Should DoxyPEP be US strategy?

“Syphilis is surging in the United States,” Susan Tuddenham, MD, MPH, told the audience at IDWeek 2023, held in Boston. Since 2017, reported cases of syphilis have increased 74%, she explained. These primarily are among men who have sex with men (MSM), but heterosexual people, including women, are also affected, which has led to a concurrent increase in congenital syphilis by more than 300% (since 2017), according to the CDC.

“We are not in a good place. These rates have continued to go up, and we have been failing to stop the increases,” Dr. Tuddenham said. What is needed, she explained, are better diagnostics, better interventions and better outreach.

The CDC has proposed one intervention, called doxy-PEP, that could make a dramatic difference in the rates of not only syphilis but other bacterial sexually transmitted infections (STIs). The agency recently advertised its strategy in the Federal Register.

Several studies have shown a benefit to giving doxycycline as post-exposure prophylaxis (doxy-PEP) after a condomless sex. The U.S. doxy-PEP strategy calls for taking 200 mg of doxycycline within 24 to 72 hours after unprotected sex.

As previously reported, the data are strong. The IPERGAY study in France among MSM found a reduction in bacterial STIs, particularly syphilis and chlamydia, but not gonorrhea (Lancet Infect Dis 2018;18[3]:308-317).

The doxy-PEP study was performed in Seattle and San Francisco among MSM and transgender women who had had at least one STI in the prior 12 months. Doxy-PEP saw reductions in bacterial STIs in people with and without HIV (N Engl J Med 2023;388[14]:1296-1306). In contrast to the IPERGAY study, there was a reduction in gonorrhea in this trial.

However, there appears to be a sexual difference that scientists have not yet been able to explain. The DPEP study among cisgender women taking HIV pre-exposure prophylaxis (PrEP) in Kenya saw no significant reduction in bacterial STIs with doxycycline (oral abstract session 03; presented at CROI 2023).

However, people have questions about this policy, most notably whether it will increase antimicrobial resistance or put patients at risk for Clostridioides difficile. During the same session, Kevin Ard, MD, an assistant professor of medicine at Harvard Medical School and affiliated with Massachusetts General Hospital, in Boston, tried to answer these questions, but he wound up asking a lot more.

ID clinicians are familiar with doxycycline and its side effects, which tend to be gastrointestinal and dermatologic, and, fortunately, serious side effects are uncommon. But, he admitted, the larger concern is antimicrobial resistance, both among organisms that cause STIs, such as Neisseria gonorrhoeae, and organisms like Staphylococcus aureus and Streptococcus pneumoniae.

However, the above studies did not provide a lot of information about resistance. The doxy-PEP study showed a mixed picture when they looked at doxycycline and tetracycline resistance. There were fewer N. gonorrhoeae infections in people assigned to doxycycline, but “when those infections did occur and could be cultured, then doxycycline resistance was more common,” Dr. Ard said. In the same study, S. aureus colonization decreased with doxy-PEP, but when S. aureus was present, resistance to doxycycline was seen more frequently.

Tetracycline resistance may travel with other forms of resistance, and the new intervention may select for more resistant strains of gonorrhea, he said. One study found chromosomally encoded tetracycline resistance is often associated with other forms of antibiotic resistance (Clin Infect Dis 2023 Aug 18:ciad488. doi: 10.1093/cid/ciad488).

“If doxy-PEP were to select for those organisms, then we might see an increase in resistance to other agents that we might be using to treat gonorrhea,” Dr. Ard said.

Unfortunately, the data from doxy-PEP studies are less clinically useful in terms of its effect on the microbiome. They were comparing doxy-PEP with a population that could have been taking any number of antimicrobials intermittently to treat infections that could affect the microbiome. These infections might be averted under the policy, he explained; however, he called doxycycline one of the least “C. diff–promoting antibacterials.”

The CDC’s draft guidelines on doxy-PEP have been released for public comment, and he urged the ID community to read them and comment.

Even if questions of resistance and side effects are answered, other questions are important to answer, according to Dr. Ard, most notably who would receive the maximum benefit.

“A fairly small proportion of people account for a larger proportion of STIs,” he said.

A group from the Fenway Health Center in Boston looked at cisgender men, transgender women and nonbinary people who were assigned male sex at birth, who had been tested for STIs at least twice between 2015 and 2020, and included them in 10 scenarios to determine which group or method of prescribing doxy-PEP would balance impact and efficacy. If the entire cohort took doxy-PEP, 71% of STIs would be averted, but everyone would get this antibiotic. If people with HIV and those using PrEP received doxy-PEP, 60% of STIs would be averted, with 64% receiving doxycycline. Giving doxycycline to people who’d had an STI for 12 months after that diagnosis would avert 39% of STIs, and doxycycline would be prescribed to 38% of the cohort (Clin Infect Dis 2023 Aug 18:ciad488. doi: 10.1093/cid/ciad488).

Other unanswered questions include how to treat STI exposures among people taking doxy-PEP; whether to treat if the exposure was with an asymptomatic person; doxy-PEP’s effects on cisgender women and other populations; and ensuring equitable access to doxy-PEP.

“We need new strategies to prevent syphilis and other STIs,” Dr. Ard said. “We know that doxycycline PEP reduces the likelihood of bacterial STIs, especially syphilis and chlamydia, but also gonorrhea in several studies among MSM and among transgender women. The benefit of this intervention for other populations, notably cisgender women, is uncertain. I would say at this point, the population level impacts really remain to be seen.”

By Marie Rosenthal, MS