Preventing HIV Infection in Women: Targeting Antiretrovirals to Mucosal Tissues

描述（由申请人提供）：我们没有赢得与艾滋病毒的战争。每有一个人接受强效抗逆转录病毒治疗，就有6个新感染者。在没有可预见的治愈方法的情况下，预防是控制艾滋病毒流行所需的药物。一个特别关键的需要是一种与性交无关的给药策略，妇女可以主动采取这种策略，而她们的伴侣却察觉不到。目前正在研究局部配方，如凝胶和阴道环，但口服抗逆转录病毒药物也有很大的预防希望。在这项计划拨款的支持下，我们将开发一种新的、基于科学的方法，通过针对生殖道和直肠粘膜组织的药物浓度，通过口服抗逆转录病毒药物预防艾滋病毒感染。这种综合方法将通过找到适当浓度的抗逆转录病毒药物，在适当的时间内将其输送到适当的生物部位，从而应对预防艾滋病毒感染的挑战。我们的目标是开发经选择的抗逆转录病毒药物在宫颈、阴道和直肠分泌物和组织中的药代动力学模型；使用外植体人体组织培养物来确定预防艾滋病毒感染的选定抗逆转录病毒药物的组织浓度；对产生的药代动力学和药效学数据进行建模，以选择最可能在所有组织部位对女性有效的与生殖无关的预防性药物方案；并在概念验证试验中确定这一方案的有效性。规划拨款的具体目的是制定临床试验方案、知情同意和监管审查所需的其他文件；获得一系列必要的审查委员会的批准，建立数据安全监测委员会，建立必要的临床试验基础设施和获取研究药物。这笔规划赠款将提供基础设施，以制定预防艾滋病毒感染的三种临床规程。这些方案的成功完成将导致确定预防艾滋病毒口服化合物的新战略，因为它们将首次确定预防艾滋病毒感染所需的细胞外和细胞内人体组织抗逆转录病毒药物浓度。当结合使用标准剂量抗逆转录病毒药物在粘膜组织中可达到的浓度的知识时，可以选择在不依赖于性交的暴露前预防方案的II/III期研究中最有可能成功的抗逆转录病毒药物。这将有助于使昂贵的随机对照试验的投资回报最大化。

DESCRIPTION (provided by applicant): We are not winning the war against HIV. For each person treated with potent antiretroviral therapy, 6 new individuals became infected. Without a foreseeable cure, prevention is the medicine needed to control the HIV epidemic. A particularly critical need is one of coitally-independent dosing strategies which women can initiate and are imperceptible to their partners. Topical formulations such as gels and vaginal rings are being investigated, but oral antiretroviral drugs also hold significant promise for prevention. With the support of this planning grant, we will develop a novel, scientifically-based method of preventing HIV infection with oral antiretroviral drugs by targeting genital tract and rectal mucosal tissue drug concentrations. This integrated approach will address the challenge of preventing HIV infection by finding the appropriate concentration of antiretroviral to deliver to the appropriate biological site for the proper length of time. Our objectives are to develop pharmacokinetic models of selected antiretrovirals in cervical, vaginal, and rectal secretions and tissues; use explant human tissue cultures to identify the tissue concentrations of the select antiretrovirals which prevent HIV infection; to model the resulting pharmacokinetic and pharmacodynamic data to select a coitally-independent preventative drug regimen most likely to be effective in women at all tissue sites; and to determine the efficacy of this selected regimen in a proof-of-concept trial. The specific aims of the planning grant are to develop the clinical trial protocols, informed consents, and other documents necessary for regulatory review; to obtain approval from the series of requisite review committees and establish the data safety monitoring committee, and to develop the necessary clinical trial infrastructure and acquire the study agents. This planning grant will provide the infrastructure to develop three clinical protocols for prevention of HIV infection. Successful completion of these protocols will result in a new strategy for identifying oral compounds for HIV prevention, as they will define, for the first time, the extracellular and intracellular human tissue concentrations of antiretrovirals required to prevent HIV infection. When combined with the knowledge of achievable concentrations in mucosal tissues using standard doses of antiretrovirals, the antiretrovirals which have the most likely probability of success in Phase II/III studies of coitally-independent pre-exposure prophylaxis regimens can be selected. This will help maximize the return on investment of expensive randomized controlled trials.