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

描述(申请人提供)：与丙型肝炎(丙型肝炎)混合感染正成为美国艾滋病毒感染者死亡的主要原因。在吸毒者中，艾滋病毒/丙型肝炎病毒混合感染的比例为50%-90%。丙型肝炎病毒感染会导致肝纤维化、肝硬变、终末期肝病和肝细胞癌。目前对艾滋病毒/丙型肝炎病毒混合感染的治疗方法导致不到50%的患者持续抑制丙型肝炎病毒RNA和改善组织学。因此，由于很大一部分患者没有资格接受治疗，符合条件的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，需要采取其他逆转纤维化的方法。氧化应激参与了丙型肝炎肝损伤导致纤维化的发病机制，并伴随着血浆微量营养素抗氧化剂的减少。虽然许多研究证实在艾滋病毒和丙型肝炎病毒单一感染中存在氧化应激升高，但没有关于艾滋病毒/丙型肝炎病毒混合感染的数据。我们的初步数据表明，与HIV单一感染相比，HIV/丙型肝炎病毒混合感染患者的氧化应激增加和抗氧化状态降低，氧化应激增加并伴有更严重的纤维化。抗氧化剂补充的研究表明，在丙型肝炎病毒单一感染中，补充抗氧化剂减少了氧化应激，减少了星形细胞的激活，并抑制了肝纤维化的形成。由于缺乏艾滋病毒/丙型肝炎病毒混合感染的数据，在开始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年的跟踪调查，其中包括133名艾滋病毒/丙型肝炎病毒混合感染者和133名艾滋病毒单一感染者。如果在基线的初始肝活检中没有体征或早期纤维化，并且他们将在研究后4年内或临床表明尽快进行再次活检，则合并感染组将有资格参加研究。临床检查、病史和图表提取的实验室结果将记录HIV分期(CD4和病毒载量)的共病、ART和其他治疗。将获得关于人口统计学、BMI、食物摄入量和微量营养素补充剂使用的问卷，并将其视为协变量。年龄和ART将受到限制，与氧化应激相关的共病情况将在基线访问之前排除。将抽取血液进行代谢谱、完整血细胞计数、血浆抗氧化性微量营养素(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艾滋病毒/丙型肝炎合并感染和肝病进展的关系，为未来潜在的辅助治疗提供基础，以减少艾滋病毒/丙型肝炎混合感染患者的氧化应激，抑制或延缓纤维化形成。研究结果：在美国，丙型肝炎病毒合并感染正成为艾滋病毒感染患者的主要死亡原因。在吸毒者中，艾滋病毒/丙型肝炎病毒混合感染的比例为50%-90%。氧化应激参与了丙型肝炎肝损伤导致纤维化的发病机制，并伴随着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/丙型肝炎合并感染和肝病进展的关系，为未来可能的辅助治疗提供基础，以减少氧化应激，抑制或延缓HIV/丙型肝炎合并感染患者的纤维化形成。

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.