HIV and HIV/HCV-Infection, Disease Progression, Oxidative Stress and Antioxidants

描述（由申请人提供）：在美国，丙型肝炎（HCV）合并感染正在成为HIV感染患者死亡的主要原因。在吸毒者中，艾滋病毒/HCV合并感染的比例为50%-90%。丙型肝炎病毒感染会导致肝纤维化、肝硬化、终末期肝脏疾病和肝细胞癌。目前对HIV/HCV共感染的治疗在少于50%的患者中导致HCV-RNA的持续抑制和组织学改善。因此，由于大部分患者不适合治疗，合格患者对治疗缺乏反应（高达71%的患者）以及由于不良反应而停止治疗，因此需要其他方法来逆转纤维化。氧化应激参与导致丙型肝炎纤维化的肝损伤的发病机制，并伴有血浆微量营养素抗氧化剂的减少。虽然许多研究证实了HIV和HCV单一感染中存在氧化应激升高，但尚无HIV/HCV合并感染的数据。我们的初步数据表明，与HIV单一感染相比，HIV/HCV合并感染的氧化应激水平升高，抗氧化状态降低，氧化应激水平升高，纤维化程度更高。抗氧化剂补充剂的研究表明，补充减少氧化应激，减少星状细胞活化，并抑制HCV单感染的纤维化。由于缺乏HIV/HCV合并感染的数据，在进行临床试验之前需要进行观察性研究。我们建议对266名参与者进行为期4年的随访，其中133名HIV/HCV合并感染者和133名HIV单一感染者。如果合并感染组在基线时的初始肝活检时没有纤维化的体征或早期阶段，则他们将有资格参加研究，并且他们将在研究的4年内再次进行活检，或一旦有临床指征。临床检查和病史以及图表提取的实验室结果将记录HIV分期（CD 4和病毒载量）共病、ART和其他治疗。将获得关于人口统计学、BMI、食物摄入和微量营养素补充剂使用的资料，并将其作为协变量处理。将限制年龄和ART，并在基线访视前排除与氧化应激相关的共病。将抽取血液用于代谢特征、全血细胞计数、血浆抗氧化微量营养素（维生素A和E、1和2-胡萝卜素、锌和硒）和氧化应激（丙二醛[MDA]、还原型谷胱甘肽[GSH]和氧化型谷胱甘肽[GSSG]）。这项观察性研究旨在确定氧化应激和抗氧化状态与HIV/HCV合并感染和肝病进展之间的关系，为未来潜在的辅助治疗提供基础，以减少HIV/HCV合并感染患者的氧化应激和抑制或延迟纤维化发生。在吸毒者中，艾滋病毒/HCV合并感染的比例为50%-90%。氧化应激参与导致丙型肝炎纤维化的肝损伤的发病机制，并伴有血浆微量营养素抗氧化剂的减少。这项观察性研究旨在确定氧化应激和抗氧化状态与HIV/HCV合并感染和肝病进展的相关性，为未来可能的辅助治疗提供基础，以减少HIV/HCV合并感染患者的氧化应激，抑制或延迟纤维化。

DESCRIPTION (provided by applicant): Co-infection with Hepatitis C (HCV) is becoming the main cause of death in HIV-infected patients in the United States. Among drug users the proportion of HIV/HCV co-infection is 50%-90%. HCV infection leads to liver fibrosis, cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Current treatments for HIV/HCV co- infection result in a sustained suppression of HCV-RNA and histological improvement in less than 50% of the patients. Thus, other approaches to reversing fibrosis are needed due to ineligibility for treatment of a large proportion of patients, lack of response of eligible patients to treatment (up to 71% of patients) and discontinuation of treatment due to adverse effects. Oxidative stress is involved in the pathogenesis of hepatic damage leading to fibrosis in hepatitis C and is accompanied by decreased plasma micronutrient antioxidants. While many studies confirm the presence of elevated oxidative stress in HIV and in HCV mono-infections, no data are available for HIV/HCV co-infection. Our preliminary data indicate elevated oxidative stress and decreased antioxidant status in HIV/HCV co-infection compared to HIV mono-infection, and increased oxidative stress with more advanced fibrosis. Studies of antioxidant supplementation indicated that supplementation reduced oxidative stress, diminished stellate cell activation, and suppressed fibrogenesis in HCV mono-infection. Due to the lack of data in HIV/HCV co-infection, observational studies are needed prior to embarking on clinical trials. We propose to follow a cohort of 266 participants, 133 HIV/HCV co-infected and 133 HIV mono-infected, for 4 years. The co-infected group will be eligible for the study if they have no signs or early stage of fibrosis at their initial liver biopsy at baseline, and they will be biopsied again within 4 years of the study, or as soon as clinically indicated. Clinical examination and medical history and laboratory results from chart abstraction will document HIV staging (CD4 and viral load) co-morbidities, ART and other treatments. Questionnaires on demographics, BMI, food intake, and use of micronutrient supplements will be obtained and treated as covariates. Age and ART will be restricted, and co-morbid conditions which are associated with oxidative stress, will be excluded before the baseline visit. Blood will be drawn for metabolic profiles, complete blood count, plasma antioxidant micronutrients (vitamins A and E, 1 and 2-carotenes, zinc and selenium), and oxidative stress (malondialdehyde [MDA], reduced glutathione [GSH], and oxidized glutathione [GSSG]). This observational study is proposed to determine the association of oxidative stress and antioxidant status with HIV/HCV co-infection and progression of liver disease to provide the basis for potential future adjuvant therapies to reduce oxidative stress and suppress or delay fibrogenesis in HIV/HCV co- infected patients.NARRATIVE: Co-infection with Hepatitis C (HCV) is becoming the main cause of death in HIV-infected patients in the United States. Among drug users the proportion of HIV/HCV co-infection is 50%-90%. Oxidative stress is involved in the pathogenesis of hepatic damage leading to fibrosis in hepatitis C and is accompanied by decreased plasma micronutrient antioxidants. This observational study is proposed to determine the association of oxidative stress and antioxidant status with HIV/HCV co-infection and progression of liver disease to provide the basis for potential future adjuvant therapies to reduce oxidative stress and suppress or delay fibrogenesis in HIV/HCV co-infected patients.