PEPpered with Disappointment: The dPEP Trial

Postexposure prophylaxis is not a new concept in medicine. The administration of antibiotic or antiviral therapy after close contact with a person who may be infectious is the current standard of care for many diseases including bacterial meningitis, human immunodeficiency virus (HIV), viral hepatitides after needlestick exposures, and pertussis.

According to the Centers for Disease Control and Prevention (CDC), the national incidence of sexually transmitted infections (STIs) is increasing steadily, specifically for gonorrhea and syphilis, and case reports may have been underestimated during the COVID-19 pandemic. Doxycycline, a tetracycline antibiotic, has proven efficacy in the treatment of syphilis and gonorrhea, although increasing tetracycline resistance has been reported for Neisseria gonorrhoeae. According to 2021 CDC STI treatment guidelines, doxycycline is the treatment of choice for chlamydial infections. Together, these data suggest that doxycycline could reduce the incidence of new STIs after sexual exposure (termed “doxy-PEP” for doxycycline post-exposure prophylaxis). However, two recent trials yielded contrasting outcomes in different populations.

In the aptly-named DoxyPEP trial published in NEJM in early 2023, researchers in the Pacific Northwest examined the efficacy of doxy-PEP in men who have sex with men and transgender women who had or were at risk for HIV and had an STI in the past year. As compared with usual care, a single 200 mg dose of doxycycline within 72 hours after condomless sexual contact reduced the primary endpoint of incident STIs during a median follow-up of 270 days. The trial was stopped early for treatment efficacy. The rate of serious adverse events was low overall, although numerically more isolates of doxycycline-resistant Staphylococcus aureus and N. gonorrhea were reported in the doxycycline group.

A more recently published dPEP trial examined the efficacy of a similar treatment regimen of doxy-PEP in cisgender Kenyan women who were receiving preexposure prophylaxis (PrEP) for HIV. After the majority of participants completed the 12 months of follow up, the incidence of STIs was not lower in the treatment group as compared with standard care (P=0.51) in both primary and subgroup analyses. Some discordance was observed between reported doxycycline use (suggesting high compliance) and doxycycline detection in hair samples (suggesting low compliance).

These two trials leave us with seemingly disparate findings, but several factors help explain why. First, the two trial populations were fundamentally different in terms of sexual behaviors, medication adherence, and rates and types of STI acquisition. As further evidence of these differences, three women in the dPEP trial and no one in the DoxyPEP trial stopped doxycycline due to social harms (i.e., verbal and physical violence) associated with taking STI prophylaxis.

Second, pharmacokinetic differences have been reported to result in lower steady state drug levels in cervicovaginal tissue than in rectal tissue. In the DoxyPEP trial, treatment reduced the incidence of all three STIs evaluated, although rectal gonorrhea was the most common infection overall. In the dPEP population, the 100% prevalence of baseline tetracycline resistance likely hampered mitigation of gonorrheal infections. Neither the concentration of doxycycline in specific genitourinary tissues nor the presence of rectal or pharyngeal STIs was measured in the dPEP trial.

Finally, the primary analysis in dPEP might have amplified disparities in STI prevention among heterosexual women who disproportionately carry the weight of STI complications. Future trials are needed to reexamine some assumptions made in the dPEP trial. For example, a placebo group was omitted with the expectation that it would increase adherence, but what if it had the opposite effect? Hopefully, the dPEP trial will act as a catalyst to carefully design future trials and treatment regimens to better serve heterosexual women.

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Clement Lee, MD, MSc, was a 2021–2022 NEJM Editorial Fellow and a 2022–2023 Senior Editorial Fellow. He is currently a Guest Editor for NEJM, an internal medicine hospitalist at Newton-Wellesley Hospital, and a pediatric hospitalist at Boston Children's Hospital. He completed his internal medicine-pediatrics residency at Penn-CHOP.