TOPICAL MICROBICIDE DRUG COMBINATIONS FOR THE PREVENTION OF SHIV

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 2007年，联合国艾滋病规划署报告说，在撒哈拉以南非洲艾滋病毒/艾滋病感染者中，妇女占61%。这突出表明，迫切需要一种有效的、由女性控制的艾滋病毒预防战略，如经阴道使用的杀微生物剂凝胶，使妇女能够保护自己免受艾滋病毒感染。不幸的是，最近使用非特异性化合物(如硫酸纤维素)作为凝胶的试验在阻断传播方面并未成功。将有效的抗逆转录病毒药物与已知的成功治疗相结合，可能是预防艾滋病毒最有希望的局部策略。为此，我们研制了一种羟乙基纤维素凝胶，其中含有两种核苷/核苷酸逆转录酶抑制剂恩曲他滨(FTC)和替诺福韦(TFV)。 在这项研究中，我们正在测试FTC/TFV凝胶与安慰剂凝胶在非人类灵长类动物中的有效性，使用公认的重复、低剂量暴露策略。这项研究设计模拟了高危性接触一种被称为猿猴/人类免疫缺陷病毒(SHIV)的类似艾滋病毒的病毒的条件。我们的结果将为FTC/TFV凝胶在预防女性HIV感染方面的潜在使用提供亟需的临床前指导。我们已经启动了一项有效性研究，使用重复暴露猕猴模型，使用SHIV162P3每周两次低剂量阴道挑战，总共14次挑战。12只雌性辫尾猕猴被分配到安慰剂凝胶手臂(2%羟乙基纤维素)(n=6)或5%FTC/1%TFV(2%羟乙基纤维素)凝胶手臂(n=6)。FTC/TFV凝胶或安慰剂凝胶在挑战前30分钟经阴道给雌性辫尾猕猴涂抹，并在挑战前立即采集血液。在每次采血后测定血浆病毒载量和血浆药物水平。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In 2007, UNAIDS reported that women comprise 61% of adults in Sub-Saharan Africa living with HIV/AIDS. This highlights the critical need for an effective, female-controlled HIV prevention strategy such as a vaginally-applied microbicide gel, which can enable women to protect themselves from HIV infection. Unfortunately, recent trials using non-specific compounds (like cellulose sulfate) as gels have not been successful in blocking transmission. Combinations of potent antiretroviral agents with known success as therapy may be the most promising topical strategy for HIV prevention. Towards this goal, we have formulated a hydroxyethylcellulose-based gel containing two nucleoside/nucleotide reverse transcriptase inhibitors, emtricitabine (FTC) and tenofovir (TFV) in combination. In this study, we are testing the efficacy of the FTC/TFV gel as compared to placebo gel using a well-established repeated, low-dose exposure strategy in nonhuman primates. The study design mimics the conditions of high-risk sexual exposure to an HIV-like virus known as Simian/human Immunodeficiency virus (SHIV). Our results will provide much needed preclinical guidance for the potential use of FTC/TFV gel in preventing HIV infection in women. We have initiated an efficacy study using a repeat-exposure macaque model with low dose twice-weekly vaginal challenges with SHIV162P3, for a total of 14 challenges. Twelve female pigtail macaques have been assigned to a placebo gel arm (2% hydroxyethylcellulose) (n = 6) or 5% FTC/1% TFV (in 2% hydroxyethylcellulose) gel arm (n=6). FTC/TFV gel or placebo gel is applied vaginally to female pigtail macaques 30 minutes prior to challenge, and blood is collected immediately prior to challenge. Plasma viral load and plasma drug levels are determined after each blood collection.