(PQ4)HIV and Aging Mechanisms for Hepatocellular Cancer

 描述（由申请人提供）：肝细胞癌（HCC）在HIV（HIV+）老年人中越来越常见。与未感染者相比，HIV+患者患HCC的风险增加了4倍。随着HIV+患者年龄的增长，HCC相关死亡率预计会随着时间的推移而增加. 尽管HCC对HIV死亡率的影响越来越大，但与老年HIV+患者发生这种恶性肿瘤相关的因素仍然未知。在HIV+患者中进行的HCC研究受到以下限制：HCC病例数量少、随访时间短、纳入人口统计学上不同的未感染对照品、缺乏纳入HCC的传统危险因素以及对HIV+患者的普遍性的担忧。该提案将通过合并超过15年的来自退伍军人老龄化队列研究（VACS）中HIV+和人口统计学上相似的未感染患者的电子病历数据（VACS是北美最大的HIV队列），以及来自这些人的HCC组织标本，来解决这些知识差距和现有限制。 HCC代表了一种理想的模型，可用于探索本RFA的挑衅性问题4，并获得对“ART背景下长期HIV感染、衰老的一般病理过程和偶发癌症之间的相互作用”的可推广见解。在这项应用中，我们将使用VACS的独特数据进行一系列流行病学和病理学分析，以发现艾滋病毒感染的衰老特异性因素（例如，免疫缺陷/激活、慢性HIV-1 RNA暴露、肝毒性抗逆转录病毒药物）与一般人群中与肝损伤相关的病症相互作用（例如，多药治疗、肥胖、糖尿病、饮酒、病毒性肝炎）以促进HCC的发展。我们将描述与HCC的关联在多大程度上完全通过晚期纤维化/肝硬化介导或与HCC直接相关。我们还将确定HIV阳性和未感染HCC患者之间HCC肿瘤和实质组织的重要病理学差异。 目的1将评估与多药治疗相关的HCC风险，以及在接受ART的HIV+患者中当前/累积使用已知肝毒性的抗逆转录病毒药物，并确定这些药物如何改变HCC组织学。目标2将检查在考虑传统的HCC风险因素（例如，病毒性肝炎、酒精）。最后，在目标3中，我们将评估其他HIV+和未感染者，以确定肥胖和糖尿病是否与肝脂肪变性、炎症和纤维化的风险有不同的相关性。 HCC或改变HCC组织学不同。这些目标的完成将为衰老生物学和HIV如何相互作用以促进HCC提供有价值的信息。这些结果也将为未来的干预措施提供信息，以降低肝癌的发病率。

 DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is increasingly common among those aging with HIV (HIV+). Compared with uninfected persons, HIV+ patients have a 4-fold increased risk of HCC. As HIV+ patients continue to age, HCC- related mortality is expected to increase over time. Despite the increasing impact of HCC on mortality in HIV, the factors associated with the development of this malignancy in aging HIV+ patients remain unknown. Studies of HCC in HIV+ patients have been limited by small numbers of HCC cases, short follow-up, inclusion of demographically different uninfected comparators, lack of inclusion of traditional risk factors for HCC, and concerns about generalizability to HIV+ patients. This proposal will address these knowledge gaps and existing limitations by merging over 15 years of electronic medical record data from HIV+ and demographically similar uninfected patients in the Veterans Aging Cohort Study (VACS), the largest HIV cohort in North America, with HCC tissue specimens from these individuals. HCC represents an ideal model with which to explore Provocative Question 4 of this RFA and gain generalizable insights into the "interplay between long-term HIV infection in the context of ART, general pathological processes of aging, and incident cancer. In this application, we will use the unique data of the VACS to conduct a series of epidemiologic and pathologic analyses to discover how factors specific to aging with HIV infection (e.g., immune deficiency/activation, chronic HIV-1 RNA exposure, hepatotoxic antiretrovirals) interact with conditions associated with liver injury in the general population (eg., polypharmacy, obesity, diabetes, alcohol use, viral hepatitis) to promote development of HCC. We will characterize the extent to which associations with HCC are mediated exclusively through advanced fibrosis/cirrhosis or have direct associations with HCC. We will also determine important pathologic differences in HCC tumor and parenchymal tissue between HIV+ and uninfected patients with HCC. Aim 1 will evaluate the risk of HCC associated with polypharmacy and current/cumulative use of antiretroviral drugs with known hepatotoxic potential among HIV+ patients on ART and determine how these alter HCC histology. Aim 2 will examine if cumulative exposure to immune deficiency, immune activation, and HIV viremia increase risk of HCC or alter HCC histology among HIV+ patients on ART, after accounting for traditional HCC risk factors (e.g., viral hepatitis, alcohol). Finally, in Aim 3, we will evaluate oth HIV+ and uninfected persons to determine if obesity and diabetes mellitus, which can each promote hepatic steatosis, inflammation, and fibrosis, have a differential association with risk of HCC or alter HCC histology differently. The completion of these Aims will provide valuable information on how the biology of aging and HIV interact to promote HCC. These results will also inform future interventions to decrease the incidence of liver cancer.