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

评估多西环素暴露后预防以减少 PrEP 使用者和男男性行为 HIV 感染者的性传播感染

• 批准号: 9914211
• 负责人: CONNIE L CELUM
• 金额: $ 146.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-12 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914211
• 关键词: Address; Adherence; Adverse event; Age; Antibiotic Resistance; Antibiotics; Anus; Bacteria; CRISPR/Cas technology; Caucasians; Chlamydia; Cities; Clinic; Clinical; Control Groups; Data; Disease; Doxycycline; Drug resistance; Effectiveness; Enrollment; Epidemic; Evaluation; Event; Feces; France; Future; Goals; Gonorrhea; HIV; HIV Infections; HIV Seronegativity; Hour; Incidence; Individual; Infection; Infection Control; Intention; Intervention; Methods; Molecular; Nasopharynx; Neisseria; Neisseria gonorrhoeae; Nucleic Acids; Oropharyngeal; Participant; Patient Self-Report; Patients; Persons; Pharmaceutical Preparations; Policies; Population; Population Heterogeneity; Prevention strategy; Prophylactic treatment; Public Health; Randomized; Recording of previous events; Risk; Safety; San Francisco; Serologic tests; Sex Behavior; Sexually Transmitted Diseases; Staphylococcus aureus; Swab; Syphilis; Techniques; Testing; Tetracycline Resistance; Time; Toxic effect; Unsafe Sex; Urine; arm; bacterial resistance; base; college; colon microbiota; commensal microbes; effectiveness evaluation; gut microbiome; high risk; high risk men; host microbiota; infection rate; infection risk; innovation; men who have sex with men; metagenomic sequencing; open label; pathogen; pre-exposure prophylaxis; prevent; primary outcome; rectal; resistance gene; secondary outcome

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.

抽象的 美国性传播感染 (STI) 发病率创历史新高，淋病发病率急剧上升 (GC)、衣原体 (CT) 和男男性行为者 (MSM) 中的梅毒。暴露前预防 (PrEP) 美国高危 MSM 人群越来越多地使用抗 HIV 药物；值得注意的是，这个人口 每年细菌性性传播感染的发病率高达>50%。感染艾滋病毒的男男性行为者也受到不成比例的影响 性传播感染，梅毒发病率和再感染率高，GC 率高出 50%，梅毒高出 30% CT 与未感染 HIV 的 MSM 进行比较。这些数据凸显了创新和有效战略的迫切需要 减少高危 MSM 中的性传播感染，包括 HIV 感染者和 HIV 阴性 MSM 服用 PrEP。一种潜力 STI 控制策略是使用多西环素进行暴露后预防 (PEP)。该策略已被证明有效 最近在法国进行的一项随机开放标签试验中，对 232 名 HIV 阴性 MSM 进行了事件驱动的 PrEP（IPERGAY 学习）。多西环素 PEP 使新发细菌性传播感染（GC、CT 或梅毒）相对减少 47%， 罕见的不良事件，并且自我报告的两臂性行为没有差异。然而，IPERGAY 参与者年龄较大，大多是白人，受过大学教育，并且高度遵守事件驱动的 PrEP（如 与美国标准每日 PrEP 不同）。因此，IPERGAY 强力霉素 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，他们的坚持， 性行为和性网络可能与未感染艾滋病毒的男男性行为者不同。此外，之前的一个 关于多西环素 PEP 的未探索和重要关注是目标中抗生素耐药性的选择 细菌性传播感染病原体、可引起疾病的定植细菌（例如金黄色葡萄球菌）、共生奈瑟菌 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以发挥作用 作为结肠微生物群的可传播 TCN 抗性的储存库。根据 IPERGAY 数据，强力霉素 PEP 似乎是解决性传播感染流行病的一项有前途的创新策略，特别是在高风险人群中 有性传播感染史和无安全套性行为的男男性行为者。需要一项足够有力、高质量的研究来评估 感染 HIV 的 MSM 和 MSM 对 PrEP 的有效性以及对目标耐药性的影响 细菌性传播感染和正常宿主微生物群。我们提出一项随机开放标签试验来评估有效性 多西环素 PEP 的使用以及对 380 名 HIV 感染者和 380 名接受 PrEP 的 MSM 的抗生素耐药性的影响 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 中性传播感染发病率的耐受性、可接受性和依从性 服用 PrEP 或感染 HIV。 2) 评估多西环素 PEP 对四环素选择的影响 淋病奈瑟菌、金黄色葡萄球菌和共生菌群（包括奈瑟菌）的耐药性 spp 和肠道微生物组。本研究将提供两个高感染率城市中多西环素 PEP 的关键数据 PrEP 覆盖率和高 STI 发生率，以便为政策提供信息。