Evaluation of doxycycline post-exposure prophylaxis to reduce sexually transmitted infections in PrEP users and HIV-infected men who have sex with men

摘要 在美国，性传播感染（STI）的发病率处于历史最高水平，淋病的发病率急剧上升 (GC)衣原体（CT）和梅毒在男男性行为者（MSM）中。暴露前预防（PrEP） 在美国，越来越多的高危MSM人群使用抗艾滋病毒药物;值得注意的是， 细菌性STI发病率高达每年50%以上。感染艾滋病毒的男男性行为者也受到不成比例的影响 梅毒的发病率和再感染率高，GC的发病率高出50%， CT与无艾滋病毒的MSM相比。这些数据突出表明迫切需要创新和有效的战略 减少高危男男性接触者的性传播感染，包括艾滋病毒感染者和艾滋病毒阴性的男男性接触者服用PrEP。 性传播感染控制策略是使用强力霉素进行暴露后预防。这一策略证明了有效性 在法国最近一项随机开放标签试验中，232名HIV阴性MSM接受了事件驱动的PrEP（IPERGAY 研究）。强力霉素PEP导致新发细菌性STI（GC、CT或梅毒）相对减少47%， 罕见的不良事件，两组之间自我报告的性行为没有差异。然而，IPERGAY 参与者年龄较大，大部分是白人和大学教育，高度坚持事件驱动的PrEP（作为 与美国标准的每日PrEP相反）。因此，IPERGAY多西环素PEP研究的结果可能无法反映 该策略在不同人群中的优势和风险，包括感染艾滋病毒的男男性行为者，其依从性， 性行为和性网络可能与未感染艾滋病毒的MSM不同。此外，此前 关于多西环素PEP的未探索的和重要的关注是在靶点中选择抗生素抗性， 细菌性STI病原体，可引起疾病的定殖细菌（例如，金黄色葡萄球菌）、葡萄球菌 spp可以将四环素（TCN）抗性基因传递给GC，并且在肠道微生物组中可能起作用 作为对结肠微生物群的可传播TCN抗性的储存库。根据IPERGAY的数据，强力霉素 PEP似乎是一个有希望的创新战略，以解决性传播感染的流行，特别是在高风险 有性传播感染史和无安全套性行为史的男男性接触者。需要一项强有力的高质量研究来评估 艾滋病毒感染者和MSM对PrEP的有效性以及对目标人群耐药性的影响 细菌性传播感染和正常宿主微生物群。我们建议进行一项随机开放标签试验来评估 多西环素PEP对380名感染HIV的MSM和380名接受PrEP的MSM抗生素耐药性的影响 弗朗西斯科和西雅图的公共卫生诊所。我们的具体目标是：1）评估有效性， 多西环素PEP降低MSM STI发病率耐受性、可接受性和依从性 服用PrEP或感染艾滋病毒。2)评价强力霉素PEP对四环素筛选的影响 淋病奈瑟菌、金黄色葡萄球菌和口腔植物群（包括奈瑟菌）的耐药性 spp和肠道微生物组。本研究将提供关于强力霉素PEP在2个城市的关键数据， PrEP覆盖率和高性传播感染率，以便为政策提供信息。

Abstract Sexually transmitted infections (STI) rates are at an all-time high in the US, with striking increases of gonorrhea (GC), chlamydia (CT), and syphilis among men who have sex with men (MSM). Pre-exposure prophylaxis (PrEP) against HIV is increasingly being used by at-risk MSM populations in the US; remarkably, this population has bacterial STI incidence rates as high as >50% per year. MSM living with HIV are also disproportionately impacted by STIs, with high incidence and reinfection rates of syphilis, 50% higher rates of GC and 30% higher rates of CT compared to MSM without HIV. These data highlight the pressing need for innovative and effective strategies to reduce STIs in high-risk MSM, both those living with HIV and HIV-negative MSM taking PrEP. One potential STI control strategy is post-exposure prophylaxis (PEP) with doxycycline. This strategy demonstrated efficacy in a recent randomized open-label trial in 232 HIV-negative MSM on event-driven PrEP in France (IPERGAY study). Doxycycline PEP resulted in a 47% relative reduction in new bacterial STIs (GC, CT, or syphilis), with rare adverse events and no difference in self-reported sexual behavior between arms. However, IPERGAY participants were older, mostly Caucasian and college educated, and highly adherent to event driven PrEP (as opposed to daily PrEP, the US norm). Thus, the results of the IPERGAY doxycycline PEP study may not reflect the advantages and risks of this strategy in diverse populations, including MSM living with HIV, whose adherence, sexual practices, and sexual networks may differ from HIV-uninfected MSM. Furthermore, a previously unexplored and important concern about doxycycline PEP is selection of antibiotic resistance among the target bacterial STI pathogens, colonizing bacteria that can cause disease (e.g., Staph aureus), commensal Neisseria spp which could transmit tetracycline (TCN) resistance genes to GC, and in the gut microbiome which may serve as a reservoir of transmissible TCN resistance to colonic microbiota. Based on the IPERGAY data, doxycycline PEP appears to be a promising innovative strategy to address the STI epidemic, particularly among higher risk MSM with a history of STIs and condomless sex. A sufficiently-powered, high-quality study is needed to evaluate the effectiveness in both MSM living with HIV and MSM on PrEP and the impact on drug resistance in the target bacterial STIs and normal host microbiota. We propose a randomized open label trial to assess the effectiveness of doxycycline PEP and impact on antibiotic resistance in 380 MSM living with HIV and 380 MSM on PrEP at public health clinics in San Francisco and Seattle. Our Specific Aims are to: 1) Evaluate the effectiveness, tolerability, acceptability, and adherence profile of doxycycline PEP to reduce STI incidence among MSM taking PrEP or living with HIV. 2) Assess the effect of doxycycline PEP on selection of tetracycline resistance in Neisseria gonorrhoeae, Staphylocccus aureus and commensal flora, including Neisseria spp and the gut microbiome. This study will provide critical data about doxycycline PEP in 2 cities with high PrEP coverage and high STI rates in order to inform policy.