Statistical methods for clinical trials of novel PrEP agents

项目摘要 在HIV阴性患者中使用共配制的恩曲他滨替诺福韦（TDF/FTC）进行HIV暴露前预防（PrEP） 对预防艾滋病毒感染是安全有效的。尽管取得了显着的成功，PrEP具有重要的 限制作为一种广泛的预防工具。一些人谁将受益于PrEP拒绝它或很差 粘附性。调查表明，许多有艾滋病毒风险的人认为，每日口服TDF/FTC很难预防艾滋病毒感染。 坚持或没有吸引力，更喜欢非口头的替代方案。这也被证明是真实的， 避孕。为了最大限度地发挥生物医学预防的益处，我们需要口服TDF/FTC的替代品。 有一个强大的管道的新的PrEP方法（NPM）的发展。抗逆转录病毒药物 作为注射剂、输注剂、植入剂和杀微生物剂。其中一些已经进入了III期随机 试验和其他可能进入试验在未来2-4年。由于PrEP已显示出有效性，试验必须 在道德上做些规定对于注射和植入，TDF/FTC可能是比较组， 在这些未来的研究中，TDF/FTC的依从性程度是非常不确定的，这大大复杂了 两种武器的比较。标准方法导致长期昂贵的研究，这将减缓PrEP 创新 我们相信可以显着增加功率和/或降低未来的活性对照随机试验的成本。 通过创新性地使用基线后TDF/FTC药理学（在既往试验中得到充分研究）， 重建一个反事实的安慰剂手臂。这允许比较新的PrEP方法， 意向治疗（ITT）和实际治疗（AT）分析中的安慰剂-获得实质性见解和统计学 效率我们还将开发模型和方法，以了解谁将与国家预防机制保持接触 但不是口服PrEP。通过充分研究TDF/FTC药理学和现代因果推理， 方法，我们将开发分析方法和非劣效性框架，使下一代PrEP 审判规模更小、速度更快、信息量更大。

PROJECT SUMMARY HIV pre-exposure prophylaxis (PrEP) with co-formulated emtricitabine tenofovir (TDF/FTC) in HIV negative persons is safe and effective for preventing HIV infection. Despite notable successes, PrEP has important limitations as a broad prevention tool. Some people who would benefit from PrEP refuse it or are poorly adherent. Surveys indicate that many of those at risk for HIV believe that daily oral TDF/FTC to be difficult to adhere to or unappealing and would be prefer a non-oral alternative. This has also been shown to be true in contraception. To maximize the benefits of biomedical prevention, we need alternatives to oral TDF/FTC. There is a robust pipeline of novel PrEP methods (NPM) in development. There are antiretrovirals formulated as injectables, infusions, implantables and microbicides. Some of these have entered phase III randomized trials and others could enter trials over the next 2-4 years. Since PrEP has shown effectiveness, the trials must make some provision for it ethically. For injections and implants, TDF/FTC will likely be a comparator arm and the degree of TDF/FTC adherence in these future studies is very uncertain – greatly complicating the comparison of the two arms. Standard methods lead to long expensive studies which will slow PrEP innovation. We believe can significantly increase power and/or lower the cost of future active-controlled randomized trials. By innovatively using post-baseline TDF/FTC pharmacology, which is well-studied in previous trials, to reconstruct a counterfactual placebo arm. This permits comparisons of the novel PrEP method to putative placebo in both intent to treat (ITT) and as-treated (AT) analyses – gaining substantial insight and statistical efficiency. We will also develop models and methods to understand who will sustain engagement with a NPM but not oral PrEP. By leveraging the well-studied TDF/FTC pharmacology and modern causal inference methods, we will to develop analysis methods and non-inferiority frameworks that allow next generation PrEP trials to be smaller, quicker and more informative.