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

描述(申请人提供)：在全球范围内，2010年每天有超过6,000例新的艾滋病毒感染病例，几乎一半是妇女。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，这些可注射的孕激素，如Depo-Provera(甲羟孕酮醋酸酯)，是全球女性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的增加。缺乏前瞻性的临床证据。如果注射避孕药增加了艾滋病毒的易感性，如果艾滋病毒感染的高危异性恋妇女希望继续使用注射避孕药具，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。对于感染艾滋病毒的高危妇女，每日口服富马酸替诺福韦/恩曲他滨(TDF/FTC)的PrEP可显著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TDF/FTC用于PrEP，并强调有效性与药物浓度密切相关。药物浓度低于预期的人有更高的艾滋病毒血清转换率。虽然坚持每天服用TDF/FTC被认为解释了血浆浓度的差异，但我们的初步数据表明，性类固醇激素也可能导致较低的抗逆转录病毒浓度和增加艾滋病毒的易感性。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共同受体的表达来增加HIV的易感性。此外，我们假设，MPA通过增加肾小球滤过和/或上调对孕酮敏感的药物转运体对CD4+T和肾脏细胞的调节，以及改变CD4+T细胞中药物的磷酸化和激活，从而增加肾脏清除量，从而降低有效的TDF/FTC浓度。我们的具体目标是：(1)确定甲孕酮对血液、宫颈组织和宫颈阴道液中HIV易感性的影响；(2)量化甲孕酮对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。迫切需要解决有关艾滋病毒感染风险妇女注射避孕药的这一两难境地。注射甲孕酮是一种高效、廉价的节育选择，它的使用是否会增加艾滋病毒感染风险，并削弱TDF/FTC PrEP的艾滋病毒保护作用？需要这些信息来为妇女的避孕选择提供信息，特别是在艾滋病毒高危人群中。

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.