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

描述（由申请方提供）：长期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。核苷逆转录酶抑制剂（NRTI）与非NRTI和蛋白酶抑制剂的组合已被证明是抗HIV-1的抗逆转录病毒药物的有效性，尽管它们有充分描述的副作用，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损伤已被认为起着关键作用。抗逆转录病毒治疗（ART）引起的线粒体DNA损伤和氧化应激增加可能会因酗酒而加重，因为长期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。我们建议随访260名HIV感染的ART初治参与者的队列，65名正在开始ART并且是重度酒精使用者的患者（第1组），65名正在开始ART并且不饮酒或中度饮酒者的患者（第2组），65名处于HIV疾病早期并且没有开始ART并且是重度酒精使用者的患者（第3组），65例HIV早期疾病患者，未开始ART治疗，不饮酒或中度饮酒者（第4组），为期2年。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。在基线访视前，将限制ART，并排除与氧化应激相关的合并症。将抽取血液进行氧化应激（丙二醛指示脂质过氧化，蛋白质羰基指示蛋白质氧化，8-羟基鸟苷指示DNA氧化）。线粒体损伤将通过线粒体DNA含量的定量和定性变化以及血浆乳酸进行评估。将通过ALT、AST、血小板、白蛋白、透明质酸以及总胆红素和结合胆红素的血浆水平确定肝细胞损伤和功能。还将测定血浆抗氧化剂（谷胱甘肽、维生素A和E、1和2-胡萝卜素、锌和硒）。该提案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诱导的损伤。 公共卫生相关性：本提案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发生的氧化应激增加和营养缺乏对HIV相关线粒体DNA损伤的影响。更好地了解酒精对艾滋病毒和肝脏疾病的影响可能会增加戒酒干预措施的利用，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.