HIV, HCV and the Menopausal Transition: Effects on Steatosis and Fibrosis Progression

 描述(申请人提供)：肝病是艾滋病毒感染者非艾滋病相关死亡的主要原因。虽然合并感染丙型肝炎病毒是导致肝脏疾病的常见原因，但所有与肝脏相关的死亡中，25%-44%发生在艾滋病毒单一感染者中，可能与非酒精性脂肪性肝病(NAFLD)或肝脏脂肪变性有关。非酒精性脂肪肝在HIV感染者中很常见，但与其进展相关的因素及其在肝纤维化进展中的作用仍不清楚。女性现在约占美国所有艾滋病毒感染者的25%。感染艾滋病毒的妇女寿命更长，许多人正在过渡到更年期。艾滋病毒和丙型肝炎病毒感染都与绝经早期有关；艾滋病毒/丙型肝炎病毒混合感染可能与更年期更早开始有关。横断面研究表明，绝经与脂肪变性的高患病率有关，但目前还没有进展的研究。内脏肥胖和代谢紊乱在绝经过渡期间增加，是脂肪变性的危险因素。更年期的荷尔蒙变化可能通过增加肠道通透性而引起炎症。艾滋病毒感染还与肠道微生物移位和炎症以及代谢参数的变化有关。我们假设，绝经过渡将加速脂肪变性和纤维化的进展，特别是在艾滋病毒/丙型肝炎合并感染的女性中，由于更年期较早，她们将因肠道微生物易位而产生更长期的内脏肥胖和全身炎症的累积影响。为了验证我们的假设，我们提出了一项前瞻性研究，利用妇女机构间艾滋病毒研究提供的研究平台。第一个目标是研究绝经过渡及其开始对感染艾滋病毒、丙型肝炎和两者都不感染的妇女脂肪变性进展的影响。第二个目标是研究内脏肥胖和肠道相关微生物易位对绝经过渡期HIV、丙型肝炎病毒携带者和两者都没有感染的女性脂肪变性进展的影响。第三个目标将确定绝经转变及其开始对女性纤维化进展的影响。在先前对WIHS三个部位的横断面研究中，我们建立了使用瞬时弹性成像(TE)来测量纤维化的方法。通过在TE中添加新的持续衰减参数软件，我们将能够同时量化脂肪变性和纤维化，以实现我们在1,650名艾滋病毒单一感染、艾滋病毒/丙型肝炎合并感染、丙型肝炎病毒单一感染和两者均未感染的女性中的目标。我们还将测量抗苗勒氏激素(AMH)水平，这比自我报告更年期更能更好地估计卵巢储备和雌激素消耗。这项研究将导致：1)关于在艾滋病毒、丙型肝炎和非HIV感染的情况下，绝经如何影响脂肪变性和纤维化进展的新信息；2)在患者中提供脂肪变性和纤维化的定量、纵向评估 疾病进展的风险；以及3)为艾滋病毒和丙型肝炎感染妇女的脂肪变性和纤维化提供有针对性的、针对性别和年龄的治疗方法的发展和最佳时机。

 DESCRIPTION (provided by applicant): Liver disease is a leading cause of non‐AIDS‐ related death in HIV‐infected men and women. While coinfection with HCV is a common cause of liver disease, 25‐44% of all liver‐related deaths occurs in HIV‐ monoinfected persons and may be related to non‐alcoholic fatty liver disease (NAFLD) or hepatic steatosis. NAFLD is common in HIV‐infected persons, but the factors associated with its progression and its role in liver fibrosis progression remains elusive. Women now represent about 25% of all HIV‐infected persons in the US. HIV‐infected women are living longer and many are transitioning to menopause. Both HIV and HCV infection are associated with early menopause; HIV/HCV coinfection may be associated with even earlier onset of menopause. Cross‐sectional studies indicate that menopause is associated with a higher prevalence of steatosis, but there are no studies of progression. Visceral obesity and metabolic perturbations increase during the menopausal transition and are risk factors for steatosis. The hormonal changes that characterize menopause may induce inflammation through increased gut permeability. HIV infection is also associated with gut microbial translocation and inflammation, as well as changes in metabolic parameters. We hypothesize that the menopausal transition will accelerate steatosis and fibrosis progression especially in HIV/HCV‐coinfected women, who will have longer cumulative effects of visceral obesity and systemic inflammation from gut microbial translocation due to earlier onset of menopause. In order to test our hypothesis, we propose a prospective study that leverages the research platform provided by the Women's Interagency HIV Study. The first Aim will examine the effects of the menopausal transition and its onset on steatosis progression in women with HIV, HCV, and neither infection. The second Aim will investigate the effects of visceral obesity and gut‐associated microbial translocation o steatosis progression during the menopausal transition in women with HIV, HCV, and neither infection. The third Aim will determine the effects of the menopausal transition and its onset on fibrosis progression in women. In a prior cross‐sectional study in three WIHS sites, we established the use of transient elastography (TE) to measure fibrosis. With the addition of new Continuous Attenuation Parameter software to TE, we will be able to quantify steatosis and fibrosis simultaneously to address our aims in 1,650 women with HIV monoinfection, HIV/HCV coinfection, HCV monoinfection, and neither infection. We will also measure Anti‐Mullerian Hormone (AMH) levels which yield a better estimate of ovarian reserve and thus estrogen depletion than self‐report of menopause. This study will lead to: 1) new information about how menopause affects steatosis and fibrosis progression in the context of HIV, HCV and neither infection; 2) provide quantitative, longitudinal assessments of steatosis and fibrosis, in patients at risk for progression; and 3) inform the development and optimal timing of focused sex‐ and age‐specific approaches to steatosis and fibrosis in HIV and HCV‐infected women.