To doxyPEP or not to doxyPEP: Experts debate the specifics

The use of doxycycline for post-exposure prophylaxis (doxyPEP) may provide a much-needed boost to the fight against bacterial sexually transmitted infections (STIs), which continue to raise public health challenges across the globe. But are there limits to the range of people to whom clinicians should recommend what is essentially a morning-after pill for STI prevention?

This was the debate that played out at the 25th International AIDS Conference (AIDS 2024) in Munich, Germany, where several presentations highlighted the benefits of doxyPEP—and the challenges that may prevent its widespread use.

A New Tool Against STIs

Doxycycline has been used for over six decades for the prevention and long-term treatment of various infectious diseases, including malaria and Lyme disease. This widely available antibiotic is now gaining attention as a biomedical intervention for curbing the spread of STIs. In a series of recent clinical trials, doxycycline was shown to reduce the incidence of STIs in men who have sex with men (MSM) and transgender women (TGW) when taken as a 200 mg dose within 72 hours after condomless sex.

While doxyPEP has a significant impact on chlamydia and syphilis, data show that it makes a much smaller dent in the incidence of gonorrhea. Nevertheless, one study demonstrated that the combined incidence of gonorrhea, chlamydia, and syphilis decreased by two-thirds among MSM with a history of bacterial STIs who took doxyPEP compared with their counterparts who received the standard of care.

Despite encouraging real-world results from communities where doxyPEP has become the standard of care for people who take HIV pre-exposure prophylaxis (PrEP), the large-scale implementation of this preventive measure across diverse populations is unlikely to follow a straightforward path. While guidelines in the United States and Australia have recently been updated to include doxyPEP as an intervention for reducing the incidence of STIs, uniform recommendations are still lacking in most parts of the world. Some experts have been reluctant to recommend its use on a larger scale, citing concerns such as potential antimicrobial resistance and the impact on the human intestinal microbiome.

“At the end of the day, we have to do more,” said Philip Chan, M.D., M.S., during a session that was specifically framed as a debate about the future of STI control in vulnerable populations. “We need more tools in the toolkit, and doxyPEP represents another potential effective tool. PrEP is a pillar of ending the HIV epidemic across the world. I believe that doxyPEP could be as effective as PrEP is in HIV in preventing [sexually transmitted] infection.”

That said, Chan, an associate professor in the department of medicine at Brown University, in Providence, Rhode Island, also noted that while doxyPEP has the potential to reduce the incidence of bacterial STIs at the individual and population levels, it may not be a one-size-fits-all intervention. The key is to focus on populations that are at high risk for acquiring bacterial STIs and recommend doxyPEP on a case-by-case basis, he said.

“To me, it’s partly about equity,” Chan explained. “We know that the LGBTQ population is historically marginalized and underserved. We have this effective STI intervention that works in MSM and transgender women. There is no way that we [should not] recommend it in those groups.”

Is Overreliance on DoxyPEP a Risk?

Henry de Vries, M.D., a professor at the University of Amsterdam, in the Netherlands, cautioned clinicians to avoid making blanket recommendations when it comes to the use of doxyPEP. “There are, at this moment, too many unknown [variables] remaining to justify broad implementation of doxyPEP,” de Vries argued during the debate at AIDS 2024. “We need to know the long-term effects of intermittent, frequent high-consumption of doxycycline, especially the potential negative impact on human microbiomes. We [are increasingly aware] that the gut microbiome is very important in health and disease. This is especially important when it is used in populations of gay and bisexual men who are often burdened with co-infections.”

De Vries, who treats STIs and skin infections at the Amsterdam Center for Sexual Health, said that clinicians should also consider the possible impact of doxyPEP on antimicrobial resistance. “DoxyPEP ignores the urgent need for antimicrobial stewardship,” he said. “Let’s follow the precautionary principle. It will be hard to de-implement doxyPEP once fully embraced.”

Chan concurred on the point of drug resistance. “Antimicrobial stewardship is always on my mind,” he said. “I like what the Centers for Disease Control and Prevention said, which is to consider doxyPEP in MSM and TGW who have had a bacterial STI in the last 12 months. Focus on the populations that are at higher risk of bacterial STIs.”

While antimicrobial resistance is rare to nonexistent in syphilis and chlamydia, clinicians should be concerned about it in relation to gonorrhea and other infections, such as cutaneous community-acquired methicillin-resistant Staphylococcus aureus infection, which is typically treated with doxycycline, Chan added.

Is DoxyPEP an Option for Cisgender Women?

Whether doxyPEP will work in other populations beyond MSM and TGW remains to be seen, de Vries said. The search for effective strategies for curbing congenital syphilis, which disproportionately affects pregnant women and neonates in sub-Saharan Africa, is ongoing.

