Doxycyline Prophylaxis for STI in Women Confounded by Low Treatment Adherence


Doxycycline postexposure prophylaxis (PEP) has reduced STIs among men who have sex with men, but poor adherence marred trial results with women.

A trial of doxycycline postexposure prophylaxis (PEP) to protect against sexually transmitted infection (STI) in women was confounded by low adherence to the regimen, as well as high prevalence of tetracycline-resistant N gonorrhoeae in the studied population.1

The investigators had sought to follow on the previously reported success with doxycyline PEP (dPEP) in reducing STIs among men who have sex with men, with a trial in women, for whom they find a lack of data despite the need.

"Women are disproportionately burdened by STI sequelae, including pelvic inflammatory disease, chronic pain, infertility, ectopic pregnancy, increased risk of HIV acquisition, and pregnancy and fetal complications," observed Jenell Stewart, DO, MPH, Division of Infectious Diseases, Hennepin Healthcare Research Institute and Department of Medicine, University of Minnesota, both in Minneapolis, Minnesota, and colleagues of the dPEP Kenya Study Team.

The investigators explain that a finding of dPEP effectiveness in 1 population does not necessarily extrapolate to another, particularly with differences in gender, sexual interaction, and primary infection sites.

"Cisgender women more commonly have endocervical infections than rectal or pharyngeal infections," Stewart and colleagues point out. "Recent evidence suggests that drug concentrations of doycycline in the vagina are sufficient to prevent C trachomatis, N gonorrhoeae, and T pallidium; but time above the minimum inhibitory concentration was higher in rectal tissue."

The use of dPEP has been proposed to stem the increase of STIs that has occurred, paradoxically, with the success of HIV PrEP and active treatments in reducing potential for transmitting and contracting HIV. With reduced risk of HIV, there has been reduced use of condoms and that loss of protection against other STIs.

The dPEP regimen in the current trial was 200mg, to be taken within 72 hours after condomless sexual intercourse, with a maximum dose of 200mg regardless of the number of exposures in the previous day.The trial population was comprised of 449 women 18 to 30 years of age in Kisumu, Kenya.The participants were not pregnant, and were receiving HIV PrEP. They were randomized 1:1 to dPEP or to standard care in the open trial that was conducted over 12 months, with quarterly follow-up visits.

What You Need to Know

The trial of doxycycline postexposure prophylaxis (PEP) for protecting women against sexually transmitted infections (STIs) was hindered by low adherence to the prescribed regimen.

The trial highlights the importance of considering gender-specific factors in the design of prophylactic interventions.

The trial faced limitations due to the high prevalence of tetracycline-resistant Neisseria gonorrhoeae in the studied population.

The investigators reasoned that women already taking a preventive medication would be more likely to adhere to the dPEP regimen.Additional measures to enhance likelihood of using dPEP included an open-label design without placebo, to ensure participants knew they had received active medication with an established safety profile; and adherence support through weekly text message, and discrete pill carriers.

To confirm that dPEP was taken, hair samples (50 to 100 strands) were collected at the quarterly visits from randomly selected 22% of the dPEP group; and the doxycyline was extracted and confirmed by means of liquid chromatrography-tandem mass spectrometry. In the standard care group, hair samples were tested in a randomly selected 5% sample.

Stewart and colleagues reported that the doxycycline group did not have fewer STIs than the standard care group, but that they also had not been adherent to the dPEP regimen. Among the dPEP group, doxycycline was detected in 58 of 200 hair samples (29%).

"Low detection of doxycyline among participants assigned to receive doxycyline PEP offers a primary explanation for the differing results between this trial and other studies of docycyline PEP," Stewart and colleagues remarked.

In addition, 100% of N gonorrhoeae-positive isolates in the cohort were resistant to doxycyline. This limitation for the trial test of dPEP effectiveness was predictable, as the investigators note that a high prevalence of tetracycline-resistant N gonorrhoeae had been documented in earlier studies in Kenya and attributed to the tet(M) gene.

In an accompanying editorial, Jeanne Marrazzo, MD, MPH, director, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, Maryland, indicated that despite no reduction in STIs, there was value from the trial.2

"Although the findings are disappointing, the trial provides a needed opportunity to reconsider how to strategically inform the design and conduct of biomedical intervention trials involving women of reproductive age," she said.


1. Stewart J, Oware K, Donnell D, et al. Doxycycline prophylaxis to prevent sexually transmitted infections in women. N Engl J Med 2023; 389:2331-2340.

2. Marrazzo J. Doxycyline postexposure prophylaxis for STIS in women—uncertain benefit, urgent need. N Engl J Med 2023; 389:2389-2390.

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