Interaction of Alcohol and HAART in HIV/AIDS and HIV/AIDS and HCV Coinfection

酒精与 HAART 在 HIV/AIDS 以及 HIV/AIDS 和 HCV 合并感染中的相互作用

• 批准号: 7589274
• 负责人: Elinore F. McCance-Katz
• 金额: $ 43.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589274
• 关键词: Address; Alcohol abuse; Alcohol consumption; Alcohols; Buprenorphine; Caring; Cause of Death; Chronic; Class; Clinical; Clinical Treatment; Cognitive; Condition; Cytochrome P450; Data; Dose; Drug Interactions; Drug Kinetics; Enzymes; Etiology; HIV; Hepatitis C; Hepatitis C virus; Hepatotoxicity; Highly Active Antiretroviral Therapy; Human Volunteers; Laboratories; Liver diseases; Medical; Metabolism; Methadone; Methadyl Acetate; Methods; Nucleosides; Opioid; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacodynamics; Physiological; Placebos; Population; Population Study; Protease Inhibitor; Public Health; Reverse Transcriptase Inhibitors; Risk; Ritonavir; Sample Size; Sampling Studies; Series; Therapeutic; Toxic effect; Treatment Protocols; United States; Virus Diseases; alcohol effect; alcohol response; antiretroviral therapy; base; clinically significant; efavirenz; experience; improved; inhibitor/antagonist; interest; non-nucleoside reverse transcriptase inhibitors; transmission process

DESCRIPTION (provided by applicant): The overall objective of this proposal is to improve the clinical care of human immunodeficiency virus (HIV)-infected, alcohol-using patients by identifying significant interactions which may occur between drugs commonly used to treat HIV disease known to be cytochrome P450 (CYP450) inducers or inhibitors and alcohol, the most frequently abused substance in the United States. We hypothesize that concomitant use of alcohol and currently utilized highly active antiretroviral therapy (HAART) will be associated with significant drug interactions including alteration of alcohol and ARV pharmacokinetics as well as altered responses to alcohol administration. Certain ARV that are frequent components of HAART are inducers of CYP 450 enzymes (e.g.: the non-nucleoside reverse transcriptase inhibitor, efavirenz), while others are known to inhibit CYP 450 enzyme function (e.g.: protease inhibitors; particularly ritonavir which is frequently co-administered with other protease inhibitors to delay their metabolism). Furthermore, chronic alcohol abuse is known to induce CYP450 enzymes, including CYP 3A4, which could contribute further to the potential for hepatotoxicity in those maintained on ARV. We plan to conduct alcohol and HAART administration studies to four study samples (n=10 each): 1.those with HIV/AIDS or and eligible for efavirenz-containing HAART, 2. those with HIV/AIDS and eligible for a ritonavir-boosted protease inhibitor based HAART, 3. those with HIV/AIDS and Hepatitis C eligible for an efavirenz-containing HAART or 4. eligible for a ritonavir-boosted protease inhibitor regimen. Study sessions will include alcohol or placebo administration followed by alcohol or placebo administration with the HAART of interest. Pharmacokinetics, subjective, and cognitive data will be serially collected over the course of the study sessions. Data collected will elucidate the presence and clinical significance of drug interactions, both pharmacokinetic and pharmacodynamic, between alcohol and HAART in these populations. These findings will provide new and important information directly applicable to enhancing the clinical care of this population. PUBLIC HEALTH RELEVANCE: Liver toxicity in HIV disease is a common occurrence and may be related to multiple etiologies including pre-existing liver disease, toxicities from treatment of HIV/AIDS and/or toxicity related to alcohol consumption. Co-occurrence of Hepatitis C is present in up to 30% of patients with HIV/AIDS and liver disease is now the second most common cause of death in those with HIV disease. These facts underscore the need to understand drug interactions that may occur between HIV therapeutics and alcohol. This project will undertake drug interaction studies of the effect of alcohol alone and in combination with highly active antiretroviral therapy (HAART) in those with HIV/AIDS and HIV/AIDS and Hepatitis C in order to illuminate the clinically significant pharmacokinetic and pharmacodynamic interactions that may occur. The urgent need to provide effective treatment to those with HIV/AIDS requires that we study the impact of concomitant use of alcohol with HAART which could potentially produce adverse drug interactions and/or alter the efficacy of these medications. The proposed studies will inform clinical treatment of comorbid HIV/AIDS, Hepatitis C and alcohol use/abuse leading to improved clinical outcomes and reduced risk of HIV transmission.

描述（由申请人提供）：该提案的总体目标是通过确定常用于治疗 HIV 疾病的药物（已知为细胞色素 P450 (CYP450) 诱导剂或抑制剂）与酒精（美国最常滥用的物质）之间可能发生的显着相互作用，来改善人类免疫缺陷病毒 (HIV) 感染、饮酒患者的临床护理。我们假设，同时使用酒精和目前使用的高效抗逆转录病毒疗法（HAART）将与显着的药物相互作用相关，包括酒精和抗逆转录病毒药代动力学的改变以及对酒精给药反应的改变。某些 ARV 是 HAART 的常见成分，是 CYP 450 酶的诱导剂（例如：非核苷逆转录酶抑制剂依非韦伦），而已知其他抗逆转录病毒药物会抑制 CYP 450 酶的功能（例如：蛋白酶抑制剂；特别是利托那韦，它经常与其他蛋白酶抑制剂共同给药以延缓其代谢）。此外，已知长期酗酒会诱导 CYP450 酶，包括 CYP3A4，这可能进一步增加服用抗逆转录病毒药物的患者潜在的肝毒性。我们计划对四个研究样本（每组 n=10）进行酒精和 HAART 给药研究： 1. HIV/AIDS 患者或有资格接受含依非韦伦 HAART 的患者，2. HIV/AIDS 患者且有资格接受基于利托那韦增强蛋白酶抑制剂的 HAART 的患者，3. HIV/AIDS 和丙型肝炎患者有资格接受含依非韦伦 HAART 的患者或 4. 适合接受利托那韦增强的蛋白酶抑制剂治疗方案。研究课程将包括酒精或安慰剂给药，然后是酒精或安慰剂给药以及感兴趣的HAART。将在研究过程中连续收集药代动力学、主观和认知数据。收集的数据将阐明这些人群中酒精和 HAART 之间药物相互作用（包括药代动力学和药效学）的存在及其临床意义。这些发现将提供直接适用于加强该人群临床护理的新的重要信息。 公共卫生相关性：HIV 疾病中的肝毒性很常见，可能与多种病因有关，包括既往存在的肝病、HIV/AIDS 治疗的毒性和/或与饮酒相关的毒性。高达 30% 的 HIV/AIDS 患者同时患有丙型肝炎，肝脏疾病目前是 HIV 患者第二大常见死因。这些事实强调需要了解艾滋病毒治疗药物和酒精之间可能发生的药物相互作用。该项目将开展药物相互作用研究，研究酒精单独使用以及与高效抗逆转录病毒疗法（HAART）联合使用对艾滋病毒/艾滋病、艾滋病毒/艾滋病和丙型肝炎患者的影响，以阐明可能发生的具有临床意义的药代动力学和药效学相互作用。为艾滋病毒/艾滋病患者提供有效治疗的迫切需要要求我们研究同时使用酒精和HAART的影响，这可能会产生不良的药物相互作用和/或改变这些药物的疗效。拟议的研究将为共病艾滋病毒/艾滋病、丙型肝炎和酗酒的临床治疗提供信息，从而改善临床结果并降低艾滋病毒传播的风险。