The Role of Alcohol in HIV Therapy Hepatotoxicity

酒精在 HIV 治疗中的作用 肝毒性

• 批准号: 8333731
• 负责人: SHIRISH S BARVE
• 金额: $ 0.76万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333731
• 关键词: Acetaminophen; Acquired Immunodeficiency Syndrome; Acute Liver Failure; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Anti-HIV Agents; Anti-HIV Therapy; Anti-Retroviral Agents; CD4 Positive T Lymphocytes; CYP2E1 gene; Cause of Death; Chronic; Clinical; Combination Drug Therapy; Communicable Diseases; Depressed mood; Development; Disease; Disease Progression; Drops; Drug Interactions; Enrollment; Enzymes; Fatty Liver; Functional disorder; Goals; Grant; HIV; HIV Infections; HIV therapy; Health; Hepatic; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocyte; Hepatotoxicity; Highly Active Antiretroviral Therapy; Histology; Human; Hypersensitivity; Immune; Immunosuppression; In Vitro; Incidence; Infection; Injury; Insulin Resistance; Lactic Acidosis; Life Expectancy; Lipodystrophy; Liver; Liver diseases; Lymphocyte Count; Lymphocyte Depletion; Lymphocyte Function; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Morbidity - disease rate; Mus; Nucleosides; Opportunistic Infections; Outcome; Oxidative Stress; Patients; Pharmaceutical Preparations; Pneumonia; Population; Predisposition; Production; Protease Inhibitor; Proteasome Inhibition; Proteins; Reaction; Reporting; Research; Reverse Transcriptase Inhibitors; Risk; Role; Screening procedure; Series; Severities; Simulate; Symptoms; TNF gene; Technology; Testing; Therapeutic Intervention; Time; Toxic effect; Tuberculosis; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Universities; Viral hepatitis; Work; World Health Organization; alcohol effect; base; cohort; cytokine; design; experience; feeding; high risk behavior; immune function; interest; killings; mitochondrial dysfunction; mortality; multicatalytic endopeptidase complex; non-nucleoside reverse transcriptase inhibitors; novel; prospective; public health relevance; reconstitution; translational approach

DESCRIPTION (provided by applicant): It is clear that alcohol abuse can alter/suppress immune function, including CD4 T-lymphocyte depletion, which can accelerate HIV progression. Subjects who consume alcohol may be more likely to develop certain infectious diseases which can complicate HIV, examples being various types of pneumonia and tuberculosis. Moreover, subjects who consume alcohol are more likely to participate in high-risk behaviors that increase the likelihood of acquiring HIV. Patients who consume alcohol also may be less compliant with their HIV therapy, which can affect disease progression. The research focus of this grant is the potential impact of alcohol use/abuse as a co-factor for HIV therapy-induced hepatotoxicity. Since the introduction of highly active antiretroviral therapy (HAART) in 1996, the life expectancy of patients with HIV has increased significantly. However, HAART is associated with significant hepatotoxicity. The severity of liver toxicity ranges from the absence of symptoms to liver decompensation, and the reported incidence of severe liver toxicity after initiating HAART ranges from 2% to 18%. The mechanisms involved in HAART-derived hepatotoxicity are not well understood, which makes its management more difficult. Some likely mechanisms of hepatotoxicity include proinflammatory cytokine production mitochondrial toxicity, hypersensitivity reactions, steatosis and insulin resistance, immune reconstitution in HCV or HBV co-infected patients, and proteasome inhibition (with dysregulated cytokine metabolism and mitochondrial and proteasome dysfunction serving as the focus of this proposal). The long-term goals of this study are to: (1) define mechanisms of hepatotoxicity induced by a combination of drug therapy and alcohol abuse in HIV patients and (2) discover potential therapeutic interventions for HAART hepatotoxicity, especially for patients in whom alcohol use/abuse may be a contributing factor. Specific Aims of this proposal are to: 1. Evaluate the potential hepatotoxic interactions of alcohol and HAART medications using rapid in vitro hepatocyte screening technology; 2. Determine the effects of anti- HIV drugs (selected agents based on preliminary toxicity studies from SO#1 and clinical hepatotoxicity risk), on the development and progression of hepatotoxicity in mice and the drug interactions with chronic alcohol intake; and 3. Evaluate in a human translational component: a) mitochondrial and proteasome function and ex vivo cytokine production in subsets of HIV patients, b) serial non-invasive measures of mitochondrial and proteasome function and cytokine production in patients who develop HAART hepatotoxicity, and c) liver histology findings including markers of proteasome and mitochondrial function, using a human translational approach from a cohort of HCV+HIV coinfected subjects enrolled in a prospective NIH study based at the University of Cincinnati. We postulate that the HAART and alcohol mediated metabolic complications of dysregulated proinflammatory cytokine production and mitochondrial and proteasome dysfunction converge on the liver in an overlapping fashion to induce hepatotoxicity. In this proposal, we test that hypothesis in a novel translational approach and we evaluate unique therapeutic interventions for this hepatotoxicity. PUBLIC HEALTH RELEVANCE: Alcohol abuse and HIV are important health problems. Liver disease is recognized as an increasingly important problem for the HIV population. Liver disease may be due to a variety of factors including co-infection with viral hepatitis, alcohol abuse, and antiretroviral hepatotoxicity. Liver disease is now a leading cause of death for patients with HIV. Hepatotoxicity due to HAART is also common, and up to 30% of patients on HAART experience World Health Organization grade 3 liver enzyme elevations. Furthermore, hepatotoxicity from antiretroviral drugs leads to adverse patient outcomes either from fulminant hepatic failure, or more commonly, AIDS following discontinuation of HAART. It is unknown why some, but not all HIV patients develop drug induced liver injury from HAART. Relevant to this proposal, alcohol/HAART interactions are emerging as critically important factors. Recent research has shown that alcohol abuse is associated with severe hepatotoxicity in patients on HAART. Importantly, alcoholic liver disease and HAART induced liver injury share many potential mechanisms of injury. These include cytokine dysregulation, mitochondrial dysfunction, and proteasomal dysfunction. Through these and other mechanisms, alcohol and antiretroviral medications converge on the liver in an overlapping fashion to produce hepatotoxicity. Here, we will study hepatotoxicity due to alcohol/HAART interactions to further define disease mechanisms and create therapeutic interventions.

