PrEP and dPEP: Doxycycline post-exposure prophylaxis for prevention of sexually transmitted infections among Kenyan women using HIV pre-exposure prophylaxis

摘要 在过去的十年中，艾滋病毒暴露前预防（PrEP）已证明在高危人群中具有很高的艾滋病毒保护作用 研究表明，PrEP可能会减少人口水平的新艾滋病毒感染。在同一 与此同时，全世界人口中可治愈的性传播感染率显著增加， 和服用PrEP的人群，包括我们在非洲妇女中的初步数据， 性传播感染率很高。已提出使用抗生素强力霉素（dPEP）进行暴露后预防（PEP） 作为一种新的STI控制策略。最近在有性行为的PrEP服用男性中进行的dPEP开放标签临床试验 与法国男性（MSM）的研究发现，新的细菌性性传播感染（沙眼衣原体， 淋病奈瑟氏菌或梅毒螺旋体），对C. trachomatis和T.苍白球，但 对N.淋病在欧洲四环素耐药率很高;两个新的 计划在2019年对男同性恋者进行dPEP研究。非洲妇女面临着不成比例的风险， 艾滋病毒/性传播感染流行病，高收入国家性传播感染率与男男性行为者相当， 炎症性疾病，输卵管不孕症，妊娠并发症）可以说比那些面临的更严重， 男男性接触者与其他依赖合作伙伴参与的性传播感染预防战略相比，按需dPEP将 受女性控制，并且强力霉素有证据表明女性使用安全。我们建议进行 第一项研究评估dPEP在服用PrEP的非洲妇女中预防性传播感染，这些妇女是性传播感染的优先人群 鉴于高风险和参与纵向预防服务，STI PEP携带大量 潜在的好处，但也有重要的潜在风险，我们已经制定了我们的工作，捕捉关键数据，以告知 这个前沿问题的风险收益计算。我们假设dPEP将大大减少 可治愈性传播感染的发病率，特别是C.沙眼，最常见的细菌性性传播感染， 最高的发病率。STI dPEP具有潜在的耐药性风险，我们已经考虑到：C. 沙眼衣原体的耐药性在世界范围内从未出现过，这使得dPEP不太可能产生新的耐药性，但N. 淋病四环素耐药性在肯尼亚很常见，因此我们假设dPEP可能提供 对病原体几乎没有保护作用，但也不会产生新的耐药性。除了阻力风险，数据 以确定dPEP是否安全，可接受，遵守和负担得起。目标1将决定 通过dPEP的开放标签1：1随机试验确定dPEP降低可治愈性STI发生率的获益 与标准治疗相比，446名年龄在18-30岁的妇女服用PrEP。目标2将评估dPEP的相关风险 通过探索a）安全性，B）可接受性，c）依从性，和d）抗性，使用新的和严格的行为和 实验室科学方法目标3将衡量dPEP的成本，并估计避免的每个病例的成本， 影响力和可承受性。如果成功的话，我们的研究将为创新的低成本战略提供第一个证据 避免可治愈的性传播感染在这一脆弱的高危人群中造成大量发病。

ABSTRACT In the past decade, HIV pre-exposure prophylaxis (PrEP) has demonstrated high HIV protection among at-risk groups, with the first indications that PrEP may be reducing population-level new HIV infections. At the same time, rates of curable sexually transmitted infections (STIs) have increased markedly in populations worldwide, and PrEP-taking populations, including in our preliminary data among African women, have been found to have very high STI rates. Post-exposure prophylaxis (PEP) with the antibiotic doxycycline (dPEP) has been proposed as a novel STI control strategy. A recent open-label clinical trial of dPEP among PrEP-taking men who have sex with men (MSM) in France found a 47% relative reduction in new bacterial STIs (Chlamydia trachomatis, Neisseria gonorrhoeae, or Treponema pallidum), with >70% protection for C. trachomatis and T. pallidum but expectedly no protection for N. gonorrhoeae given high rates of tetracycline resistance in Europe; two new studies of dPEP among MSM are planned for 2019. African women face disproportionate risk from overlapping HIV-STI epidemics, with STI rates comparable to MSM in high-income countries and with consequences (pelvic inflammatory disease, tubal infertility, complications of pregnancy) arguably more severe than those faced by MSM. In contrast to other STI prevention strategies that rely on partner participation, on-demand dPEP would be woman-controlled, and doxycycline has evidence of safety for use by women. We propose to conduct the first study evaluating dPEP to prevent STIs in PrEP-taking African women, who are a priority population for STI prevention, given high risk and engagement in longitudinal prevention services. STI PEP carries substantial potential benefits but also important potential risks, and we have framed our work as capturing key data to inform the risk-benefit calculus for this cutting-edge question. We hypothesize that dPEP will substantially reduce the incidence of curable STIs, particularly C. trachomatis, the most common bacterial STI and the one responsible for greatest morbidity. STI dPEP carries potential risk of antimicrobial resistance, which we have considered: C. trachomatis resistance has never been seen worldwide, making new resistance from dPEP unlikely, but N. gonorrhoeae tetracycline resistance is common in Kenya, and for that reason we hypothesize dPEP may provide little protection for that pathogen but will also not generate new resistance. In addition to resistance risk, data are needed to determine whether dPEP is safe, acceptable, adhered to, and affordable. Aim 1 will determine the benefit of dPEP to reduce the incidence of curable STIs through an open-label 1:1 randomized trial of dPEP versus standard of care among 446 women aged 18-30 taking PrEP. Aim 2 will assess associated risks of dPEP by exploring a) safety, b) acceptability, c) adherence, and d) resistance, using novel and rigorous behavioral and laboratory science methods. Aim 3 will measure the cost of dPEP and estimate the cost per case averted, budget impact, and affordability. If successful, our study will provide the first evidence for an innovative, low-cost strategy to avert substantial morbidity due to curable STIs in this vulnerable, high-risk population.