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

描述(由申请人提供)：长期饮酒与肝脏氧化应激增加和抗氧化防御能力降低有关，从而导致酒精诱导的肝损伤。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有效，尽管它们有众所周知的副作用，包括肝脏毒性。虽然这些副作用是多因素的，但氧化应激和线粒体DNA损伤被认为发挥了关键作用。酒精中毒可能会加重抗逆转录病毒治疗(ART)所产生的线粒体DNA损伤和氧化应激增加，因为长期饮酒与肝脏氧化应激增加和抗氧化防御降低有关，从而导致酒精诱导的肝损伤。我们建议跟踪一组260名HIV感染的ART幼稚参与者，65名接受ART治疗的重度酒精使用者(第1组)，65名开始ART治疗但不饮酒或中度饮酒的患者(第2组)，65名HIV疾病早期未开始ART且大量饮酒的患者(第3组)，65名HIV疾病早期未开始ART且不饮酒或中度饮酒的患者(第4组)，为期2年。HIV分期(CD4和病毒载量)共病、抗逆转录病毒治疗和其他治疗将被记录在案。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。抗逆转录病毒治疗将受到限制，与氧化应激相关的共病情况将在基线检查之前排除。将抽取血液进行氧化应激(丙二醛表示脂质过氧化，蛋白质羰基表示蛋白质氧化，8-羟基鸟苷表示DNA氧化)。线粒体损伤将通过线粒体DNA含量和血浆乳酸的数量和质量变化来评估。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)也将被检测。这项建议将确定长期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联合影响，为保护肝脏免受酒精和抗逆转录病毒药物损伤的潜在预防性治疗方法提供基础。 公共卫生相关性：这项建议的目的是确定长期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，并确定慢性酒精中毒可能导致的氧化应激增加和营养不足对艾滋病毒相关线粒体DNA损伤的影响。更好地认识酒精对艾滋病毒和肝病的影响可能会增加戒酒干预措施的使用，从而改善治疗结果，并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肝损伤。

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.