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 性传播感染(STI)的发病率在美国处于历史最高水平，淋病的发病率显著上升 男男性行为者(MSM)中的GC、衣原体(CT)和梅毒。暴露前预防(PrEP) 在美国，高危MSM人群越来越多地使用抗艾滋病毒药物；值得注意的是，这一人群 细菌性传播感染的发病率每年高达50%。感染艾滋病毒的男男性同性恋者也受到不成比例的影响 通过性传播感染，梅毒的发病率和再感染率较高，GC的发病率较高50%， CT与未感染HIV的男男性接触者比较。这些数据突显了创新和有效战略的迫切需要 为了减少高危MSM的性传播感染，HIV携带者和HIV阴性的MSM都在服用PrEP。一种潜力 STI的控制策略是多西环素暴露后预防(PEP)。这一策略证明了它的有效性。 最近在法国对232名HIV阴性MSM进行的事件驱动PrEP的随机开放试验(IPERGAY) 研究)。多西环素PEP导致新的细菌性STI(GC、CT或梅毒)的相对减少47%， 罕见的不良事件和两臂之间自我报告的性行为没有差异。然而，IPERGAY 参与者年龄较大，主要是受过大学教育的高加索人，并高度遵守事件驱动型PrEP(AS 与美国规范的每日PrEP相反)。因此，IPERGAY多西环素PEP研究的结果可能不能反映 这一战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接触者，他们坚持 性行为和性网络可能不同于未感染艾滋病毒的MSM。此外，以前的一个 多西环素PEP是抗生素耐药的靶点之一，尚未被探索和关注 细菌性传播感染病原体，可引起疾病的定植细菌(如金黄色葡萄球菌)，共生性奈瑟氏菌 可将四环素(TCN)耐药基因传递给GC的SPP，以及可能起作用的肠道微生物群 作为可传播的TCN对结肠微生物区系的抵抗力的储存库。基于IPERGAY数据，多西环素 PEP似乎是应对STI流行的一种很有前途的创新策略，特别是在风险较高的人群中 有性病史和无避孕套性行为的男男性接触者。需要一个足够强大的、高质量的研究来评估 男男性接触者与HIV感染者对PrEP的疗效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区系。我们提出了一个随机开放标签试验来评估其有效性 380名HIV感染者和380名男男性接触者多西环素PEP及PrEP对耐药性的影响 旧金山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性病发病率的耐受性、可接受性和依从性 服用PrEP或携带艾滋病毒。2)评价多西环素PEP对四环素选择的影响 淋球菌、金黄色葡萄球菌和共生菌，包括奈瑟氏菌的耐药性 SPP和肠道微生物群。这项研究将提供多西环素PEP在两个高风险城市的关键数据 准备覆盖率和高STI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.