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Study Authors: Juliana S. Grant, Chrysovalantis Stafylis, et al.

Target Audience and Goal Statement: Infectious disease specialists, urologists, family physicians, internists

The goal of this study was to explore the latest research on pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) with doxycycline, particularly whether it can reduce bacterial sexually transmitted infections (STIs) in gay, bisexual, and other men who have sex with men (MSM).

Question Addressed:

• What was the latest evidence on the benefit/risk/cost-effectiveness profile of PrEP/PEP with doxycycline in MSM?

Study Synopsis and Perspective:

Proof that highly active could decrease HIV transmission and that PrEP could lower the risk of HIV acquisition ushered in an era of optimism. Known biological synergy between HIV and bacterial STIs, e.g., the ability of co-occurring genital herpes to facilitate the spread of HIV, "faded" from collective memory. While PrEP adherence can provide substantial protection against HIV acquisition for high-risk uninfected people, several studies have shown that receipt of PrEP was associated with an .

Moreover, decreased use of condoms has been linked with bacterial STIs increasing globally. Hence, there has been a growing interest in determining whether giving doxycycline before or after unprotected sex could prevent syphilis, caused by Treponema pallidum, and other common bacterial STIs such as chlamydia and Neisseria gonorrhoeae. In the wake of increasing STIs among MSM, Jeffrey Klausner, MD, of UCLA David Geffen School of Medicine and Fielding School of Public Health in Los Angeles, and colleagues recently conducted a state-of-the-art review to examine the current state of research, knowledge gaps, and challenges around the use of doxycycline prophylaxis to prevent syphilis and other STIs.

This review follows a meeting convened by international healthcare stakeholders on March 3, 2019 in Seattle, to frame the initial inquiry, which was then supplemented by focused literature searches to address specific questions of interest. Writing in , the team's provocative takeaways included suggestions that doxycycline use was linked to a lower incidence of select bacterial STIs among men who had unprotected sex with other men in two small, short-term randomized controlled trials. Klausner's group also outlined five additional trials with different designs, populations, outcomes, and safety measures, which were currently in development or underway. While the tenor of the review was optimistic, the team cautioned that better and more robust data were needed on efficacy; target population; community acceptability; behavioral risk compensation; doxycycline dose, regimen, and formulation; long-term safety; antimicrobial resistance; cost-effectiveness; and risk-benefit.

Two studies and a modeling analysis suggested that doxycycline prophylaxis held promise for the treatment of bacterial STIs. One open-label of (the French national HIV research agency's On Demand Antiretroviral Pre-exposure Prophylaxis for HIV Infection in Men Who Have Sex With Men trial) involved an assessment of PEP with doxycycline (200 mg within 24-72 hours of condomless sexual encounters up to 3 times per week) in 232 HIV-negative men or transgender women having sex with men (age ≥18 years). Participants were defined as high-risk if they had condomless anal sex with at least two different partners during the previous 6 months. Overall, PEP with doxycycline was associated with a lower bacterial STI incidence (hazard ratio [HR] 0.57, P=0.014), especially for syphilis (70%-73% in the intention-to-treat analysis).

In a separate, open-label, , a total of 30 HIV-infected MSM with prior syphilis were randomized 1:1 to PrEP with doxycycline for 48 weeks or a financial incentive-based behavioral intervention. Compared with the control group, researchers observed that syphilis, gonorrhea, and chlamydia were reduced by 73% (P=0.02) in the doxycycline group. Additionally, if 50% of MSM used PrEP with doxycycline and it was 70% effective, then syphilis would decrease by 50% after 12 months and 85% after 10 years, according to a separate focused on evaluating syphilis among Australian MSM.

