Preventing HIV Infection in Women: Targeting Antiretrovirals to Mucosal Tissues

预防女性艾滋病毒感染：针对粘膜组织的抗逆转录病毒药物

基本信息

批准号：
8284294
负责人：
Angela D Kashuba
金额：
$ 95.31万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8284294
关键词：
AIDS prevention Address Animal Model Anti-Retroviral Agents Antiviral Agents Attenuated Behavioral Biological Biopsy Blood Breast Feeding Cell Count Cell Density Cells Cervical Clinical Clinical Research Clinical Trials Collaborations Coupled Data Dose Drug Formulations Drug Kinetics Epidemic Event FDA approved Female Flow Cytometry Gel Genital system HIV HIV Infections HIV vaccine HIV-1 Hour Human Human Herpesvirus 2 Immunohistochemistry Immunologics Immunology Individual Infection Investigation Knowledge Laboratories Length Liquid substance Location Macaca Measures Methods Modeling Molecular Cloning Mononuclear Mucous Membrane Operative Surgical Procedures Oral Persons Pharmaceutical Preparations Phase I Clinical Trials Prevention Prevention strategy Prophylactic treatment Protective Agents Regimen Reporting Research Infrastructure Risk Sampling Sampling Studies Secondary Prevention Series Site Surface Tenofovir Testing Time Tissue Sample Tissues Topical application Vaccines Vagina Vaginal Ring Validation Vertical Disease Transmission Woman antiretroviral therapy base design drug development drug testing efficacy trial emtricitabine healthy volunteer human tissue in vivo mathematical model novel novel strategies pharmacodynamic model pharmacokinetic model prevent rectal response sex standard care success tissue culture transmission process validation studies volunteer

AIDS prevention Address Animal Model Anti-Retroviral Agents Antiviral Agents Attenuated Behavioral Biological Biopsy Blood Breast Feeding Cell Count Cell Density Cells Cervical Clinical Clinical Research Clinical Trials Collaborations Coupled Data Dose Drug Formulations Drug Kinetics Epidemic Event FDA approved Female Flow Cytometry Gel Genital system HIV HIV Infections HIV vaccine HIV-1 Hour Human Human Herpesvirus 2 Immunohistochemistry Immunologics Immunology Individual Infection Investigation Knowledge Laboratories Length Liquid substance Location Macaca Measures Methods Modeling Molecular Cloning Mononuclear Mucous Membrane Operative Surgical Procedures Oral Persons Pharmaceutical Preparations Phase I Clinical Trials Prevention Prevention strategy Prophylactic treatment Protective Agents Regimen Reporting Research Infrastructure Risk Sampling Sampling Studies Secondary Prevention Series Site Surface Tenofovir Testing Time Tissue Sample Tissues Topical application Vaccines Vagina Vaginal Ring Validation Vertical Disease Transmission Woman antiretroviral therapy base design drug development drug testing efficacy trial emtricitabine healthy volunteer human tissue in vivo mathematical model novel novel strategies pharmacodynamic model pharmacokinetic model prevent rectal response sex standard care success tissue culture transmission process validation studies volunteer

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项目摘要

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.

描述（由申请人提供）：2007年UNAIDS报告估计，对于接受有效抗逆转录病毒疗法治疗的每个人，4-6个新人被感染。没有可预见的艾滋病毒治疗方法，预防措施必须控制艾滋病毒的流行和结构/障碍/行为方法，仅具有有限的疗效或适用性。对于妇女可以发起的，对伴侣无法察觉的剂量策略，这是一个迫切的需求。越来越明显的是，抗逆转录病毒药代动力学可以预测功效：使用CAPRISA 004研究的样品，我们的实验室表明，维持尾腹动液中最高替代性替代性替代性替代性替代性动物（以及在生殖道组织中）的受试者是最不可能感染了HIV-1和HSV2。尽管正在研究诸如凝胶和阴道环之类的局部配方，但口服抗逆转录病毒药物也对预防也有很大的前景。目前，预防研究中使用的抗逆转录病毒剂量是FDA批准的用于治疗HIV感染的剂量。但是，没有数据可以确认使用这些标准治疗剂量的暴露会保护粘膜细胞免受艾滋病毒的获取，或为替代剂量策略提供信息。我们提出了一个非常重要的计划，以制定口服抗逆转录病毒预防策略的模型。在健康的女性志愿者中，我们将确定3剂4剂4剂抗逆转录病毒药物在3个处于危险的粘膜表面中浓缩的能力。在外植体组织培养物中，将确定这些药物的浓度，即保护暴露于多个感染性分子克隆的组织所需的浓度。还将实施一种对细胞数和组成的归一化响应的新方法。一旦已知体内组织药代动力学结果和离体靶浓度结果，将开发数学模型，以预测所有粘膜表面上最大的抗逆转录病毒剂量/方案。最后，提出了第二次概念证明研究，以剂量剂量的剂量剂量抗逆转录病毒方案，并挑战患有HIV的组织活检，以确定感染的风险。