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

酒精

• 批准号: 7590839
• 负责人: Marianna K Baum
• 金额: $ 34.59万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590839
• 关键词: 8-hydroxy-2' -deoxyguanosine; 8-hydroxyguanosine; Accounting; Adverse effects; Albumins; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcoholic liver damage; Alcoholism; Alcohols; Anti-Retroviral Agents; Antioxidants; Bilirubin; Blood; Blood Platelets; Blood specimen; CD4 Lymphocyte Count; Carotene; Cell Count; Characteristics; Chronic; Clinic; Clinic Visits; Clinical Trials; Condition; Consent; DNA; DNA Damage; Daily; Disease; Disease Progression; Drops; Eating; Effectiveness; Enrollment; Family; Fasting; Glutathione; HIV; HIV Infections; HIV-1; Hepatic; Hepatocellular Damage; Hepatotoxicity; Hyaluronic Acid; Injury; Intervention; Life; Lipid Peroxidation; Liver; Liver Dysfunction; Liver diseases; Longitudinal Studies; Malnutrition; Malondialdehyde; Mediating; Mental disorders; Micronutrients; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Nucleosides; Numbers; Obesity; Oxidative Stress; Participant; Pathology; Patients; Persons; Pharmaceutical Preparations; Plasma; Play; Ploidies; Preventive; Protease Inhibitor; Proteins; Public Health; Questionnaires; Recruitment Activity; Reverse Transcriptase Inhibitors; Role; Selenium; Severities; Staging; System; Testing; Therapeutic; Treatment outcome; Viral Load result; Visit; Vitamin A; Zinc; alcohol abstinence; alcohol effect; antiretroviral therapy; base; chronic alcohol ingestion; cohort; day; demographics; drinking; follow-up; improved; novel therapeutics; oxidation; prevent; problem drinker; transmission process; viral RNA

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.

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，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，已证明其作为抗逆转录病毒药物对抗 HIV-1 的有效性，尽管其副作用已广为人知，包括肝毒性。虽然这些副作用是多因素造成的，但氧化应激和线粒体 DNA 损伤被认为起着关键作用。酗酒可能会加剧抗逆转录病毒治疗 (ART) 产生的线粒体 DNA 损伤和氧化应激增加，因为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，从而导致酒精性肝损伤。我们建议对 260 名感染 HIV 的初次接受 ART 的参与者、65 名正在开始接受 ART 且酗酒的患者（第 1 组）、65 名正在接受 ART 且不饮酒或适度饮酒的患者（第 2 组）、65 名处于 HIV 疾病早期且未开始接受 ART 且酗酒的患者（第 3 组）、65 名处于 HIV 疾病早期且未开始接受 ART 的患者以及不 饮酒或适度饮酒者（第 4 组），持续 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的调查问卷，并将其视为协变量。 ART 将受到限制，并且在基线访视之前将排除与氧化应激相关的共病。抽取血液用于氧化应激（丙二醛用于指示脂质过氧化，蛋白质羰基用于蛋白质氧化，8-羟基鸟苷用于DNA氧化）。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线粒体损伤。肝细胞损伤和功能将通过血浆 ALT、AST、血小板、白蛋白、透明质酸以及总胆红素和结合胆红素的水平来确定。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，为保护肝脏免受酒精和抗逆转录病毒药物引起的损伤的潜在预防性治疗方法提供基础。 公共健康相关性：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，并确定长期酗酒可能导致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，并为保护肝脏免受酒精和抗逆转录病毒药物引起的肝损伤的潜在预防性治疗方法提供基础。