描述（由申请人提供）：很明显，酒精滥用可以改变/抑制免疫功能，包括CD4 T淋巴细胞耗竭，可以加速HIV的进展。食用酒精的受试者可能更有可能患上某些可能使HIV复杂化的传染病，例如各种类型的肺炎和结核病。此外，食用酒精的受试者更有可能参与增加获取艾滋病毒可能性的高风险行为。食用酒精的患者也可能不符合其HIV疗法，这可能会影响疾病的进展。该赠款的研究重点是酒精使用/滥用作为艾滋病毒治疗引起的肝毒性的共同因素的潜在影响。自1996年引入高度活跃的抗逆转录病毒疗法（HAART）以来，HIV患者的预期寿命显着增加。但是，Haart与明显的肝毒性有关。肝脏毒性的严重程度从缺乏症状到肝脏代偿作用，以及启动HAART后严重肝毒性的发生率范围为2％至18％。 HAART衍生的肝毒性所涉及的机制尚不清楚，这使其管理更加困难。肝毒性的某些可能机制包括促炎性细胞因子生产线粒体毒性，超敏反应，脂肪变性和胰岛素抵抗，HCV或HBV共感染的患者的免疫重建患者的免疫重建，以及蛋白酶体抑制（蛋白酶体抑制作用） 提议）。这项研究的长期目标是：（1）定义艾滋病毒患者药物治疗和酗酒的肝毒性机制，以及（2）发现对HAART肝毒性的潜在治疗干预措施，尤其是对于那些可能是酗酒/滥用可能是促成因素的患者。该提案的具体目的是：1。使用快速的体外肝细胞筛选技术评估酒精和HAART药物的潜在肝毒性相互作用； 2。确定抗HIV药物（基于SO＃1的初步毒性研究和临床肝毒性风险的初步毒性研究）对小鼠肝毒性的发育和进展以及药物与慢性酒精摄入的药物相互作用的影响； and 3. Evaluate in a human translational component: a) mitochondrial and proteasome function and ex vivo cytokine production in subsets of HIV patients, b) serial non-invasive measures of mitochondrial and proteasome function and cytokine production in patients who develop HAART hepatotoxicity, and c) liver histology findings including markers of proteasome and mitochondrial function, using a human translational approach从辛辛那提大学的一项前瞻性NIH研究中入学的HCV+HIV共同感染的受试者中。我们假设HAART和酒精介导的促炎性细胞因子产生的代谢并发症以及线粒体和蛋白酶体功能障碍以重叠的方式在肝脏上融合，以诱导肝毒性。在此提案中，我们在一种新型的翻译方法中检验了该假设，并评估了这种肝毒性的独特治疗干预措施。 公共卫生相关性：酗酒和艾滋病毒是重要的健康问题。肝病被认为是艾滋病毒人群越来越重要的问题。肝病可能是由于多种因素引起的，包括与病毒性肝炎共同感染，酗酒和抗逆转录病毒肝毒性。肝病现在已成为HIV患者的主要死亡原因。由于HAART引起的肝毒性也很常见，HAART的患者中，最多30％的患者体验了世界卫生组织3级肝酶升高。此外，抗逆转录病毒药物的肝毒性会导致暴发性肝衰竭或更常见的HAART脱离HAART后的艾滋病。尚不清楚为什么有些但并非所有艾滋病毒患者都会出现药物引起的HAART诱导肝损伤。与该提案相关的是，酒精/HAART相互作用正在成为至关重要的因素。最近的研究表明，酗酒与HAART患者的严重肝毒性有关。重要的是，酒精性肝病和HAART诱导的肝损伤具有许多潜在的损伤机制。这些包括细胞因子失调，线粒体功能障碍和蛋白酶体功能障碍。通过这些和其他机制，酒精和抗逆转录病毒药物以重叠的方式在肝脏上汇聚，以产生肝毒性。在这里，由于酒精/HAART相互作用，我们将研究肝毒性，以进一步定义疾病机制并创建治疗性干预措施。