Infectious Disease

New evidence ‘seals the case’ for doxy-PEP as STI prevention tool

March 04, 2024

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Key takeaways:

  • Sexually transmitted infections have been on the rise for years in the United States.
  • Research continues to show that taking doxycycline can reduce a person’s risk for STIs, but questions remain.

DENVER — As clinicians await national guidelines on its use, evidence continues to mount that doxy-PEP can help curtail the prolonged epidemic of sexually transmitted infections in the United States.

The strategy, which involves taking doxycycline within 3 days of having condomless sex, was again shown to be effective in three new studies presented here at the Conference on Retroviruses and Opportunistic Infections (CROI).

Antibiotics Adobe Stock

Taking doxycycline after condomless sex can reduce a person’s risk for STIs, studies have shown. Image: Adobe Stock

In each study, use of doxy-PEP resulted in reduced rates of STIs among transgender women and men who have sex with men (MSM). To boot, the studies produced a diversity of evidence uncommon for interventions that are still under investigation, one expert said. The data came from a clinical trial, a clinical cohort and population-level surveillance from a major American city.

“This is really unusual,” CROI chair Landon Myer, MD, who was not involved in any of the research, said during a press conference. “It’s not often in public health that we would have [this] all at the same time. This really, to my mind, kind of seals the case” for doxy-PEP.

The findings presented at CROI were not met with surprise. Doxy-PEP has produced encouraging results for years. One major study conducted in San Francisco and Seattle by Annie Luetkemeyer, MD, and colleagues showed that it reduced bacterial STIs by more than 60% among transgender women and MSM who were either HIV positive or taking HIV PrEP, according to results initially reported in 2022. Follow-up data presented by Luetkemeyer this year at CROI continued to show its effectiveness.

Still, some questions remain unanswered, including whether doxy-PEP will work for cisgender women, how much it will actually reduce STIs, whether it will be distributed equitably and what its effect on resistance might be, Luetkemeyer and others said.

Adherence issues

Based on the outcomes of multiple trials, the CDC developed draft guidelines for doxy-PEP last year, but only for transgender women and MSM, although experts think the strategy could benefit patients outside those two groups.

The draft guidelines were limited by evidence from a trial conducted in Kenya that found doxy-PEP did not significantly reduce STIs among cisgender women compared with a test-and-treat approach.

The reasons for this were initially unclear, but findings published in December in The New England Journal of Medicine offered a possible explanation: The presence of doxycycline in hair samples taken from women in the study was low — only 29% came back positive, far lower than the participant’s own reported adherence — and there was evidence that 44% of participants may not have taken any doxycycline.

Adherence, while challenging for many people, “is a necessary component of effective medical interventions when under individual control,” the authors of the study wrote, noting that low adherence has also muddied the results of HIV PrEP studies conducted among women.

The researchers mentioned other possible reasons for the failure, including a high level of antibiotic-resistant gonorrhea in Kenya.

‘Not great for gonorrhea’

In 2022, cases of gonorrhea declined for the first time in a decade while rates of chlamydia remained stagnant and cases of syphilis continued to surge, according to data released by the CDC in January.

It remains unclear whether there has been a real reduction in gonorrhea or if the decline can be attributed to other factors, such as changes in diagnosing or reporting, the CDC said. Either way, the number of reported gonorrhea infections in 2022 — around 648,000 — was still an 11% increase over the 2018 total.

Compared with chlamydia and syphilis, it is less clear whether doxy-PEP will have a marked impact on the rates of gonorrhea.

After the success of their initial study, Luetkemeyer and colleagues offered doxy-PEP to participants from the control groups who had not received it, and almost all of them accepted it. The results held up: Doxy-PEP was associated with sustained and comparable decreases in the three STIs compared with rates reported in the initial study, Luetkemeyer reported.

But findings from the two other studies presented at CROI raised questions about doxy-PEP’s ability to prevent gonorrhea, which is commonly resistant to tetracycline antibiotics, including doxycycline.

In in one, Hyman Scott, MD, MPH, medical director of clinical research at Bridge HIV in San Francisco, and colleagues tested doxy-PEP among more than 1,200 PrEP users at a city clinic who received doxycycline for at least 30 days and compared their rates of STIs to clients who did not receive it. Both groups were racially and ethnically diverse and most were cisgender gay men.

Compared with the 6 months before the intervention, there was a 58% decrease in any STIs with doxy-PEP. This included a 67% decrease in chlamydia and a 78% decrease in syphilis, but no statistically significant decrease in gonorrhea, Scott and colleagues reported.

San Francisco has been ground zero for doxy-PEP research. The city health department was a year ahead of the CDC when it recommended doxy-PEP in October 2022 for MSM and transgender women with a history of STIs or multiple sex partners.

Within roughly a year after that recommendation, more than 3,200 patients at three sexual health clinics in San Francisco had initiated doxy-PEP, according to data presented at CROI by Madeline Sankaran, MPH, from city health department.

The quick uptake resulted in a 51% decrease in chlamydia and 50% reduction in early syphilis compared with monthly rates that would have been expected without doxy-PEP, but no significant reduction in gonorrhea, the researchers reported.

“It’s not great for gonorrhea,” Luetkemeyer remarked. “We need better strategies.”

Other questions

Still, the bulk of the evidence so far has indicated that doxy-PEP could be an important new tool in the battle to lower the rates of STIs.

“This is an incredibly exciting topic,” Myer said. “Doxy-PEP has really changed the face of STI prevention and control.”

In fact, Scott said, a wider rollout of doxy-PEP could prove to have an even bigger impact on the rate of new infections. He noted the rapid reduction in STIs recorded in his study in less than a year after San Francisco recommended doxy-PEP.

“The question I have is: How far is this going to suppress STIs? I think we are just starting to see the beginning of it, and it might actually [lead to] a more dramatic decline in STIs,” Scott said.

Doxy-PEP’s ultimate impact may depend on getting it into patients’ hands, Luetkemeyer said.

“We didn’t do a good job with PrEP,” Luetkemeyer said. “We’ve seen what a great job PrEP can do, but it only works if people who need it get access to it. Doxy-PEP isn’t for everyone, but for the people who can benefit, we have to figure out how best to deliver it to them and we have a lot of work to do on that front.”


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Luetkemeyer reports receiving consulting or advisory fees from Vir Biotechnology; provisions of medicine to her institution from Cepheid, Hologic and Mayne Pharma; and grants or grants pending paid to her institution from Gilead Sciences, Merck and ViiV Healthcare. Myer, Sankaran and Scott report no relevant financial disclosures.

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