Studies underway or in development include:

• The Canadian (Tenofovir/Emtricitabine With Doxycycline for Combination HIV and Syphilis Pre-exposure Prophylaxis in HIV-negative MSM) study in which HIV-negative, sexually active MSM received immediate PrEP with doxycycline or delayed initiation after 6 months, with 1 year of daily HIV PrEP; as of March 2019, no bacterial STIs were identified in the doxycycline arm, whereas three chlamydia cases were seen in the delayed arm
• In the Australian study, the primary aim was to assess acceptability of a daily dosing regimen for doxycycline prophylaxis, and measure the efficacy of 100-mg daily doxycycline STI prophylaxis against reinfection with gonorrhea, chlamydia, and syphilis
• A total of 700 participants of the larger (n=3,000) will be randomized 2:1 to PEP with doxycycline (200 mg) or no PEP as part of an effort to evaluate whether prophylaxis with this antibiotic can prevent chlamydia and syphilis in participants with a prior STI diagnosis in the past 18 months
• Another U.S. study will assess the efficacy of PEP with doxycycline (200 mg) post-condomless sexual contact in 780 MSM and assess the evolution of tetracycline resistance with a novel targeted sequencing technique

Klausner's group pointed out that the two current doxycycline dosing regimen options (100 mg daily or 200 mg single dose post-condomless sex event) were actually based on experience with doxycycline prophylaxis in other infectious diseases and the minimum inhibitory concentration of Treponema pallidum. Because of the small sample sizes, the estimated effect sizes were imprecise for the two trials that showed efficacies of about 70% with doxycycline prophylaxis. It was also not clear which specific sex acts were protected with this strategy.

Furthermore, it would be of interest to perform modeling studies or pooled analyses to identify population subsets most impacted by doxycycline prophylaxis. For instance, the Australian modeling study suggested that focusing on MSM with higher numbers of sex partners (>20 partners in 6 months) would be almost as effective as focusing on broader doxycycline PrEP use.

With respect to doxycycline safety, the evidence compiled by Klausner's group showed that adults generally tolerate the antibiotic very well. Even serious side effects resolved with discontinuation of doxycycline. Since the doxycycline formulation (enteric-coated vs uncoated pills) may impact side effects and treatment adherence, the team recommended that this factor should be tracked closely in randomized controlled trials. Antimicrobial resistance is an omnipresent concern, with resistance against gonococci often being higher among MSM -- the population subset most likely to use doxycycline PrEP/PEP. Since both doxycycline PrEP/PEP and HIV PrEP can be used daily or intermittently, an educational campaign, designed using evidence from ongoing and future studies, will be critical to address any concerns, such as explaining that HIV PrEP does not provide protection against bacterial STIs and doxycycline PrEP/PEP does not protect high-risk HIV-negative individuals from HIV.

Source Reference: 2019; DOI: 10.1093/cid/ciz866

Study Highlights: Explanation of Findings

Doxycycline is an inexpensive, moderate-spectrum, liposoluble, well-tolerated, oral antibiotic that has been around for more than 50 years. It has mainly been used in the management of several bacterial infections, particularly involving intracellular pathogens, as well as in the treatment of acne or for the prophylaxis of malaria.

Bacterial STIs may be amenable to doxycycline prophylaxis, based on current evidence and ongoing studies summarized in this state-of-the-art review. But the evidence base on the efficacy of doxycycline PrEP/PEP needs to be expanded, cautioned Klausner's group. They suggested that researchers should carefully consider which populations to focus on, doxycycline formulation and regimen, and ensuring that findings can be implemented in the real world.

Among the suggestions offered by the group for future evaluations were pooled analyses across studies to identify populations most likely to benefit from doxycycline PrEP/PEP. Evaluating doxycycline resistance in Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, and Mycoplasma genitalium, as well as other common pathogens like Staphylococcus aureus and Streptococcus pneumoniae, also requires the development of consistent laboratory methods.

Eradicating opportunistic pathogens while commensal bacteria will necessitate broader guidance on how to interpret and use microbiome and (i.e., the collection of all genes that directly or indirectly contribute to antibiotic resistance) data in the context of sexual health.

"Finally, cost-effectiveness and modeling studies that consider different scenarios around the most suitable population to focus on and individual versus population-level impacts of Doxy [doxycycline] PEP/PrEP are needed to guide conclusions around the appropriateness of Doxy PEP/PrEP to prevent bacterial STIs," the team wrote.

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