Microbicide Development Program (MDP)

描述（由申请人提供）：本提案解决了从临床前到人类探索性研究开发局部直肠杀微生物剂的合理、成本效益和科学可靠方法的需求。个别项目探索不同的，但重叠的杀微生物剂研究领域，累积起来，将定义直肠杀微生物剂发展的未来。支持这一提议的关键前提是，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起着重要作用。异性恋RAI很常见，在美国女性中发病率为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。如果不承认艾滋病毒感染在全球艾滋病大流行中发挥的作用，可能会限制干预战略的成功，并损害开发安全有效的阴道杀微生物剂的努力。该MDP项目申请是一项U19，是与美国国立卫生研究院和私营部门的合作努力，旨在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。我们专注于一类杀微生物剂，即逆转录酶（RT）抑制剂（PMPA， UC-781和TMC-120），其中两种以阴道杀微生物剂形式进行临床试验。我们得到了三家企业赞助商（Biosyn, Inc.， Gilead Sciences和Tibotec-Virco）的支持来启动这些工作。“临床前”阶段包括对杀微生物剂的安全性和有效性进行细胞系、肠道外植体和猕猴研究（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的安全性评估，提供初步的离体/体外功效数据，以及有关RT杀微生物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。如果不调整这些安全性和有效性调节剂，可能会导致(1)错误地将RAI毒性归因于杀微生物剂；(2)由于RAI同时增强了艾滋病毒的传播，因此无法证明其有效性。从这些研究中获得的信息将对RT的发展至关重要，但也将为开发其他类型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.