Risk factors and prediction of liver disease in HIV/HCV

描述(由申请者提供)：该奖项将为首席研究员在传染病流行病学方面的职业生涯做好准备，特别关注那些合并感染艾滋病毒的人感染丙型肝炎病毒(丙型肝炎病毒)的临床结果。这项建议的培训部分将包括：1)在宾夕法尼亚大学临床流行病学和生物统计学中心进行高级流行病学课程，获得流行病学博士学位；2)来自国际公认的流行病学家的指导；3)与宾夕法尼亚大学的研究人员在艾滋病毒流行病学、慢性丙型肝炎病毒感染和生物统计学方面进行合作；以及4)与正在进行的两项艾滋病毒队列研究的调查人员进行合作。丙型肝炎病毒合并感染在HIV感染者中非常普遍，而终末期肝病(ESLD)是丙型肝炎病毒感染的主要临床结局，目前已成为发达国家HIV患者发病和死亡的主要原因。尽管艾滋病毒/丙型肝炎合并感染的高流行率和ESLD的影响，但在艾滋病毒/丙型肝炎患者中，影响这种临床结果的危险因素尚未得到很好的研究。已发表的研究已经初步评估了组织学结果的预测因素，但很少有艾滋病毒/丙型肝炎患者接受肝活检，因为他们拒绝或由于禁忌症(例如，积极饮酒或凝血障碍)而不被提供。因此，这些研究无法准确地确定相关危险因素对艾滋病毒/丙型肝炎患者肝病进展的真实影响。相比之下，专注于ESLD等临床结果的研究要好得多，因为它们可以包括典型的艾滋病毒/丙型肝炎合并感染患者。由于数据显示，女性的肝病进展比男性慢得多，因此，感染艾滋病毒/丙型肝炎的女性的ESLD的风险因素和预测因素可能与男性不同，应该单独进行检查。为了开始解决这些问题，这项建议有三个具体目标：1)确定艾滋病毒/丙型肝炎合并感染男性中的ESLD风险因素，2)推导并内部验证一个临床预测指数，以根据进展为ESLD的风险对艾滋病毒/丙型肝炎合并感染的男性进行分层，以及3)验证由女性机构间艾滋病毒研究收集的临床、实验室和药房数据的特定组合，以确定艾滋病毒/丙型肝炎联合感染的女性患有ESLD的能力。特殊目标1和2将利用退伍军人老龄化队列研究的数据，这是一项多中心的前瞻性队列研究，对8个退伍军人管理局医疗中心的艾滋病毒阳性和阴性退伍军人进行护理。具体目标3将利用妇女机构间艾滋病毒研究中三个站点的数据，这是一项针对艾滋病毒阳性和阴性妇女的前瞻性队列研究。在完成这些目标后，国际丙型肝炎协会将为了解感染艾滋病毒的男性合并感染丙型肝炎病毒的自然历史和风险因素做出实质性贡献，并准备在未来为了解感染艾滋病毒的女性合并感染丙型肝炎病毒的自然历史做出类似贡献。

DESCRIPTION (provided by applicant): This award will prepare the principal investigator for a career as an independent investigator in Infectious Disease epidemiology, with a particular focus on the clinical outcomes of hepatitis C virus (HCV) infection in those co-infected with HIV. The training component of this proposal will include: 1) advanced epidemiologic coursework at the Center for Clinical Epidemiology and Biostatistics at Penn leading to a Ph.D. in Epidemiology, 2) mentorship from an internationally recognized epidemiologist, 3) collaboration with researchers at Penn in HIV epidemiology, chronic HCV infection, and biostatistics, and 4) collaboration with investigators from two ongoing HIV cohort studies. HCV co-infection is highly prevalent among HIV-infected patients, and end-stage liver disease (ESLD), the main clinical outcome of HCV infection, now represents the major cause of morbidity and mortality among HIV patients in the developed world. Despite the high prevalence of HIV/HCV co-infection and impact of ESLD, the risk factors for this clinical outcome have not been well examined among HIV/HCV patients. Published studies have evaluated primarily predictors of histological outcomes, but few HIV/HCV patients undergo liver biopsy because they refuse or are not offered due to contraindications (e.g., active alcohol use or coagulopathy). These studies are therefore unable to determine accurately the true effects of relevant risk factors for liver disease progression among HIV/HCV patients. In contrast, studies focused on a clinical outcome such as ESLD are far preferable because they can include the typical patients with HIV/HCV co-infection. Since data show that liver disease progression is substantially slower in women versus men, the risk factors and predictors of ESLD are likely to be different in HIV/HCV-co-infected women than in men and should be examined separately. To begin to address these issues, this proposal has three Specific Aims: 1) To determine the risk factors for ESLD among HIV/HCV-co-infected men, 2) To derive and internally validate a clinical predictive index to stratify HIV/HCV-co-infected men by risk of progression to ESLD, and 3) To validate the ability of specified combinations of clinical, laboratory, and pharmacy data collected by the Women's Interagency HIV Study to identify HIV/HCV-co-infected women with ESLD. Specific Aims 1 and 2 will utilize data from the Veterans Aging Cohort Study, a multi-center, prospective cohort study of HIV-positive and -negative veterans in care at eight Veterans Administration medical centers. Specific Aim 3 will utilize data from three sites in the Women's Interagency HIV Study, a prospective cohort study of HIV-positive and -negative women. Upon completion of these aims, the PI will have made substantive contributions to knowledge of the natural history and risk factors for HCV co-infection in HIV-infected men and be poised to make similar contributions in the future to knowledge of the natural history of HCV co-infection in HIV-infected women.