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 在美国，性传播感染（STI）率在历史悠久的高度中，淋病的增加 （GC），衣原体（CT）和梅毒与男性发生性关系（MSM）。暴露前预防（PREP） 在美国，处于风险的MSM种群中越来越多地使用艾滋病毒。值得注意的是，这个人口有 细菌性STI发病率每年高至50％。艾滋病毒感染的MSM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高，GC率提高50％，高30％ 与没有HIV的MSM相比，CT。这些数据突出了对创新有效策略的紧迫需求 为了减少高危MSM的性传播感染，均患有HIV和HIV阴性MSM的人进行PREP。一个潜力 STI控制策略是具有强力霉素的暴露后预防（PEP）。该策略证明了功效 在最近的232个HIV阴性MSM的随机开放标签试验中，法国事件驱动的PREP（Ipergay） 学习）。强力霉素PEP导致新细菌性传播疾病（GC，CT或梅毒）的相对相对降低47％，并且具有47％ 罕见的不良事件，双臂之间的自我报告的性行为没有差异。但是，ipergay 参与者年龄较大，主要是高加索和大学受过教育，并且高度遵守事件驱动的预备 反对日常准备，美国规范）。因此，IPERGAY强力霉素PEP研究的结果可能无法反映 这种策略在不同人群中的优势和风险，包括艾滋病毒的MSM，其坚持， 性实践和性网络可能与艾滋病毒未感染的MSM不同。此外，以前 对强力霉素PEP的未开发和重要关注是靶标的抗生素抗性 细菌性STI病原体，可导致疾病的细菌定植（例如，金黄色葡萄球菌），共生奈瑟氏菌 可以将四环素（TCN）抗性基因传输到GC的SPP，并且在肠道微生物组中可以使用 作为对结肠微生物群的可传播TCN耐药性的储层。基于ipergay数据，多西环素 PEP似乎是解决Sti流行病的有前途的创新策略，尤其是在更高的风险中 MSM具有性传播感染和无避孕套的历史。需要一项足够动力的高质量研究来评估 患有艾滋病毒和MSM的MSM对PREP的有效性以及对目标中耐药性的影响 细菌性传播感染和正常宿主微生物群。我们提出了一项随机开放标签试验，以评估有效性 强力霉素PEP和对380 MSM抗生素耐药性的影响，患有HIV和380 msm的PREP 旧金山和西雅图的公共卫生诊所。我们的具体目的是：1）评估有效性， 强力霉素PEP的耐受性，可接受性和依从性，以降低MSM之间的性传播感染发生率 服用艾滋病毒的准备或生活。 2）评估强力霉素PEP对选择四环素的影响 Neisseria Gonorrhoeae，葡萄球菌金黄色葡萄球菌和共生菌群的耐药性，包括Neisseria SPP和肠道微生物组。这项研究将在两个城市中提供有关强力霉素PEP的关键数据 为了为政策提供信息，准备覆盖率和高传播税率。