Unfortunately, doxyPEP did not reduce STIs in a study often referred to as the dPEP Kenya study, which enrolled 449 cisgender women aged 18 to 30 years in Kenya. But that may not be because the drug itself was ineffective: “We believe that the dPEP study in Kenya failed because of the lack of adherence,” Chan said. “This is a theme in HIV and STI prevention. We also saw that in the [initial] studies for HIV PrEP. We have to start considering some of these issues, especially some of these social questions, when it comes to designing studies.”

Benn Kwach, a research scientist at the Centre for Microbiology Research affiliated with Kenya Medical Research Institute, in Kisumu, Kenya, cited several possible explanations for a lack of doxyPEP efficacy in cisgender women, such as anatomy, resistance, and adherence. Kwach discussed barriers to the uptake of doxyPEP in the Kenya study in an oral abstract session at AIDS 2024. While initial major barriers included side effects, stigma, and privacy concerns, repeated interviews at six and 12 months after the end of the study showed that stigma and privacy concerns became the main barriers, along with forgetfulness. Other barriers included inconvenient dosing schedules, misconceptions, lack of knowledge, peer influence, and social dynamics. The speaker explained that three key themes emerged as facilitators to the use of doxyPEP in women: the perceived value of doxyPEP in preventing STIs, familiarity with doxycycline, and use of a discrete pill case.

“Adherence to doxycycline prophylaxis could be better supported in this population by decreasing frequency of dosing and urgency of dosing to allow for optimal location and timing of dosing,” the authors wrote. “Understanding both barriers and facilitators is crucial in developing effective drugs. Effective barrier management and [facilitator] promotion are essential for success.” Kwach noted that food security, which was not assessed during the study, may have also played a role in increasing the side effects associated with doxyPEP.

Women in areas where STIs are endemic and likely to go undetected, such as countries in sub-Saharan Africa, could benefit from clear guidance on the use of doxyPEP. “Efforts to include doxyPEP in national prevention guidelines are crucial and call for urgent consideration for Zambia and other countries,” said Henry Muzuwandile, on behalf of the Key Population Consortium, in Zambia. “We do understand the implications of cost and possible resistance, however, it is more expensive to host a funeral than it is to spend a dollar on prevention. It is more complicated to deal with pelvic inflammatory disease in females than it is to put forth an intervention that can prevent it.”

Self-Medication and Role of Providers

Another facet to the conversation is that the broad availability of doxycycline is likely to result in expanded access to, and usage of, doxyPEP by people who feel it could benefit them. “Whether you like it or not, doxy will be widely spread in the community,” Nikolay Lunchenkov said during the doxyPEP debate.

Lunchenkov, who represented the Estonia-based Eurasian Coalition on Male Health, pointed out that people across Eastern Europe and Central Asia may have easy access to antibiotics without prescriptions. Since interest in doxyPEP has increased following results from the efficacy trials, clinicians should educate their patients on correct dosage and precautions when taking doxycycline, he added.

As guidelines around doxyPEP use rapidly evolve, current utilization appears highly inconsistent. Survey results from Italy presented during a poster session at AIDS 2024 showed that, while 28% of individuals who received HIV PrEP at a community clinic were aware of doxyPEP, only 9% reported using it. Almost half of the users reported inadequate dosing. “The lack of national guidelines on doxyPEP leaves a gap in STI prevention where individuals with perceived high risk of exposure are informally self-administering doxycycline as PEP,” the study authors said. “DoxyPEP needs to be implemented within appropriate national guidelines to reduce STIs circulation.”

Understanding the factors that influence willingness, such as perceived STI risk, and receiving a recommendation from a health care provider may facilitate doxyPEP uptake. Findings from an online questionnaire completed by more than 1,000 MSM from Taiwan who were living with HIV or taking HIV PrEP between October 2023 and March 2024 showed that after receiving counseling, 86% of participants were willing to take doxyPEP and 46% were given doxyPEP prescriptions.

Bridging Populations: A Key Link in the Chain of Transmission

Chan pointed out that doxyPEP offers a unique opportunity to interrupt the chains of STI transmission within and across sexual networks. For example, “Bisexual males are bridging populations between MSM and cisgender heterosexual women,” he said. “Even if doxyPEP only reduced—and there is good data on that—incidence of bacterial STIs in MSM, I would expect that there would be some effect in reducing incidence of bacterial STIs in cisgender heterosexual women as well, just by the bridging partners.”

Presenters at AIDS 2024 generally appeared to agree that doxyPEP has the best chance of success when combined with other preventive strategies, including condom use, counseling, and STI screening. DoxyPEP may play a key role in the combined efforts to prevent the transmission of HIV and STIs, which have a “serious cousinship relationship,” Muzuwandile said.

By Iulia Filip