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DoxyPEP and DoxyPrEP
An Ounce of Prevention: A Canadian Perspective on DoxyPEP and DoxyPrEP

Released: August 16, 2024

Expiration: August 15, 2025

Darrell H S Tan
Darrell H S Tan, MD, FRCPC, PhD
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Key Takeaways
  • Among men who have sex with men, doxyPEP and doxyPrEP are highly effective for the prevention of bacterial STIs like chlamydia, syphilis, and gonorrhea.
  • In the ANRS DOXYVAC trial, doxyPEP was associated with increases in tetracycline resistance but not resistance to azithromycin, ciprofloxacin, or ceftriaxone.
  • A small study in Japan suggests that doxyPrEP is effective for preventing bacterial STIs in cisgender women.

Doxycycline-based prevention of bacterial sexually transmitted infections (STIs) was a major theme at the AIDS 2024 conference. In recent trials, doxycycline as postexposure prophylaxis (doxyPEP) has had high efficacy for preventing STIs among men who have sex with men, and data from the Kaiser Permanente health system in northern California reaffirmed the real-world effectiveness of this approach: From November 2022 to December 2023, among the 11,551 HIV pre-exposure prophylaxis (PrEP) users in the system, 2253 (19.5%) initiated doxyPEP. This coincided with significant declines in test positivity for chlamydia (9.6% to 2.0%), syphilis (1.7% to 0.3%), and gonorrhea (10.2% to 9.0%) after starting doxyPEP compared with before doxyPEP. 

DoxyPEP and Antimicrobial Resistance?
However, a major concern with the implementation of doxyPEP is the risk of antimicrobial resistance. To address this issue, investigators from the ANRS DOXYVAC trial assessed antibiotic resistance profiles among men who have sex with men in France who were using HIV PrEP and who were randomized to receive either doxyPEP or no intervention.

Throughout the study, investigators collected 78 isolates of Neisseria gonorrhoeae for resistance testing. They observed no significant difference between groups in the proportion of isolates resistant to azithromycin, ciprofloxacin, or ceftriaxone or in the distribution of minimum inhibitory antibiotic concentrations after initiation of doxyPEP. Similarly, they found no differences between groups in the presence of molecular determinants of resistance to azithromycin (23S RNA mutations) and ciprofloxacin (gyrA and parC mutations).

By contrast, during follow-up, more isolates in the doxyPEP vs no PEP arms displayed high-level (>8 mg/L) tetracycline resistance (35.5% vs 12.5%, respectively; P = .04), as well as a correspondingly higher prevalence of the tetM gene that confers this resistance. There was also a higher frequency of cefixime-resistant isolates in the doxyPEP arm (19.3% vs 2.5%, corresponding to just 6 vs 1 isolates; P = .038).

In Canada, the most recently published data on antimicrobial resistance in N gonorrhoeae are from 2021, which was after the first large trial of doxyPEP but before its implementation became more widespread. At that time, the prevalence of doxycycline resistance was at an all-time high of 65.9%, and cefixime resistance had risen from 0.6% in 2017 to 1.5% in 2021.

In all, I believe this trend of rising cefixime resistance warrants caution, particularly in the context of emerging doxyPEP use.

The Canadian guidelines on gonorrhea treatment were last updated in 2023, and they still recommend first-line treatment with ceftriaxone 250 mg intramuscularly plus azithromycin 1 g orally, with cefixime 800 mg plus azithromycin 1 g as a recommended alternative. Fortunately, updated Canadian guidance on antimicrobial treatment is forthcoming.

DoxyPrEP: No Panic at the DISCO
In light of the high prevalence of doxycycline resistance in gonorrhea in the Canadian data, it was perhaps surprising that our Canadian pilot trial of oral doxycycline PrEP (doxyPrEP) among men who have sex with men and with HIV demonstrated not only a statistically significant decrease in chlamydia (incidence rate ratio [IRR]: 0.08; 95%CI: 0.01-0.49) and syphilis infections (IRR: 0.21; 95% CI: 0.04-0.97) compared with placebo over 48 weeks, but also a significant decrease in gonorrhea infections (IRR: 0.32; 95% CI: 0.12-0.86).

We observed excellent adherence and no differences in sexual behavior, adverse events, or tetracycline resistance in Staphylococcus aureus between arms. Although this trial was small, with only 52 participants recruited from 2 sites in Vancouver and Toronto, it mirrors earlier Canadian data on doxyPrEP among HIV-negative men who have sex with men.

To further build upon these data, a large, randomized trial comparing doxyPEP with doxyPrEP (DISCO) among men who have sex with men, regardless of HIV status, is actively recruiting at multiple sites across Canada. 

DoxyPrEP for Cisgender Women
I was also interested in a small study of doxyPrEP, from a single center in Tokyo, that enrolled 40 cisgender female sex workers. Participants initiated doxycycline 100 mg/day in the context of shared decision-making with their healthcare professionals. The presenter at AIDS 2024 shared that these women were informed about doxyPEP, but they tended to choose the PrEP approach owing to the high (nearly daily) frequency of commercial sex activity.

During 69.2 person-years of follow-up, there was a lower incidence of chlamydia, gonorrhea, and syphilis compared with before initiating doxyPrEP (composite IRR: 0.33; 95% CI: 0.13-0.84), while the rates of control conditions – bacterial vaginosis and vulvovaginal candidiasis – were unchanged.

These data are encouraging, given that the only other published study on doxycycline as prevention in cisgender women was a study on doxyPEP, and it reported no change in incidence of STIs vs standard care. That trial, conducted among 449 women at risk of STI in Kenya, reported data from a qualitative substudy in which women described adverse effects, forgetfulness, and concerns about stigma and privacy as key barriers to sustained doxyPEP use.

Clearly, data on doxycycline as STI prophylaxis continue to evolve. These new data from AIDS 2024 emphasize the importance of the population, drug regimen, social context, and local antimicrobial resistance patterns in determining the effectiveness and other health impacts of doxyPEP and doxyPrEP. The Public Health Agency of Canada is currently developing clinical guidelines on doxycycline use as STI prophylaxis that will hopefully guide healthcare professionals in Canada in navigating this exciting but complex area.

Your Thoughts:
Do these new data from AIDS 2024 affect your likelihood to recommend doxyPEP or doxyPrEP for your patients? Leave a comment to join the discussion!