Microbicide Development Program (MDP)

描述(由申请人提供)：这项建议解决了开发一种合理的、成本效益高的和科学上可靠的方法来开发局部直肠杀微生物剂的必要性，从临床前研究到人体探索性研究。这些单独的项目探索了不同但重叠的杀微生物剂研究领域，这些领域累积起来将定义直肠杀菌剂发展的未来。支持该提议的关键前提是接受性肛交(RAI)是一种常见的活动，在艾滋病毒感染的传播中发挥着重要作用。异性RAI很常见，在美国女性中的发病率为5%-10%，被认为是男男性行为者中最常见的艾滋病毒传播途径。如果不承认RAI在全球艾滋病大流行中的作用，可能会限制干预策略的成功，并损害开发安全有效的阴道杀菌剂的努力。该MDP项目申请是U19，是与美国国立卫生研究院和私营部门的合作努力，以启动协调的多学科研究，涉及与直肠杀菌剂开发相关学科的许多世界专家。我们重点研究了一类杀菌剂，逆转录酶(RT)抑制剂(PMPA、UC-781和TMC-120)，其中两种正在进行临床试验，为阴道杀菌剂。我们得到了三家企业赞助商(Biosyn，Inc.、Gilead Sciences和Tibotec-Virco)的支持来发起这些努力。“临床前”阶段包括细胞系、肠道外植体和猕猴对杀微生物剂的安全性和有效性的研究(McGowan项目)，该阶段将使杀微生物剂进入探索性人体试验，旨在优化杀微生物剂的安全性评估，提供初步的体外/体外药效数据，以及有关RT杀菌剂的分布和生物利用度的信息(Corner项目)。未来5年的目标将是评估在未来的杀微生物剂开发中使用的最具成本效益和预测性的分析方法。戈尔巴赫的项目将针对RAI在粘膜功能中的作用，RAI的行为相关性，以及候选配方的可接受性研究。未能调整这些安全性和有效性的修饰物可能导致(1)错误地将RAI毒性归因于杀菌剂，以及(2)由于RAI同时增强艾滋病毒传播而未能证明有效性。从这些研究中获得的信息将是RT开发的关键，但也将为开发其他类别的直肠杀菌剂提供合理的基础。

DESCRIPTION (provided by applicant): This proposal addresses the need to develop a rational, cost effective, and scientifically robust approach to the development of topical rectal microbicides from preclinical to exploratory studies in humans. The individual projects explore distinct, but overlapping areas of microbicide research that, cumulatively, will define the future of rectal microbicide development. The key premise that underpins the proposal is that receptive anal intercourse (RAI) is a common activity, playing a significant role in the transmission of HIV infection. Heterosexual RAI is common, with rates of 5-10% in US women and is considered to be the most common route of HIV transmission in men who have sex with men. Failure to acknowledge the role that RAI plays in the global AIDS pandemic is likely to limit the success of intervention strategies and compromise attempts to develop safe and effective vaginal microbicides. This MDP Project application is a U19, a collaborative effort with NIH and private sectors, to initiate coordinated, multidisciplinary research involving many of the world's experts in disciplines related to rectal microbicide development. We have focused our efforts on one class of microbicides, the reverse-transcriptase (RT) inhibitors (PMPA, UC-781, and TMC-120), two of which are in clinical trials as vaginal microbicide form. We have the support of three corporate sponsors (Biosyn, Inc., Gilead Sciences, and Tibotec-Virco) to initiate these efforts. The "preclinical" phase includes cell line, intestinal explant and macaque studies of microbicide safety and efficacy (Project by McGowan) which will progress microbicides into exploratory human trials designed to optimize microbicide safety evaluation, provide initial ex vivo/in vitro efficacy data, and information about distribution and bioavailability of RT microbicides (Project by Corner). The goal, over 5 years, will be to assess, what are the most cost effective and predictive assays for use in future microbicide development. Projects by Gorbach will target the role of RAI on mucosal function, the behavioral correlates of RAI, and acceptability studies of candidate formulations. Failure to adjust for these modifiers of safety and efficacy may result in (1) falsely attributing RAI toxicity to the microbicide and (2) failing to demonstrate efficacy because of simultaneous enhancement of HIV transmission due to RAI. The information derived from these studies will be critical for RT development, but will also provide a rational basis for the development of other classes of rectal microbicides.