Rates of sexually transmitted infections (STIs)—especially gonorrhea, chlamydia, and syphilis—have been on the rise among gay, bisexual, and other men who have sex with men (MSM) in the U.S. for two decades. The resurgence of bacterial STIs among MSM has been particularly marked in the past decade, as science has coalesced around the power of modern antiretroviral medications to suppress HIV viral load and prevent HIV transmission. This relatively new reality has been correlated with a reduction in condom use among MSM, which may have helped fuel the rise of bacterial STIs.
In recent years, some public health professionals and medical providers have championed the idea of using doxycycline as prophylaxis against bacterial STIs, especially within high-risk populations—in particular, MSM on pre-exposure prophylaxis (PrEP) for HIV prevention, and even more specifically, MSM on PrEP who have other risk factors, including multiple partners, anal intercourse without condoms, and a history of STIs. This potential strategy has been studied in two forms, known as doxyPrEP and doxyPEP.
DoxyPrEP involves taking daily doxycycline as pre-exposure prophylaxis for bacterial STIs. DoxyPEP involves taking doxycycline as post-exposure prophylaxis for bacterial STIs between 24 and 72 hours after an episode of sex without a condom.
These proposed strategies, however, are not without risks—chief among them being that they may contribute to antimicrobial resistance, not only in sexually transmitted pathogens, but also in other bacteria that cause common community-acquired infections, such as Staphylococcus aureus.
At a debate-style session during the IDWeek 2020 clinical science conference in October, the specific intervention under discussion was doxyPEP, targeted in particular at MSM on PrEP with a history of STIs. The pro side was argued by Annie Luetkemeyer, M.D., a professor of medicine at University of California-San Francisco. The con side was argued by Douglas Krakower, M.D., an assistant professor at Harvard Medical School.
The Case for DoxyPEP
Arguing in favor of doxyPEP, Luetkemeyer noted that people on HIV PrEP have relatively high rates of bacterial STIs, citing evidence from several recent studies. Luetkemeyer underscored that in the Australian Pre-exposure Prophylaxis Expanded (PrEPX) study of 2,981 MSM on HIV PrEP, not only did 25% of participants have more than one STI during one-year follow-up, but these 25% accounted for 75% of all STIs occurring during the study, with some participants having as many as five STIs during the one-year study period.
“We have an opportunity for a highly targeted intervention,” Luetkemeyer said. “I’m not arguing that doxyPEP should be given to everyone, but to those taking PrEP who are at the highest risk, and have had repeated previous STIs, and are motivated to have an additional tool to reduce these.”
Luetkemeyer further argued that STIs are not merely an inconvenience, but can have serious physical consequences. Syphilis can cause hearing loss or blindness. Neurosyphilitic vasculitis can lead to stroke. Lymphogranuloma venereum, a manifestation of chlamydia, can cause many debilitating effects, including severe proctitis and other pelvic, perirectal, and genital symptoms in both women and men. Gonorrhea has become increasingly difficult to treat due to rising antimicrobial resistance. Syphilis can cause infertility among women, and the rate of congenital syphilis in the U.S. has increased 185% since 2014.
Luetkemeyer also underscored the role STIs play in increasing risk of HIV transmission—both in terms of making the partner living with HIV more infectious and the uninfected partner more susceptible.
Turning to the efficacy of doxycycline in MSM on PrEP, Luetkemeyer pointed to an open-label, randomized substudy of the IPERGAY trial in France that evaluated the use of doxyPEP among high-risk MSM on PrEP (defined as people who were having anal sex with at least two different partners during the previous six months). The IPERGAY doxyPEP substudy found a 70% reduction in chlamydia and a 73% reduction in syphilis among the study population.
Notably, the study did not observe any change in rates of gonorrhea. This was not unexpected, as over 50% of gonorrhea strains in France were known to be resistant to tetracyclines, the class of antibiotics to which doxycycline belongs. In the U.S., about 25% of gonorrhea is resistant to tetracyclines. (In fact, Luetkemeyer is the co-lead investigator in an open-label, randomized, controlled trial to evaluate doxyPEP in San Francisco and Seattle, and one of the trial’s objectives is to determine whether doxyPEP will reduce rates of gonorrhea in a U.S. cohort of high-risk MSM on PrEP.)
In terms of safety, Luetkemeyer argued that doxycycline—which has been in use for over 50 years—is known to be generally safe and well tolerated. This holds even when the drug is used over long periods, at is often the case when it is used to treat malaria, spirochetal diseases such as Lyme disease and leptospirosis, and dermatologic conditions such as acne and rosacea. Its major toxicities, such as phototoxicity and pill esophagitis, are well known and avoidable.
