Preventing HIV Infection in Women: Targeting Antiretrovirals to Mucosal Tissues

描述（由申请人提供）：2007年联合国艾滋病规划署的报告估计，每一个接受强效抗逆转录病毒治疗的人，就有4-6个新感染者。由于没有可预见的治愈艾滋病毒的方法，预防措施必须控制艾滋病毒的流行，结构/障碍/行为方法的效力或适用性有限。迫切需要一种与性交无关的给药策略，妇女可以主动采取这种策略，而其伴侣不会察觉。越来越清楚的是，抗逆转录病毒药代动力学可以预测疗效：使用CAPRISA 004研究的样本，我们的实验室证明，在宫颈阴道液（以及生殖道组织）中保持最高替诺福韦浓度的受试者感染HIV-1和HSV2的可能性最小。虽然正在研究凝胶和阴道环等外用制剂，但口服抗逆转录病毒药物在预防方面也有很大的希望。目前，用于预防研究的抗逆转录病毒剂量是fda批准的用于治疗HIV感染的剂量。然而，没有数据证实暴露于这些标准治疗剂量将保护粘膜细胞免受HIV感染，或告知替代剂量策略。我们提出了一个非常重要的计划，以开发一个模型的口服抗逆转录病毒预防策略。在健康女性志愿者中，我们将确定4种抗逆转录病毒药物的3剂在3个危险粘膜表面集中的能力。在外植体组织培养中，将确定这些药物的浓度，单独或联合使用，以保护暴露于多个感染性分子克隆的组织。一种新的方法来正常化组织对细胞数量和组成的反应也将实施。一旦体内组织药代动力学结果和体外靶浓度结果已知，将建立一个数学模型来预测在所有粘膜表面具有最大保护作用的抗逆转录病毒剂量/方案。最后，提出了第二项概念验证研究，给妇女服用最后的抗逆转录病毒治疗方案，并对组织活检进行艾滋病毒感染，以确定感染风险。

DESCRIPTION (provided by applicant): The 2007 UNAIDS report estimated that for each person treated with potent antiretroviral therapy, 4-6 new individuals became infected. Without a foreseeable cure for HIV, prevention measures must control the HIV epidemic and structural/barrier/behavioral methods simply have limited efficacy or applicability. There is a critical need, for coitally-independent dosing strategies which women can initiate and are imperceptible to their partners. It is increasingly clear that antiretroviral pharmacokinetics predict efficacy: using samples from the CAPRISA 004 study, our laboratory demonstrated that subjects who maintained the highest tenofovir concentrations in cervicovaginal fluid (and thus in genital tract tissues) were the least likely to become infected with HIV-1 and HSV2. Although topical formulations such as gels and vaginal rings are being investigated, oral antiretroviral drugs also hold significant promise for prevention. Currently, antiretroviral doses used in prevention studies are those that are FDA-approved for treatment of HIV infection. However, there are no data to confirm that exposures with these standard treatment doses will protect mucosal cells from HIV acquisition, or to inform alternative dosing strategies. We propose a highly significant plan to develop a model for oral antiretroviral prevention strategies. In healthy women volunteers, we will determine the ability of 3 doses of 4 antiretroviral drugs to concentrate in 3 at-risk mucosal surfaces. In explant tissue cultures, the concentration of these drugs, alone and in combination, required to protect tissues exposed to multiple infectious molecular clones will be identified. A new approach to normalizing tissue responses to cell numbers and composition will also be implemented. Once the in vivo tissue pharmacokinetic results and ex vivo target concentration results are known, a mathematical model will be developed to predict the antiretroviral doses/regimen maximally protective at all mucosal surfaces. Finally, a second proof-of-concept study is proposed to dose women with the final antiretroviral regimen and challenge tissue biopsies with HIV to determine risk of infection.