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

酒精

• 批准号: 8080463
• 负责人: Marianna K Baum
• 金额: $ 51.22万
• 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/8080463
• 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; Comorbidity; Consent; DNA; DNA Damage; 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; Nucleosides; Obesity; Oxidative Stress; Participant; Pathology; Patients; Persons; Pharmaceutical Preparations; Plasma; Play; Ploidies; Preventive; Protease Inhibitor; Proteins; Questionnaires; RNA; Recruitment Activity; Reverse Transcriptase Inhibitors; Selenium; Severities; Staging; System; Testing; Therapeutic; Toxic effect; Treatment outcome; Viral Load result; Visit; Vitamin A; Zinc; alcohol abstinence; alcohol effect; antiretroviral therapy; base; chronic alcohol ingestion; cohort; demographics; drinking; follow-up; improved; novel therapeutics; oxidation; oxidative damage; prevent; problem drinker; public health relevance; transmission process

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）：慢性酒精消耗与肝氧化应激增加和抗氧化剂防御减少有关，从而导致酒精引起的肝损伤。核苷逆转录酶抑制剂（NRTI）与非NRTIS和蛋白酶抑制剂结合使用，尽管其描述良好的副作用，包括肝毒性，但它们作为针对HIV-1的抗逆转录病毒药物的有效性。尽管这些副作用是多因素的，但已建议氧化应激和线粒体DNA损伤起关键作用。酒精中毒可能会加剧线粒体DNA损伤和抗逆转录病毒治疗（ART）产生的氧化应激（ART），因为慢性酒精消耗与肝氧化应激的增加有关，抗氧化剂减少了抗氧化剂防御，导致酒精诱导的肝损伤。我们建议遵循由260名HIV感染的ART参与者组成的同类，有65名患者是在艺术上发起的，是重型酒精使用者（第1组），有65名患者是在艺术上发起的，不喝酒或中度饮酒者或中度饮酒者（第2组），在HIV疾病中且不在Art and Art和65例患者（65例）中（65例），而不是Art和65患者（65例），而不是65例，而不是65例（65例）。喝酒或中度饮酒者（第4组），持续2年。将记录HIV分期（CD4和病毒载荷）共同病毒，ART和其他治疗方法。将获取有关人口统计，BMI，食物摄入量以及微量营养补充剂的使用问卷，并将其视为协变量。将受到限制，并在基线访问之前排除与氧化应激相关的合并条件。血液将用于氧化应激（丙二醛表明脂质过氧化，蛋白羰基用于蛋白质氧化，8-羟基鸟苷用于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进行评估。肝细胞损伤和功能将由血浆，AST，血小板，白蛋白，透明质酸以及总和共轭胆红素的血浆水平确定。还将确定血浆抗氧化剂（谷胱甘肽，维生素A和E，1和2-偶然，锌和硒）。该提案将确定慢性酒精消耗和抗逆转录病毒疗法对氧化应激，抗氧化剂状态，线粒体毒性和肝功能障碍的综合作用，为潜在的预防性治疗方法提供了保护肝脏免受酒精和抗雷神病毒药物诱导损伤的基础。 公共卫生相关性：该提案的目的是确定慢性酒精消耗和抗逆转录病毒治疗对氧化应激，抗氧化剂状态，线粒体毒性和肝功能障碍的综合作用，并确定氧化应激和营养不足的氧化应激和营养缺乏症的影响。对酒精对艾滋病毒和肝病的影响的更好欣赏可能会增加对酒精停止干预措施的利用，从而改善治疗结果，并为潜在的预防性治疗方法提供了保护肝脏免受酒精和抗逆转录病毒药物诱导的肝损伤的基础。