Relative to other types of antibiotics, doxycycline is associated with lower rates of Clostridioides difficile (C. diff), a gastrointestinal infection that is a common side effect of prolonged exposure to some antibiotics. Nor is resistance to doxycycline associated with syphilis or chlamydia. And although resistance to doxycycline is associated with gonorrhea, the drug is not generally used to treat gonorrhea, and its role in gonorrhea prophylaxis is still being evaluated.
Perhaps most importantly, since even the most potent medication won’t work unless people take it: Studies have demonstrated that those on HIV PrEP who are at high risk for bacterial STIs want access to doxyPEP and would adhere to the treatment, Luetkemeyer said.
The Case Against DoxyPEP–Kind Of
This summary will not go into as much detail about Krakower’s arguments against doxyPEP. This is because, frankly, the debate-style, pro-and-con format was set up more to offer a dramatic effect than because the issue was considered truly up for debate. In fact, Krakower’s opening statement was, “Let me start out by saying I love the idea of doxyPEP.” He said that he was not against the strategy in principle, but rather that, upon doing further research after being invited to participate in this debate, “I realized that there were a few important points on the other side that were really strong that we need to consider before this is ready for prime time.”
The argument Krakower mounted against the immediate use of doxyPEP boiled down to the following points:
- DoxyPEP could promote antimicrobial resistance.
- It is important to wait for more data from randomized controlled trials.
- HIV PrEP use is very low among heterosexual men and women, limiting the potential population impact of doxyPEP.
Luetkemeyer anticipated these very objections in her initial argument, and she addressed them again in a rebuttal she offered in response to Krakower’s presentation.
Regarding antimicrobial resistance, Luetkemeyer reiterated that clinicians do not use doxycycline to treat gonorrhea, and there is no evidence of reduced efficacy against syphilis or chlamydia despite years of use. Krakower warned that increased antimicrobial resistance in the wake of doxyPEP might have a negative impact on clinicians’ ability to treat Neisseria and Staphylococcus infections, but Luetkemeyer pointed out that doxycycline is not used to treat serious Neisseria and Staphylococcus infections.
Krakower argued that doxyPEP might lead to excessive exposure to antibiotics on a population level. In response, Luetkemeyer reiterated a point she made in her initial presentation; namely, that preventing STIs in the short term leads to less antibiotic use in the long term, including use of ceftriaxone (used to treat gonorrhea), azithromycin (used to treat chlamydia), and longer-course doxycycline. She employed a memorable fractured proverb about this: “An ounce of antibiotic prevention is worth a pound of antibiotic cure.”
To Krakower’s assertion that more data from randomized, controlled trials are needed, Luetkemeyer’s rebuttal was: “You got me there.” The point is especially salient since, as noted earlier, she is the co-lead investigator of the DoxyPEP study collaboration between the University of Washington and the University of California, San Francisco.
Finally, to Krakower’s objection that doxyPEP will have only a limited impact on the population beyond MSM, Luetkemeyer’s rebuttal was that doxyPEP is indeed an intervention targeted very narrowly at high-risk MSM on PrEP—and that, in fact, is a major reason why concerns about its potential negative impact on a population basis are overstated.
Care Providers Appear Eager to Employ DoxyPEP
While fully aware of the potential risks, experts in the field are enthusiastic about the likely benefits of doxyPEP for high-risk MSM on HIV PrEP. “We need new strategies to turn the tide of the STI epidemic,” said Matthew Spinelli, M.D., an assistant professor of medicine at University of California-San Francisco, and the lead author of a study that documented high interest in doxyPEP among MSM using a gay social-networking app. “I am hopeful that some of this enthusiasm can bring new patients into primary care and comprehensive sexual health care, and serve as a portal towards offering other services such as PrEP and vaccines.”
Enthusiasm for doxyPEP among MSM is not limited to the U.S., according to Darrell H. S. Tan, M.D., an associate professor of medicine at the University of Toronto. “We have published data showing that nearly two-thirds of sexually active gay/bi/other MSM attending sexual health clinics in Toronto and Vancouver would be willing to use doxyPEP, so uptake of this intervention could potentially be high,” he said.
That said, some physicians are likely to await further study results before going all-in on DoxyPEP for STIs. “The concerns that have been raised about doxyPEP are important, but are best addressed with data,” said Tan. “Clinical trials are underway, and it is fantastic that several research groups worldwide have devoted attention to studying the issue thoroughly.”
Krakower, who argued the "con" point of view in the IDWeek 2020 debate, concurs. “High rates of bacterial STIs among people using PrEP suggests a need for improved strategies to decrease STI rates in this population. Based on data from a single trial with men who have sex with men, DoxyPEP seems to have a substantial positive impact on rates of chlamydia and syphilis, but not gonorrhea,” he affirmed.
But Krakower stressed the importance of those additional, ongoing studies. “Several new trials are poised to provide important data on the net benefits versus harms of DoxyPEP in the near future, which are likely to guide clinical practice,” he said.