Microbicide Development Program (MDP)

描述（由申请方提供）：本提案旨在解决开发一种合理、经济有效且科学可靠的方法的需求，以开发从临床前到人类探索性研究的局部直肠杀微生物剂。各个项目探索不同的，但杀微生物剂研究的重叠领域，累积起来，将确定未来的直肠杀微生物剂的发展。支持该提案的关键前提是，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。异性恋RAI很常见，在美国女性中的发病率为5-10%，被认为是与男性发生性关系的男性中最常见的艾滋病毒传播途径。不承认RAI在全球艾滋病流行中所起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微生物剂的努力。该MDP项目申请是U19，与NIH和私营部门合作，启动协调的多学科研究，涉及许多世界上与直肠杀微生物剂开发相关学科的专家。我们的努力集中在一类杀微生物剂，逆转录酶（RT）抑制剂（PMPA，UC-781和TMC-120），其中两个是在临床试验中作为阴道杀微生物剂的形式。我们得到了三家公司赞助商（Biosyn，Inc.，吉利德科学和Tibotec-Virco）发起这些努力。“临床前”阶段包括杀微生物剂安全性和有效性的细胞系、肠外植块和猕猴研究（McGowan项目），这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安全性评估，提供初步的离体/体外有效性数据，以及关于RT杀微生物剂分布和生物利用度的信息（Corner项目）。5年内的目标是评估在未来杀微生物剂开发中使用的最具成本效益和预测性的检测方法。Gorbach的项目将针对RAI对粘膜功能的作用，RAI的行为相关性以及候选制剂的可接受性研究。 如果不对这些安全性和有效性的修饰因素进行调整，可能会导致（1）错误地将RAI毒性归因于杀微生物剂，以及（2）由于RAI同时增强了HIV传播而无法证明疗效。从这些研究中获得的信息对于RT的开发至关重要，但也将为其他类型的直肠杀微生物剂的开发提供合理的基础。

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.