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:
    8493986
  • 负责人:
  • 金额:
    $ 66.88万
  • 依托单位:
  • 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

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 年联合国艾滋病规划署报告估计,每接受有效的抗逆转录病毒治疗,就有 4-6 个人被感染。如果没有可预见的艾滋病毒治愈方法,预防措施必须控制艾滋病毒的流行,而结构/障碍/行为方法的功效或适用性有限。迫切需要女性可以发起且伴侣无法察觉的独立性交给药策略。越来越清楚的是,抗逆转录病毒药代动力学预测疗效: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最不可能感染 HIV-1 和 HSV2。尽管正在研究凝胶和阴道环等局部制剂,但口服抗逆转录病毒药物也具有重要的预防作用。目前,预防研究中使用的抗逆转录病毒剂量是 FDA 批准用于治疗 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遭艾滋病毒感染,或为替代剂量策略提供信息。我们提出了一项非常重要的计划来开发口服抗逆转录病毒预防策略的模型。在健康女性志愿者中,我们将确定 3 剂 4 种抗逆转录病毒药物在 3 个危险粘膜表面集中的能力。在外植体组织培养中,将确定保护暴露于多种感染性分子克隆的组织所需的这些药物的单独或组合浓度。还将实施一种使组织对细胞数量和组成的反应正常化的新方法。一旦已知体内组织药代动力学结果和离体目标浓度结果,将开发数学模型来预测对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,对女性进行最终的抗逆转录病毒治疗,并用 HIV 进行组织活检,以确定感染风险。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
HIV-1 treatment as prevention: the good, the bad, and the challenges.
  • DOI:
    10.1097/coh.0b013e32834788e7
  • 发表时间:
    2011-07
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Smith K;Powers KA;Kashuba AD;Cohen MS
  • 通讯作者:
    Cohen MS
Drug concentrations after topical and oral antiretroviral pre-exposure prophylaxis: implications for HIV prevention in women.
  • DOI:
    10.1016/s0140-6736(11)60878-7
  • 发表时间:
    2011-07-16
  • 期刊:
  • 影响因子:
    168.9
  • 作者:
    Karim, Salim S. Abdool;Kashuba, Angela D. M.;Werner, Lise;Karim, Quarraisha Abdool
  • 通讯作者:
    Karim, Quarraisha Abdool
Preexposure prophylaxis for HIV infection among African women.
  • DOI:
    10.1056/nejmoa1202614
  • 发表时间:
    2012-08-02
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Van Damme L;Corneli A;Ahmed K;Agot K;Lombaard J;Kapiga S;Malahleha M;Owino F;Manongi R;Onyango J;Temu L;Monedi MC;Mak'Oketch P;Makanda M;Reblin I;Makatu SE;Saylor L;Kiernan H;Kirkendale S;Wong C;Grant R;Kashuba A;Nanda K;Mandala J;Fransen K;Deese J;Crucitti T;Mastro TD;Taylor D;FEM-PrEP Study Group
  • 通讯作者:
    FEM-PrEP Study Group
Pharmacology of HIV integrase inhibitors.
  • DOI:
    10.1097/coh.0b013e328356e91c
  • 发表时间:
    2012-09
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Adams JL;Greener BN;Kashuba AD
  • 通讯作者:
    Kashuba AD
Formulation, pharmacokinetics and pharmacodynamics of topical microbicides.
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Angela D Kashuba其他文献

Angela D Kashuba的其他文献

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{{ truncateString('Angela D Kashuba', 18)}}的其他基金

Novel Mass Spectrometry Imaging Methods to Quantify Antiretroviral Adherence
量化抗逆转录病毒依从性的新型质谱成像方法
  • 批准号:
    9040663
  • 财政年份:
    2016
  • 资助金额:
    $ 66.88万
  • 项目类别:
Novel Mass Spectrometry Imaging Methods to Quantify Antiretroviral Adherence
量化抗逆转录病毒依从性的新型质谱成像方法
  • 批准号:
    10260722
  • 财政年份:
    2016
  • 资助金额:
    $ 66.88万
  • 项目类别:
Multi-Species Mechanisms of Drug Bio-distribution in HIV Tissue Reservoirs
HIV组织储库中药物生物分布的多物种机制
  • 批准号:
    9226028
  • 财政年份:
    2014
  • 资助金额:
    $ 66.88万
  • 项目类别:
Multi-Species Mechanisms of Drug Bio-distribution in HIV Tissue Reservoirs
HIV组织储库中药物生物分布的多物种机制
  • 批准号:
    9003024
  • 财政年份:
    2014
  • 资助金额:
    $ 66.88万
  • 项目类别:
Multi-Species Mechanisms of Drug Bio-distribution in HIV Tissue Reservoirs
HIV组织储库中药物生物分布的多物种机制
  • 批准号:
    8706563
  • 财政年份:
    2014
  • 资助金额:
    $ 66.88万
  • 项目类别:
Clinical Pharmacology & Analytical Chemistry Core
临床药理学
  • 批准号:
    8531837
  • 财政年份:
    2013
  • 资助金额:
    $ 66.88万
  • 项目类别:
Clinical Pharmacology & Analytical Chemistry Core
临床药理学
  • 批准号:
    8329990
  • 财政年份:
    2011
  • 资助金额:
    $ 66.88万
  • 项目类别:
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
  • 批准号:
    8284294
  • 财政年份:
    2011
  • 资助金额:
    $ 66.88万
  • 项目类别:
UPLC-MS/MS to Support Preclinical and Clinical Antiretroviral Pharmacology Studie
UPLC-MS/MS 支持临床前和临床抗逆转录病毒药理学研究
  • 批准号:
    8051351
  • 财政年份:
    2011
  • 资助金额:
    $ 66.88万
  • 项目类别:
Pharmacology Core
药理学核心
  • 批准号:
    8326902
  • 财政年份:
    2011
  • 资助金额:
    $ 66.88万
  • 项目类别:

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