the DoxyPEP randomized trials, a prescription of 60 pills, or 30 doses, for a 3-month period provided most participants with complete coverage. ¹⁹ Potential side effects of doxycycline include pill esophagitis (which can be mitigated by drinking a full glass of water and staying upright for 30 min) and sun sensitivity (which can be mitigated by the use of sunscreen, hats, and long-sleeved shirts and long pants or skirts). ²⁰ No routine laboratory monitoring is necessary. ¹⁹ In addition to DoxyPEP use for bacterial STI prevention, a comprehensive sexual health approach includes STI screening at anatomic sites of exposure (e.g., oropharyngeal, rectal, and/or urogenital) every 3 to 6 months, HIV screening, linkage to HIV prevention and care, and risk reduction counseling. ⁷

For populations not currently included in CDC guidelines due to insufficient evidence for or against DoxyPEP use, additional recommendations are available: The San Francisco Department of Public Health recommends offering DoxyPEP to: (1) individuals assigned male at birth (including gender diverse people) who have had a bacterial STI and condomless anal or oral sex with 1 or more partners assigned male at birth in the past year, and (2) people who have had condomless anal or oral sex with 2 or more partners assigned male at birth in the past year, regardless of STI history. ²¹ DoxyPEP has not been studied in adolescents but may be considered for individuals assigned male at birth who are at least 12 years old and meet the aforementioned eligibility criteria. ²² Similarly, DoxyPEP may be offered to cisgender men with partners assigned female at birth in the context of personal STI history and local STI rates.^23,24 Concurrent or recurrent STIs may help predict the need for DoxyPEP. ²⁵

While DoxyPEP has not yet been shown to significantly reduce the incidence of bacterial STIs in cisgender women, transgender men, and other individuals assigned female at birth, more studies are urgently needed. A randomized controlled trial of DoxyPEP in cisgender women conducted in Kenya saw low adherence to DoxyPEP in the intervention arm. ²⁶ Physiologically, doxycycline is expected to concentrate sufficiently in vaginal and cervical tissue to be effective. ²⁷ A small study of cisgender women sex workers in Japan found that use of daily doxycycline pre-exposure prophylaxis (DoxyPrEP) was associated with a two-thirds reduction in bacterial STI incidence. ²⁸ Updated and more robust studies are also needed on doxycycline use during pregnancy and breast or chestfeeding, which have historically been discouraged due to the effects of tetracycline (a related antibiotic) on fetal dentition and bone growth. ²⁹ People who might become pregnant may elect to use DoxyPEP and should be supported by shared decision-making.

Because of the relative ease and safety of DoxyPEP, different models of prescribing should be further explored. A new bacterial STI diagnosis could trigger automatic orders for both treatment and DoxyPEP to follow. DoxyPEP may be well-suited to adaptation as a standing order for nurses and pharmacists, as has been seen with asthma medications and opioid reversal agents. ³⁰ The potential for DoxyPEP use as expedited partner prevention, in which 1 prescription covers both patient and partner, requires further study.

Additional studies are needed to understand the possible long-term impacts of DoxyPEP on changes to the antibiotic resistance genes of Neisseria gonorrhoeae, the individual microbiome, and population-level antimicrobial resistance rates (e.g., selection for doxycycline-resistant Staphylococcus aureus).^31,32 We recommend, however, balancing concerns about potential risks against the real demonstrated benefits in preventing STIs and downstream transmission. ³³ As prevention of STIs will reduce overall antibiotic prescribing, DoxyPEP meets all the tenets of antimicrobial stewardship: the right drug at the right dose and right time for the right duration. ³⁴ DoxyPEP remains a critical tool in addressing the ongoing epidemics of syphilis and chlamydia, and its widespread adoption in primary care settings is essential to advancing our STI prevention and control efforts.