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: 8186519
• 负责人: Elinore F. McCance-Katz
• 金额: $ 15.15万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8186519
• 关键词: Acquired Immunodeficiency Syndrome; Address; Alcohol abuse; Alcohol consumption; Alcohols; Buprenorphine; Cause of Death; Chronic; Clinical; Clinical Treatment; Cognitive; 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; Regimen; Reverse Transcriptase Inhibitors; Risk; Ritonavir; Sample Size; Sampling Studies; Series; Therapeutic; Toxic effect; United States; Virus Diseases; alcohol effect; alcohol response; base; clinical care; clinically significant; efavirenz; effective therapy; experience; improved; inhibitor/antagonist; interest; non-nucleoside reverse transcriptase inhibitors; public health relevance; 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（由申请方提供）：本提案的总体目标是通过确定通常用于治疗HIV疾病的药物（已知为细胞色素P450（CYP 450）诱导剂或抑制剂）与酒精（美国最常滥用的物质）之间可能发生的显著相互作用，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，酒精和目前使用的高效抗逆转录病毒治疗（HAART）的伴随使用将与显着的药物相互作用，包括酒精和ARV药代动力学的改变，以及改变对酒精管理的反应。作为HAART的常见组分的某些ARV是HAART 450酶的诱导剂（例如：非核苷类逆转录酶抑制剂，依法韦仑），而其它已知的药物可抑制β 450酶功能（例如：蛋白酶抑制剂;特别是利托那韦，其经常与其它蛋白酶抑制剂共同施用以延迟它们的代谢）。此外，已知慢性酒精滥用会诱导CYP 450酶，包括CYP 3A 4，这可能进一步导致接受ARV治疗的患者出现肝毒性。我们计划对4个研究样本（每组10例）进行酒精和HAART给药研究：1. HIV/AIDS患者或符合含依法韦仑HAART治疗条件的患者，2.那些患有HIV/AIDS并符合利托那韦增强的蛋白酶抑制剂为基础的HAART的患者，3.有资格接受含依法韦仑的HAART的HIV/AIDS和丙型肝炎患者或4.符合利托那韦增强的蛋白酶抑制剂方案。研究阶段将包括酒精或安慰剂给药，随后是酒精或安慰剂给药和感兴趣的HAART。将在研究期间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之间药物相互作用的存在和临床意义，包括药代动力学和药效学。这些研究结果将提供新的和重要的信息，直接适用于加强这一人群的临床护理。 公共卫生相关性：HIV疾病中的肝毒性是常见的，可能与多种病因有关，包括既存肝病、HIV/AIDS治疗的毒性和/或与饮酒有关的毒性。高达30%的艾滋病毒/艾滋病患者同时患有丙型肝炎，肝病现在是艾滋病毒感染者死亡的第二大常见原因。这些事实强调需要了解HIV治疗剂和酒精之间可能发生的药物相互作用。本项目将在HIV/AIDS和HIV/AIDS和丙型肝炎患者中进行单独酒精和与高效抗逆转录病毒疗法（HAART）联合的药物相互作用研究，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。迫切需要提供有效的治疗，以那些与艾滋病毒/艾滋病要求我们研究的影响，同时使用酒精与HAART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。拟议的研究将为艾滋病毒/艾滋病、丙型肝炎和酒精使用/滥用共病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。