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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：
Angela D Kashuba
金额：
$ 66.88万
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/8493986
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 Measures 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 cervicovaginal 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

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)：联合国艾滋病规划署2007年的报告估计，每接受有效的抗逆转录病毒治疗的人中，就有4-6人新感染。在没有可预见的艾滋病毒治愈方法的情况下，预防措施必须控制艾滋病毒的流行，结构/屏障/行为方法的效力或适用性有限。迫切需要一种性交独立的给药策略，女性可以发起这种策略，但她们的伴侣不会察觉。越来越清楚的是，抗逆转录病毒药物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，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。虽然凝胶和阴道环等外用制剂正在研究中，但口服抗逆转录病毒药物也有很大的预防前景。目前，用于预防研究的抗逆转录病毒剂量是FDA批准的用于治疗艾滋病毒感染的剂量。然而，没有数据证实暴露在这些标准治疗剂量下将保护粘膜细胞免受艾滋病毒感染，或为替代剂量策略提供参考。我们提出了一项非常有意义的计划，以开发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种剂量的4种抗逆转录病毒药物在3种高危粘膜表面的浓缩能力。在外植体组织培养中，将确定保护暴露于多个感染性分子克隆的组织所需的这些药物单独和组合的浓度。还将实施一种新的方法，使组织对细胞数量和组成的反应正常化。一旦知道体内组织药代动力学结果和体外目标浓度结果，将建立一个数学模型来预测在所有粘膜表面最大限度保护的抗逆转录病毒剂量/方案。最后，建议进行第二项概念验证研究，给妇女服用最终的抗逆转录病毒方案，并挑战艾滋病毒组织活检，以确定感染的风险。

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：
Current opinion in HIV and AIDS
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：
LANCET
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：
The New England journal of medicine
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.