By Marie Rosenthal, MS
Data presented at CROI 2024, in Denver, not only confirmed the efficacy of taking on-demand doxycycline after condomless sex (doxyPEP) as prophylaxis against bacterial sexually transmitted infections (STIs) but that many people for whom it is recommended have embraced it.
“This is an incredibly exciting topic,” said Landon Myer, MD, PhD, who moderated a CROI press briefing. “DoxyPEP has really changed STI prevention control,” he said, adding that this year’s presentations validate data about doxyPEP reported at CROI 2023.
The results of several studies of doxyPEP, including the doxyPEP study, were so compelling the CDC recommended doxyPEP be offered to people who would benefit.
DoxyPEP was a randomized controlled trial with men who have sex with men (MSM) and transgender women who had an STI in the past year. The participants were randomly selected to receive doxyPEP or standard of care without doxyPEP.
“The randomized portion of the study was stopped in May 2022 due to high efficacy with a two-thirds reduction overall in bacterial sexually transmitted infections,” explained Annie Luetkemeyer, MD, a professor of medicine at the University of California, San Francisco School of Medicine, who presented the data.
Participants remaining in the study, regardless of which arm they were in originally, were offered the opportunity to join an open-label extension study in which everyone received doxyPEP. The open-label study consisted of 289 participants, of which 82 had been in the original standard-of-care arm and 207 were in the original doxyPEP arm. The study provided 200-mg pills of doxycycline to patients. Dr. Luetkemeyer said that some settings provided two 100-mg pills. This has caused some confusion for people comparing results from one study with another, she explained. So, basically the regimen is 200 mg of doxycycline after condomless sex but taking no more than one dose per day. Those in the open-label extension were followed for a median of two quarters.
“Only one eligible participant who was in the standard-of-care [arm] declined to go into the open-label extension,” Dr. Luetkemeyer said.
During the open-label extension, those initially selected for doxyPEP had a sustained reduction in any of the bacterial STIs of 13% per quarter. Those who switched from the standard-of-care arm to the open-label group saw the incidence of STI per quarter decrease from 31% in the original trial to 17% in the extension study.
There were some notable behavioral differences between the original randomized doxyPEP study and the open-label follow-up, but since the median follow-up of the extension study was only two quarters, “it’s difficult to make long-term conclusions about what sustained sexual behavior changes [would be].”
However, during the original study, people took a median of about five doses per month, but it increased to about six doses per month in the open-label extension.
“But I want to point out also that the dose range was quite wide, because people had variable sexual activity. So some people took substantially more than that, and some people took less. But we did see a slight uptick in the median amount of doxy that was reported,” Dr. Luetkemeyer said.
There were also changes in sexual behavior. “We did see that participants reported an increasing number of sex partners and condomless, insertive and receptive sex acts with a greater increase in those who originally who were on standard of care and who now are rolled over into starting doxyPEP,” she said.
“During the open-label extension of the doxyPEP trial, when effectiveness of doxyPEP was known to the participants and when both arms were provided ongoing doxyPEP, we observed a sustained and comparable decrease in STI incidence, despite a short-term increase in sexual partners and condomless sex acts,” she added.
Once doxyPEP became available, the community was receptive to trying the new regimen, according to Hyman Scott, MD, MPH, the clinical research medical director of Bridge HIV, and an assistant clinical professor at the UCSF School of Medicine.
Shortly after the CDC’s recommendations came out in October 2022, they were adopted by California. The San Francisco AIDS Foundation, which offers sexual health services and pre-exposure prophylaxis (PrEP) for HIV to people who might be at risk, wanted to “move very rapidly to implement this new intervention in our communities,” Dr. Scott explained.
They enrolled at-risk people from among the clinic and compared the STI incidence before and after doxyPEP became an option (June 2022 to September 2023). We wanted to evaluate that for equity, ensuring that we were getting it to those who could most benefit, and what happened to our incidence and the numbers of STIs that we saw.
“There was a strong demand for it,” Dr. Hyman explained. “About 39% of individuals ultimately decided that they wanted doxyPEP as an STI prevention tool.” As a result, they saw a rapid decline in STIs.
“Overall, we saw a 58% reduction in any bacterial STI that was higher for chlamydia at 67% and even higher for syphilis at 78%,” Dr. Scott said. However, they did not see a great reduction in gonorrhea incidence before and after doxyPEP implementation—“only about 11% difference in incidence before we offered doxyPEP.”
He said the remarkable declines were seen over two to three quarters.
They are still reviewing the data looking at adherence and resistance, which is a concern with doxyPEP, but overall “we’ve been really impressed by how much our community wanted this when we offered it to them, how many people took it when it was available and what the impact of it was, which was both dramatic and quick.”
Another study, also in San Francisco, saw similar results, according to Madeline Sankaran, MPH, of the San Francisco Department of Public Health. Once the San Francisco health department released its guidelines, “local providers quickly implemented them, and eligible people rapidly adopted its use.”
Health department officials wanted to know whether the implementation resulted in changes in STI rates at the population level in the city, so they conducted an ecological analysis to look at whether trends in the number of monthly reported cases of chlamydia, gonorrhea and early syphilis in the 16 months before doxyPEP guidelines were implemented differed from trends in the 13 months after doxyPEP was available.
Using statistical modeling, they found “significant decreases in the number of monthly cases of chlamydia and early syphilis observed post-doxyPEP compared with what we would've expected based on model predictions. By the end of the period of our analysis, we were seeing about 50% fewer cases of chlamydia and early syphilis per month compared with model predictions,” Ms. Sankaran said. However, they did not see a decline in gonorrhea.
The main limitation of the study is that it is looking at reported STI cases over time at the population level, so they could not control for outside factors that could have resulted in the change, such as changes in screening patterns, she said.
However, they compared their rates with reports of STIs in cisgender women and did not observe declines in their STI rates. A large study reported at CROI 2023 found that while doxyPEP has seen remarkable results in MSM and transgender women, it was not effective in cisgender women, so doxyPEP is not recommended for them—even if they are at risk for STIs.
Comparing those results, Ms. Sankatan said, strengthens the conclusions reached in her study: that the reductions in STIs seen were related to the intervention.
“These data support the current CDC draft grade A1 recommendation for doxyPEP use in men who have sex with men and transgender women,” Dr. Luetkemeyer said. “But it will be important to get longer term evaluation of doxyPEP under more real-world conditions to understand effectiveness, sustained sexual behavior changes and the potential impact on antimicrobial resistance.”
Dr. Myer, who is the head of the School of Public Health and Family Medicine at the University of Cape Town, South Africa, said considering all three studies gives clinicians a good, rounded perspective of doxyPEP and its effectiveness.
“It’s not often in public health you have population-level surveillance in concordance with clinical service delivery cohorts in concordance with clinical trial results all at the same time,” Dr. Myer said. “It really, to my mind, kind of seals the case.”
A lot of questions remain to be answered as more people use doxyPEP, added Dr. Luetkemeyer, most notably, how people take it, what changes to sexual behaviors result, whether resistance develops, and how to distribute it equitably.
“We didn't do a good job with access to HIV PrEP,” she admitted. “It’s been 10 years, and we've seen what a great job PrEP can do, but it only works when people who need it get access to it. DoxyPEP isn't for everyone, but for the people who may benefit, we have to figure out how best to deliver it to them.”
