Modifies of PrEP Efficacy in US & African Women: Age, Hormones, Sex & Microbiota

美国 PrEP 疗效的修改

基本信息

  • 批准号:
    8448509
  • 负责人:
  • 金额:
    $ 89.57万
  • 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:
    2013-01-18 至 2017-12-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY (See instructions): Young women are in urgent need of female-controlled HIV prevention strategies, including antiretroviral (ARV) drugs for topical or oral pre-exposure prophylaxis (PrEP). Two daily oral ARV PrEP studies and one vaginal gel study demonstrated efficacy in preventing HIV-1 infection in women. However, two other studies of daily oral PrEP and one of daily tenofovir (TFV) gel were stopped early for futility. Prior studies suggest differences in ARV metabolism and cervical immune cell populations between otherwise similar U.S. and sub-Saharan African women, but specific differences in the genital mucosal environment that may impact ARV pharmacokinetics (PK), pharmacodynamics (PD) and efficacy are understudied. We hypothesize that young age, bacterial vaginosis (BV), semen exposure, and depot medroxyprogesterone acetate (DMPA) use are associated with increased activation of CD4-i- T cells, changes in soluble immunity, and loss of vaginal lactobacilli, which increase HIV acquisition risk and alter topical ARV PK/PD. In Project 3, mechanisms by which known HIV risks impact PK/PD will be investigated in four clinical studies: women will be studied at BV diagnosis and after successful treatment, in the setting of unprotected vaginal sexual intercourse, before and after initiation of DMPA, and by comparing sexually active adolescents to adult women. The ultimate goal is to utilize knowledge of the mechanisms underlying HIV acquisition risk to advance selection of effective, female-controlled PrEP strategies. We also propose a pre-Phase 1 tenofovir disoproxil fumarate (TDF) intravaginal ring (IVR) study in U.S. and African women at risk for HIV to assess the hypothesis that changes in mucosal immunity related to hormonal effects and/or changes in vaginal microbiota modulate PK/PD of TDF. Drug levels will be measured in plasma, genital tract secretions and epithelial tissue following 14 days of TDF ring use (Core B). Pyrosequencing and species-specific quantitative PCR assays will be performed to examine changes in vaginal microbiota that may modulate PK/PD of TDF. These studies will utilize innovative approaches to inform the development of topical ARV PrEP strategies and will investigate the key hypothesis that distinct populations of high risk women may require differential preventative strategies
项目摘要(见说明):年轻妇女迫切需要女性控制的艾滋病毒预防战略,包括用于局部或口服暴露前预防的抗逆转录病毒药物(PrEP)。每天两次口服ARV PrEP研究和一次阴道凝胶研究证明了在预防妇女感染HIV-1方面的有效性。然而,另外两项每日口服PrEP和一项每日替诺福韦(TFV)凝胶的研究因无效而提前停止。先前的研究表明,在其他方面相似的美国和撒哈拉以南非洲妇女之间,ARV新陈代谢和宫颈免疫细胞群存在差异,但生殖器粘膜环境中可能影响ARV药代动力学(PK)、药效学(PD)和疗效的具体差异研究不足。我们假设,年轻、细菌性阴道病(BV)、精液暴露和使用醋酸甲羟孕酮(DMPA)与CD4-I-T细胞激活增加、可溶性免疫改变和阴道乳酸菌丢失有关,这些因素增加了HIV感染的风险,改变了局部ARV PK/PD。在项目3中,将通过四项临床研究来研究已知的艾滋病毒风险影响PK/PD的机制:在BV诊断和成功治疗后,在无保护的阴道性交环境中,在DMPA开始之前和之后,通过比较性行为活跃的青少年和成年女性来研究妇女。最终目标是利用艾滋病毒感染风险潜在机制的知识,推动选择有效的、由女性控制的PrEP战略。我们还建议在美国和非洲HIV高危妇女中进行一项替诺福韦富马酸二异丙酯(TDF)阴道环(IVR)1期前研究,以评估与激素效应相关的粘膜免疫变化和/或阴道微生物区系变化调节TDF的PK/PD的假设。在TDF环使用14天后,将测量血浆、生殖道分泌物和上皮组织中的药物水平(核心B)。将进行焦磷酸测序和特定物种的定量PCR分析,以检查可能调节TDF的PK/PD的阴道微生物区系的变化。这些研究将利用创新的方法为局部ARV PrEP策略的发展提供信息,并将调查关键假设,即不同的高危女性人群可能需要不同的预防策略

项目成果

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MARLA J KELLER其他文献

MARLA J KELLER的其他文献

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{{ truncateString('MARLA J KELLER', 18)}}的其他基金

Einstein-Montefiore Clinical and Translational Science Award Hub
爱因斯坦-蒙蒂菲奥里临床和转化科学奖中心
  • 批准号:
    10622099
  • 财政年份:
    2023
  • 资助金额:
    $ 89.57万
  • 项目类别:
Convalescent Plasma to Limit Coronavirus Associated Complications: A Randomized Blinded Phase 2 Study Comparing the Efficacy and Safety of Anti-SARS-CoV-2 Plasma to Placebo in COVID-19 hospitalized pa
恢复期血浆限制冠状病毒相关并发症:一项随机盲法 2 期研究,比较抗 SARS-CoV-2 血浆与安慰剂在 COVID-19 住院患者中的功效和安全性
  • 批准号:
    10166008
  • 财政年份:
    2020
  • 资助金额:
    $ 89.57万
  • 项目类别:
CTSA Administrative Supplement for Informatics Core: A novel AI/ML system to predict respiratory failure and ARDS in Covid-19 patients
CTSA 信息学核心行政补充:一种预测 Covid-19 患者呼吸衰竭和 ARDS 的新型 AI/ML 系统
  • 批准号:
    10158737
  • 财政年份:
    2020
  • 资助金额:
    $ 89.57万
  • 项目类别:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    10112978
  • 财政年份:
    2018
  • 资助金额:
    $ 89.57万
  • 项目类别:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    9886296
  • 财政年份:
    2018
  • 资助金额:
    $ 89.57万
  • 项目类别:
Clinical and Translational Science Award
临床和转化科学奖
  • 批准号:
    10357784
  • 财政年份:
    2018
  • 资助金额:
    $ 89.57万
  • 项目类别:
Safety of Non-Medicated Intravaginal Rings for Microbicide Delivery
用于杀菌剂递送的非药物阴道环的安全性
  • 批准号:
    8012508
  • 财政年份:
    2010
  • 资助金额:
    $ 89.57万
  • 项目类别:
Clinical Study to Measure Pharmacokinetics, Pharmacodynamics and Safety of a TDF
测量 TDF 的药代动力学、药效学和安全性的临床研究
  • 批准号:
    8210597
  • 财政年份:
    2009
  • 资助金额:
    $ 89.57万
  • 项目类别:
EFFECTS OF HORMONES ON MUCOSAL IMMUNE MEDIATORS ACROSS THE MENSTRUAL CYCLE
激素对整个月经周期粘膜免疫介质的影响
  • 批准号:
    7718170
  • 财政年份:
    2008
  • 资助金额:
    $ 89.57万
  • 项目类别:
EFFECTS OF HORMONES ON MUCOSAL IMMUNE MEDIATORS ACROSS THE MENSTRUAL CYCLE
激素对整个月经周期粘膜免疫介质的影响
  • 批准号:
    7605356
  • 财政年份:
    2007
  • 资助金额:
    $ 89.57万
  • 项目类别:
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