The effect of Depo-Provera on HIV susceptibility, immune activation, and PrEP PK

Depo-Provera 对 HIV 易感性、免疫激活和 PrEP PK 的影响

基本信息

  • 批准号:
    8588047
  • 负责人:
  • 金额:
    $ 41.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-19 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Worldwide, there were over 6,000 new HIV infections a day in 2010 and almost half were among women. Injectable contraceptives have been associated with a 2-4 fold increased risk of HIV acquisition in some observational studies. Yet, these injectable progestin's, like Depo-Provera" (medroxyprogesterone acetate [MPA]), are the second most common contraceptive method used by women worldwide. Animal data support the increased HIV risk. Prospective clinical evidence is lacking. If injectable contraceptives increase HIV susceptibility, and if heterosexual women at high-risk for HIV infection desire to continue injectable contraception use, effective HIV prevention methods such as pre-exposure prophylaxis (PrEP) become even more important. For women at high risk of HIV infection, PrEP with daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) can substantially reduce the risk of HIV acquisition. In July 2012, the U.S. Food and Drug Administration approved TDF/FTC for PrEP and emphasized that effectiveness is strongly correlated with drug concentrations. Individuals with lower than expected drug concentrations had higher HIV seroconversion rates. While adherence to daily TDF/FTC is thought to explain the differences in plasma concentrations, our preliminary data indicate that sex steroid hormones may also contribute to lower antiretroviral concentrations and increase HIV susceptibility. Given these findings, we hypothesize that the injectable contraceptive, MPA, increases HIV susceptibility through inducing immune activation and increasing HIV co-receptor expression on genital tract target cells. Further, we hypothesize that MPA decreases effective TDF/FTC concentrations through increased renal clearance secondary to increased glomerular filtration and/or up-regulation of progesterone-sensitive drug transporters on CD4+T and kidney cells, as well as alteration of drug phosphorylation and activation in CD4+T cells. Our specific aims are to: (1) determine the effect of MPA on HIV susceptibility in blood, cervical tissue, and cervicovaginal fluid; and (2) quantify the impact of MPA on TDF/FTC in vivo pharmacokinetics and, secondarily, in vitro pharmacodynamics in blood, cervical tissue, and cervicovaginal fluid. There is an urgent need to address this dilemma regarding injectable contraceptives in women at risk for HIV infection. Does the use of injectable MPA, a highly effective and inexpensive birth control option, increase HIV acquisition risk and diminish the HIV protective effects of TDF/FTC PrEP? This information is needed to inform women's contraceptive choice, especially among those at high risk of HIV.
描述(由申请人提供):2010年,全球每天有超过6000例新的艾滋病毒感染,其中几乎一半是女性。在一些观察性研究中,注射避孕药与感染艾滋病毒的风险增加2-4倍有关。然而,这些可注射的黄体酮,如醋酸甲孕酮(MPA),是全世界妇女使用的第二常用避孕方法。动物数据支持艾滋病毒风险增加。缺乏前瞻性临床证据。如果注射避孕药增加了艾滋病毒的易感性,如果处于艾滋病毒感染高风险的异性恋妇女希望继续使用注射避孕药,那么有效的艾滋病毒预防方法,如暴露前预防(PrEP)就变得更加重要。对于艾滋病毒感染高危妇女,每日口服富马酸替诺福韦二氧吡酯/恩曲他滨(TDF/FTC)的PrEP可大大降低感染艾滋病毒的风险。2012年7月,美国食品和药物管理局批准了TDF/FTC用于PrEP,并强调有效性与药物浓度密切相关。低于预期药物浓度的个体有较高的HIV血清转化率。虽然坚持每日TDF/FTC被认为可以解释血浆浓度的差异,但我们的初步数据表明,性类固醇激素也可能导致抗逆转录病毒浓度降低,增加艾滋病毒易感性。鉴于这些发现,我们假设注射避孕药MPA通过诱导免疫激活和增加生殖道靶细胞上HIV共受体的表达来增加HIV易感性。此外,我们假设MPA通过增加肾小球滤过和/或上调CD4+T细胞和肾细胞上黄体酮敏感药物转运体的肾清除率,以及改变CD4+T细胞中的药物磷酸化和活化,从而降低有效的TDF/FTC浓度。我们的具体目的是:(1)确定MPA对血液、宫颈组织和宫颈阴道液中HIV易感性的影响;(2)量化MPA对TDF/FTC体内药代动力学的影响,其次是血液、宫颈组织和宫颈阴道液中的体外药效学影响。迫切需要解决有感染艾滋病毒风险的妇女注射避孕方面的这一难题。使用注射性兆帕,一种高效和廉价的避孕选择,是否会增加感染艾滋病毒的风险并降低TDF/FTC PrEP的艾滋病毒保护作用?需要这些信息来告知妇女,特别是艾滋病毒高风险妇女的避孕选择。

项目成果

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Craig Walter Hendrix其他文献

Craig Walter Hendrix的其他文献

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{{ truncateString('Craig Walter Hendrix', 18)}}的其他基金

Phosphorylation of Drugs in Colonic Tissue
结肠组织中药物的磷酸化
  • 批准号:
    10653625
  • 财政年份:
    2022
  • 资助金额:
    $ 41.31万
  • 项目类别:
Population Pharmacokinetic Modeling and Clinical Trial Simulation to optimize HIV Prevention in Pregnancy and Postpartum
群体药代动力学模型和临床试验模拟可优化妊娠期和产后的艾滋病毒预防
  • 批准号:
    10316144
  • 财政年份:
    2021
  • 资助金额:
    $ 41.31万
  • 项目类别:
Development of Rectal Enema As Microbicide (DREAM)
直肠灌肠剂作为杀菌剂的开发(DREAM)
  • 批准号:
    9088326
  • 财政年份:
    2014
  • 资助金额:
    $ 41.31万
  • 项目类别:
Exploratory Pharmcokinetics of UC781 & Tenofovir Vaginal Microbicide Gel V Film
UC781 的探索性药代动力学
  • 批准号:
    8660270
  • 财政年份:
    2014
  • 资助金额:
    $ 41.31万
  • 项目类别:
Clinical optimization of a tenofovir enema and adherence tracking
替诺福韦灌肠和依从性跟踪的临床优化
  • 批准号:
    8768695
  • 财政年份:
    2014
  • 资助金额:
    $ 41.31万
  • 项目类别:
Exploratory Pharmcokinetics of UC781 & Tenofovir Vaginal Microbicide Gel V Film
UC781 的探索性药代动力学
  • 批准号:
    8471644
  • 财政年份:
    2013
  • 资助金额:
    $ 41.31万
  • 项目类别:
Clinical Laboratory & Biomarker Core
临床实验室
  • 批准号:
    10458362
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:
Pre-Phase I Evaluations
第一阶段前期评估
  • 批准号:
    8404840
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:
Clinical Laboratory & Biomarker Core
临床实验室
  • 批准号:
    10612986
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:
Laboratory and Biomarkers Core
实验室和生物标志物核心
  • 批准号:
    10153642
  • 财政年份:
    2012
  • 资助金额:
    $ 41.31万
  • 项目类别:

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针对男男性行为且感染艾滋病毒的黑人男性进行行为干预,以解决交叉耻辱并提高抗逆转录病毒治疗的依从性
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