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

描述（由申请人提供）：2010年，全球每天有6,000多名新的艾滋病毒感染者，其中近一半是妇女。在一些观察性研究中，注射避孕药与艾滋病毒感染风险增加2-4倍有关。然而，这些可注射的孕酮，如Depo-Provera（醋酸甲羟孕酮[MPA]），是全世界妇女使用的第二种最常见的避孕方法。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，有效的艾滋病毒预防方法，如暴露前预防（PrEP）变得更加重要。对于HIV感染高风险的女性，每日口服富马酸替诺福韦酯/恩曲他滨（TDF/FTC）的PrEP可以大大降低HIV感染的风险。2012年7月，美国食品和药物管理局批准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具有较高的HIV血清转换率。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有助于降低抗逆转录病毒药物浓度并增加HIV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的HIV辅助受体表达来增加HIV易感性。此外，我们假设MPA通过增加继发于肾小球滤过增加的肾清除率和/或上调CD 4 +T细胞和肾细胞上的孕酮敏感性药物转运蛋白，以及改变CD 4 +T细胞中的药物磷酸化和活化，降低有效TDF/FTC浓度。我们的具体目标是：（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，其次是对血液、宫颈组织和宫颈阴道液中体外药效学的影响。迫切需要解决在有感染艾滋病毒风险的妇女注射避孕药方面的这一难题。使用注射型MPA（一种高效且廉价的避孕选择）是否会增加HIV感染风险并降低TDF/FTC PrEP的HIV保护作用？需要这些信息来指导妇女，特别是艾滋病毒高风险妇女选择避孕方法。

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.