TOPICAL MICROBICIDE DRUG COMBINATIONS FOR THE PREVENTION OF SHIV

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 2007年，联合国艾滋病规划署报告说，在撒哈拉以南非洲，妇女占成年艾滋病毒/艾滋病感染者的61%。 这突出表明，迫切需要一个有效的，由女性控制的艾滋病毒预防战略，如阴道应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。第一代杀微生物剂具有类似洗涤剂的活性，已被证明是无效的，并激发了我们扩大研究工作的兴趣，开发与抗逆转录病毒（ARV）药物配制的局部杀微生物剂凝胶。与第一代不同，这些凝胶更有前途，因为它们可以提供高剂量的强效药物，可以在粘膜进入点阻断HIV复制。为此，我们已经成功地制定和评估了几个凝胶含有单一或组合的核苷/核苷酸逆转录酶（恩曲他滨和替诺福韦）或整合酶（L-870812）抑制剂。 我们已经完成了两个凝胶含有替诺福韦（TFV）单独或联合恩曲他滨（FTC）对阴道传播使用重复挑战猕猴模型的疗效研究。两种凝胶均具有完全保护性，表明有效的局部预防可能不需要药物组合。此外，我们还启动了另一项研究，以评估替诺福韦凝胶的保护窗口，并检查凝胶应用后3天病毒暴露时的疗效。 我们还完成了一项试点研究，以评估整合酶抑制剂凝胶的疗效，并表明它具有高度保护性，首次证明了这类药物的实用性。 我们的研究结果强调了局部抗逆转录病毒预防作为生物医学预防策略的高疗效，支持人类临床试验，并通过确定高效的方式为其设计提供信息。

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 acquiring HIV. First-generation microbicides that had detergent-like activities proved ineffective and have fueled interest in expanding our research efforts on developing topical microbicide gels formulated with antiretroviral (ARV) drugs. Unlike first-generation, these gels are more promising because they can deliver a high dose of potent drugs that can block HIV replication at the mucosal point of entry. To this end, we have successfully formulated and evaluated several gels containing single or combinations of nucleoside/nucleotide reverse transcriptase (emtricitabine and tenofovir) or integrase (L-870812) inhibitors. We have completed efficacy studies for two gels containing tenofovir (TFV) alone or in combination with emtricitabine (FTC) against vaginal transmission using a repeat-challenge macaque model. Both gels were fully protective indicating that drug combinations may not be needed for effective topical prophylaxis. In addition, we have initiated another study to evaluate the window of protection by the tenofovir gel and examine efficacy when virus exposure occurs 3 days after gel application. We also completed a pilot study to assess the efficacy of a gel with an integrase inhibitor and show that it was highly protective demonstrating for the first time the utility of this class of drugs. Our results highlight the high efficacy of topical antiretroviral prophylaxis as a biomedical prevention strategy, support clinical trials in humans, and inform their design by identifying highly effective modalities.