Alcohol & Antiretrovirals in HIV Infection, Oxidative Stress and Liver Disease

描述（由申请人提供）：慢性饮酒与肝脏氧化应激增加和抗氧化防御降低有关，导致酒精性肝损伤。核苷逆转录酶抑制剂（NRTI）与非NRTI和蛋白酶抑制剂联合使用已证明它们作为抗HIV-1的抗逆转录病毒药物是有效的，尽管它们有很好的副作用，包括肝毒性。虽然这些副作用是多因素的，但氧化应激和线粒体DNA损伤被认为起着关键作用。抗逆转录病毒治疗（ART）产生的线粒体DNA损伤和氧化应激增加可能因酒精中毒而加重，因为慢性饮酒与肝脏氧化应激增加和抗氧化防御降低相关，导致酒精诱导的肝损伤。我们建议对260名初次接受抗逆转录病毒治疗的艾滋病毒感染者进行随访，其中65名患者正在开始接受抗逆转录病毒治疗，并且大量饮酒（第1组），65名患者正在开始接受抗逆转录病毒治疗，但不饮酒或适度饮酒（第2组），65名患者处于艾滋病毒早期，尚未开始接受抗逆转录病毒治疗，并且大量饮酒（第3组）。65名早期艾滋病毒患者，未开始抗逆转录病毒治疗，不饮酒或中度饮酒（第4组），为期2年。HIV分期（CD4和病毒载量）、合并症、ART和其他治疗将被记录。将获得有关人口统计、体重指数、食物摄入量和微量营养素补充剂使用情况的问卷，并将其作为协变量处理。抗逆转录病毒治疗将受到限制，与氧化应激相关的合并症将在基线访视前排除。抽血检测氧化应激（丙二醛检测脂质过氧化，蛋白质羰基检测蛋白质氧化，8-羟基鸟苷检测DNA氧化）。线粒体损伤将通过线粒体DNA含量和血浆乳酸的定量和定性变化来评估。肝细胞损伤和功能将通过血浆ALT、AST、血小板、白蛋白、透明质酸、总胆红素和结合胆红素水平来确定。血浆抗氧化剂（谷胱甘肽、维生素A和E、1和2-胡萝卜素、锌和硒）也将被测定。该建议将确定慢性饮酒和抗逆转录病毒治疗对氧化应激、抗氧化状态、线粒体毒性和肝功能障碍的综合影响，为潜在的预防性治疗方法提供基础，以保护肝脏免受酒精和抗逆转录病毒药物引起的损伤。

DESCRIPTION (provided by applicant): Chronic alcohol consumption is associated with increased hepatic oxidative stress and reduced antioxidant defense resulting in alcohol-induced liver injury. Nucleoside reverse transcriptase inhibitors (NRTI) in combination with non-NRTIs and protease inhibitors have demonstrated their effectiveness as antiretroviral drugs against HIV-1 despite their well-described side-effects, including liver toxicity. While these side-effects are multi-factorial, oxidative stress and mitochondrial DNA damage has been suggested to play a key role. Mitochondrial DNA damage and increased oxidative stress produced by antiretroviral treatment (ART) may be aggravated by alcoholism, as chronic alcohol consumption is associated with increased hepatic oxidative stress and reduced antioxidant defense resulting in alcohol-induced liver injury. We propose to follow a cohort of 260 HIV infected ART naive participants, 65 patients who are being initiated on ART and are heavy alcohol users (Group 1), 65 patients who are being initiated on ART and do not drink alcohol or are moderate alcohol drinkers (Group 2), 65 patients who are early in HIV disease and are not being initiated on ART and are heavy alcohol users (Group 3), 65 patients who are early in HIV disease and are not being initiated on ART and do not drink alcohol or are moderate alcohol drinkers (Group 4), for 2 years. HIV staging (CD4 and viral load) co- morbidities, ART and other treatments will be documented. Questionnaires on demographics, BMI, food intake, and use of micronutrient supplements will be obtained and treated as covariates. 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 oxidative stress (malondialdehyde to indicate lipid peroxidation, protein carbonyls for protein oxidation, 8-hydroxyguanosine for DNA oxidation). Mitochondrial damage will be assessed with quantitative and qualitative changes in mitochondrial DNA content and with plasma lactate. Hepatocellular injury and function will be determined with plasma levels of ALT, AST, platelets, albumin, hyaluronic acid and total and conjugated bilirubin. Plasma antioxidants (glutathione, vitamins A and E, 1 and 2-carotenes, zinc and selenium) will also be determined. This proposal will determine the combined effects of chronic alcohol consumption and antiretroviral therapy on oxidative stress, antioxidant status, mitochondrial toxicity and liver dysfunction to provide the basis for potential preventive therapeutic approaches to protect the liver from alcohol and antiretroviral drug induced injury. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to determine the combined effects of chronic alcohol consumption and antiretroviral therapy on oxidative stress, antioxidant status, mitochondrial toxicity and liver dysfunction, and to determine the effect of increased oxidative stress and nutritional deficiencies that might occur with chronic alcoholism on HIV-associated mitochondrial DNA damage. A better appreciation for alcohol's effects on HIV and liver disease may increase utilization of alcohol cessation interventions, thus improving treatment outcomes and providing the basis for potential preventive therapeutic approaches to protect liver from alcohol and antiretroviral drug-induced liver injury.