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

描述(申请人提供)：这项提案的总体目标是通过确定治疗艾滋病毒疾病的常用药物(已知的细胞色素P450(CyP450)诱导剂或抑制剂)与酒精(美国最常见的滥用物质)之间可能发生的重大相互作用，改善对感染艾滋病毒(HIV)的酒精患者的临床护理。我们假设，同时使用酒精和目前正在使用的高效抗逆转录病毒疗法(HAART)将与显著的药物相互作用有关，包括酒精和ARV药代动力学的改变以及对酒精给药的反应改变。某些作为HAART常见成分的ARV是CYP 450酶的诱导剂(例如：非核苷类逆转录酶抑制剂efavirenz)，而其他ARV则已知抑制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联合使用以延缓其代谢)。此外，众所周知，长期酗酒会诱导细胞色素P450酶，包括细胞色素P450 3A4，这可能进一步有助于潜在的肝毒性的那些维持在ARV。我们计划对四个研究样本(n=10)进行酒精和HAART给药研究：1.那些艾滋病毒/艾滋病患者或那些有资格接受含有EFAVERANZ的HAART的患者，2.那些艾滋病毒/艾滋病患者并有资格接受基于利托那韦增强型蛋白酶抑制剂的HAART，3.那些有资格接受含有EFNAVERZ的HAART的艾滋病毒/艾滋病患者，或4.有资格接受利托那韦增强型蛋白酶抑制疗法的患者。研究过程将包括酒精或安慰剂注射，然后是HAART感兴趣的酒精或安慰剂注射。药代动力学、主观和认知数据将在研究过程中连续收集。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。这些发现将提供直接适用于加强这一人群的临床护理的新的重要信息。 公共卫生相关性：艾滋病毒疾病中的肝脏毒性是常见的，可能与多种病因有关，包括先前存在的肝病、艾滋病毒/艾滋病治疗的毒性和/或与饮酒有关的毒性。在高达30%的艾滋病毒/艾滋病患者中，丙型肝炎并存，肝病现在是艾滋病毒患者的第二大最常见的死亡原因。这些事实突显了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的必要性。该项目将对酒精单独和与高效抗逆转录病毒疗法(HAART)联合应用于艾滋病毒/艾滋病、艾滋病毒/艾滋病和丙型肝炎患者的药物相互作用进行研究，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酒精与HAART同时使用的影响，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。拟议的研究将为临床治疗艾滋病毒/艾滋病、丙型肝炎和酗酒/滥用提供信息，从而改善临床结果并降低艾滋病毒传播的风险。

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.