Risk factors and prediction of liver disease in HIV/HCV

描述（由申请人提供）：该奖项将使首席研究者成为传染病流行病学的独立研究者，特别关注丙型肝炎病毒（HCV）感染合并艾滋病毒感染者的临床结果。该计划的培训内容将包括：1)宾夕法尼亚大学临床流行病学和生物统计学中心的高级流行病学课程，培养流行病学博士学位；2)国际知名流行病学家的指导；3)与宾夕法尼亚大学HIV流行病学、慢性HCV感染和生物统计学方面的研究人员合作；4)与两项正在进行的HIV队列研究的研究人员合作。丙型肝炎病毒合并感染在艾滋病毒感染患者中非常普遍，终末期肝病（ESLD）是丙型肝炎病毒感染的主要临床结果，现在是发达国家艾滋病毒患者发病和死亡的主要原因。尽管HIV/HCV合并感染的高流行率和ESLD的影响，但这种临床结果的危险因素尚未在HIV/HCV患者中得到很好的检查。已发表的研究主要评估了组织学结果的预测因素，但很少有HIV/HCV患者因为拒绝或由于禁忌症（例如，主动饮酒或凝血功能障碍）而没有接受肝活检。因此，这些研究无法准确确定相关危险因素对HIV/HCV患者肝脏疾病进展的真正影响。相比之下，侧重于临床结果（如ESLD）的研究要可取得多，因为它们可以包括典型的HIV/HCV合并感染患者。由于数据显示，女性肝病的进展比男性慢得多，因此，女性HIV/ hcv合并感染的ESLD的危险因素和预测因素可能与男性不同，应单独检查。为了开始解决这些问题，本提案有三个具体目标：1)确定HIV/ hcv合并感染男性中发生ESLD的危险因素；2)得出并内部验证一个临床预测指标，根据进展为ESLD的风险对HIV/ hcv合并感染男性进行分层；3)验证妇女跨机构HIV研究收集的临床、实验室和药房数据的特定组合识别HIV/ hcv合并感染女性ESLD的能力。具体目标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、前瞻性队列研究，在8个退伍军人管理局医疗中心对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地点的数据，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，该计划将对了解艾滋病毒感染男性中丙型肝炎病毒合并感染的自然历史和风险因素作出实质性贡献，并准备在今后对艾滋病毒感染女性中丙型肝炎病毒合并感染的自然历史作出类似贡献。

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.