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

• 批准号: 8588047
• 负责人: Craig Walter Hendrix
• 金额: $ 41.31万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8588047
• 关键词: AIDS prevention; Address; Adherence; Affect; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Biological Response Modifiers; Blood; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Cervical; Clinical; Clinical Research; Clinical Trials; Contraceptive Agents; Contraceptive methods; Data; Depo Provera; Dose; Drug Kinetics; Drug-sensitive; Effectiveness; Future; Genital system; Glomerular Filtration Rate; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; HIV Seropositivity; HIV risk; Heterosexuals; High Risk Woman; Immune; Immunologic Factors; In Vitro; Individual; Inflammatory; Inflammatory Response; Injectable; Link; Liquid substance; Lymphocyte; Measurable; Measurement; Measures; Mediating; Medroxyprogesterone 17-Acetate; Membrane Transport Proteins; Methods; Observational Study; Oral; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Phosphorylation; Phosphotransferases; Plasma; Predisposition; Progesterone; Progestins; Prophylactic treatment; Proteins; Renal clearance function; Research; Risk; Secondary to; Site; Substrate Specificity; Tenofovir; Tenofovir disoproxil fumarate; Testing; Tissues; Tubular formation; United States; United States Food and Drug Administration; Up-Regulation; Woman; animal data; birth control; cervicovaginal; emtricitabine; glomerular filtration; high risk; immune activation; in vivo; kidney cell; mRNA Expression; prospective; protective effect; public health relevance; receptor expression

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）：全球，2010年每天有6,000多个新的艾滋病毒感染，其中有几乎一半的女性。在某些观察性研究中，可注射的避孕药与2-4倍增加了艾滋病毒获取的风险。然而，这些可注射的孕激素，例如depo-provera”（乙酸甲状腺毒素[mpa]）是全球妇女使用的第二大最常见的避孕方法。动物数据支持增加的HIV风险。缺乏前瞻性临床证据。缺乏可注射的避孕药来增加HIV的概念，如果持续的HIV符合性较高的妇女在HIV上有效，如果有效地在HIV上有效，如果HIV型在HIV上有效，并且在HIV上有效地在HIV上有效，并且在HIV上有效地在HIV上有效，并且在HIV上有效地在HIV上有效，并且在HIV上有效，并且在HIV上有效地在HIV上有效，并且在HIV上有效，并且在HIV上有效，并且在HIV上有效，并且在HIV上有效，并且在HIV上有效地在HIV上均具有高度的影响。诸如预防前的预防方法（PREP）对艾滋病毒感染的高风险变得更加重要。浓度低于预期的药物浓度的较高的HIV血清转化率。鉴于这些发现，我们假设可注射的避孕药MPA通过诱导免疫激活并增加HIV共受体在生殖道靶细胞上的表达来提高HIV敏感性。此外，我们假设MPA通过增加肾小球过滤和/或上调CD4+T和肾细胞上孕激素敏感的药物转运蛋白的肾脏清除率的增加，从而降低了有效的TDF/FTC浓度，以及CD4+T细胞中药物磷酸化和激活的改变。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在体内药代动力学中的影响，其次，在血液，宫颈组织和子宫颈阴道流体中的体外药效学。迫切需要解决有关患有艾滋病毒感染风险的妇女的可注射避孕药的困境。使用可注射的MPA是一种高效且廉价的节育选择，增加了HIV获取风险并减少TDF/FTC PREP的HIV保护作用？需要此信息来为妇女的避孕选择提供信息，尤其是在艾滋病毒高风险的避孕药上。