Differential HIV infection and tenofovir activity in pre and postmenopausal women

绝经前和绝经后妇女的艾滋病毒感染差异和替诺福韦活性

• 批准号: 9081627
• 负责人: Gustavo F. Doncel
• 金额: $ 45.57万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9081627
• 关键词: Address; Behavioral; Biopsy; Clinical Research; Clinical effectiveness; Confounding Factors (Epidemiology); Data; Drug Kinetics; Endocrine; Enrollment; Environment; Epithelial; Estrogen Therapy; Estrogens; Experimental Designs; Exposure to; Female; Gel; Genital system; HIV; HIV Infections; HIV-1; Hour; Human; Hysterectomy; Immune; In Vitro; Incubated; Infection; Infection prevention; Intervention; Knowledge; Life; Luteal Phase; Menopause; Menstrual cycle; Menstruation; Mucous Membrane; Pathogenesis; Pharmacodynamics; Phase; Postmenopause; Predisposition; Premenopause; Prevention; Prevention strategy; Progesterone; Prophylactic treatment; Replacement Therapy; Risk; Sampling; Sexual Transmission; Specimen; Staging; Structure; Tenofovir; Testing; Tissues; Vagina; Vaginal Gel; Variant; Visit; Woman; animal data; cervicovaginal; cohort; experience; hormonal contraception; hormone therapy; human data; improved; in vivo; innovation; male; microbicide; prevent; proliferative phase Menstrual cycle; reproductive; reproductive hormone; reproductive tract; research study; screening; success; transmission process

DESCRIPTION (provided by applicant): Male-to-female sexual transmission of human immunodeficiency virus type 1 (HIV-1) infection is approximately twice as efficient as the opposite. Progress has been made in defining the initial steps of HIV-1 pathogenesis in women. A landmark study released in 2010 showed proof of concept that a vaginal gel containing 1% tenofovir was effective in preventing male-to-female transmission in 39-54% of women using the gel peri-coitally. However, major gaps exist in understanding HIV-1 acquisition in women and in predicting the success of worldwide implementation of HIV-1 prevention products. Specifically, the influence of female reproductive hormones, whether during the menstrual cycle or in menopause, on HIV-1 acquisition and transmission remains to be clearly elucidated? All women will naturally experience fluctuations of reproductive hormones throughout their life. Animal data and information from small cohorts of women suggest that women may be more susceptible to HIV-1 infection in estrogen-deplete or progesterone-dominant states, such as menopause and luteal phase of the menstrual cycle. No human data exist on the effects of the female reproductive cycle or hormonal therapy on the pharmacokinetics and pharmacodynamics of tenofovir vaginal gel. Our studies will fill major gaps in our knowledge about HIV-1 infection and prevention. Primarily, we will elucidate the effect of women's reproductive cycles on HIV-1 susceptibility and tenofovir pharmacokinetics and pharmacodynamics at the level of the cervicovaginal mucosa. We will characterize these parameters through innovative experiments which include obtaining ectocervical tissue explants and biopsies from pre and post menopausal women. In order to better control for potential confounding variables, we will obtain genital tract biopsies in a longitudinal clinical study of premenopausal women in the follicular and luteal phases, both at baseline and after exposure to vaginal tenofovir gel. Similarly, we will obtain genital tract biopsies from postmenopausal women at baseline and after exposure to tenofovir vaginal gel. Through these experiments, we will test the hypotheses that progesterone dominant states (high progresterone/estrogen ratio), such as the luteal phase of menses and menopause, increase cervicovaginal susceptibility to HIV-1 and alter tenofovir pharmacokinetics and pharmacodynamics.

描述（由申请人提供）：人类免疫缺陷病毒1型（HIV-1）感染的性传播的效率大约是相反的两倍。在定义女性HIV-1发病机理的初始步骤方面取得了进展。 2010年发布的一项具有里程碑意义的研究表明，含有1％替诺福韦的阴道凝胶可有效防止39-54％的女性使用凝胶骨蛋白乳头的妇女的男性到女性传播。但是，在理解妇女中的HIV-1获取以及预测全球预防产品实施的成功方面存在主要差距。具体而言，女性生殖激素的影响，无论是在月经周期还是在更年期中，对HIV-1采集和传播的影响仍然有待清楚地阐明吗？所有妇女一生都会自然会经历生殖激素的波动。动物数据和来自少数女性的动物数据表明，女性可能更容易受到雌激素失败或孕激素主导状态的HIV-1感染，例如月经周期的更年期和黄体期。不存在关于女性生殖周期或荷尔蒙治疗对替诺福韦阴道凝胶的药代动力学和药效学的影响的数据。我们的研究将填补我们对HIV-1感染和预防的了解的主要空白。首先，我们将阐明女性生殖周期对宫颈阴道粘膜水平上HIV-1易感性以及Tenofovir药代动力学和药效学的影响。我们将通过创新的实验来表征这些参数，其中包括从前后更年期妇女那里获得肠道组织外植体和活检。为了更好地控制潜在的混杂变量，我们将获得生殖道 在基线和暴露于阴道Tenofovir凝胶后，在卵泡和黄体阶段对绝经前妇女进行纵向临床研究的活检。同样，我们将在基线和暴露于替诺福韦阴道凝胶后从绝经后妇女那里获得生殖道活检。通过这些实验，我们将测试孕酮占主导地位的假设（较高的预酯/雌激素比），例如月经和更年期的黄体阶段，增加了对HIV-1的宫颈阴道敏感性，并改变了Tenofovir药物动力学和药物学。

项目成果

Effects of hormonal contraception on antiretroviral drug metabolism, pharmacokinetics and pharmacodynamics.

• DOI: 10.1111/aji.12210
• 发表时间: 2014-06
• 期刊: American journal of reproductive immunology (New York, N.Y. : 1989)
• 作者: Thurman AR;Anderson S;Doncel GF
• 通讯作者: Doncel GF

Comparison of Mucosal Markers of Human Immunodeficiency Virus Susceptibility in Healthy Premenopausal Versus Postmenopausal Women.

健康绝经前与绝经后妇女人类免疫缺陷病毒易感性粘膜标志物的比较。

• DOI: 10.1089/aid.2016.0320
• 发表时间: 2017
• 期刊: AIDS research and human retroviruses
• 影响因子: 1.5
• 作者: Thurman,AndreaRies;Yousefieh,Nazita;Chandra,Neelima;Kimble,Thomas;Asin,Susana;Rollenhagen,Christiane;Anderson,SharonM;Herold,BetsyC;Freiermuth,JamieL;Starkman,BrianS;Mesquita,PedroMM;Richardson-Harman,Nicola;Cunningham,Tina
• 通讯作者: Cunningham,Tina