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

描述（由申请人提供）：本申请的总体目标是通过确定通常用于治疗HIV疾病的药物（已知的细胞色素P450 （CYP450）诱导剂或抑制剂）与酒精（美国最常滥用的物质）之间可能发生的显著相互作用，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）将与显著的药物相互作用有关，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的反应改变。某些ARV是HAART的常见成分，是CYP 450酶的诱导剂（例如：非核苷类逆转录酶抑制剂，依非韦伦），而其他已知的ARV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，已知慢性酒精滥用可诱导CYP450酶，包括cyp3a4，这可能进一步增加抗逆转录病毒治疗患者肝毒性的可能性。我们计划对四个研究样本（每个样本n=10）进行酒精和HAART给药研究：1 .感染艾滋病毒/艾滋病或符合含依非韦伦的HAART治疗条件者；2 . HIV/AIDS感染者和符合条件的基于利托那韦增强蛋白酶抑制剂的HAART治疗。艾滋病毒/艾滋病和丙型肝炎患者有资格接受含依非韦伦的HAART或4。符合利托那韦增强蛋白酶抑制剂方案。研究将包括酒精或安慰剂治疗，然后是酒精或安慰剂治疗和HAART治疗。药代动力学、主观和认知数据将在研究过程中依次收集。收集的数据将阐明这些人群中酒精和HAART药物相互作用的存在及其临床意义，包括药代动力学和药效学。这些发现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。

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.