Hepatitis C Virus Infection Influences the S-Methadone Metabolite Plasma Concentration

Background and ObjectivesHeroin-dependent patients typically contract hepatitis C virus (HCV) at a disproportionately high level due to needle exchange. The liver is the primary target organ of HCV infection and also the main organ responsible for drug metabolism. Methadone maintenance treatment (MMT) is a major treatment regimen for opioid dependence. HCV infection may affect methadone metabolism but this has rarely been studied. In our current study, we aimed to test the hypothesis that HCV may influence the methadone dosage and its plasma metabolite concentrations in a MMT cohort from Taiwan.MethodsA total of 366 MMT patients were recruited. The levels of plasma hepatitis B virus (HBV), HCV, human immunodeficiency virus (HIV) antibodies (Ab), liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were measured along with the urine morphine concentration and amphetamine screening.ResultsOf the 352 subjects in our cohort with HCV test records, 95% were found to be positive for plasma anti-HCV antibody. The liver functional parameters of AST (Wilcoxon Rank-Sum test, P = 0.02) and ALT (Wilcoxon Rank-Sum test, P = 0.04), the plasma methadone concentrations (Wilcoxon Rank-Sum test, P = 0.043) and the R-enantiomer of methadone concentrations (Wilcoxon Rank-Sum test, P = 0.032) were significantly higher in the HCV antibody-positive subjects than in the HCV antibody-negative patients, but not the S-EDDP/methadone dose ratio. The HCV levels correlated with the methadone dose ( = 14.65 and 14.13; P = 0.029 and 0.03) and the S-EDDP/methadone dose ratio ( = −0.41 and −0.40; P = 0.00084 and 0.002) in both univariate and multivariate regression analyses.ConclusionsWe conclude that HCV may influence the methadone dose and plasma S-EDDP/methadone dose ratio in MMT patients in this preliminary study.研究背景与研究目的 海洛因依赖患者因共用针具（针具交换）感染丙型肝炎病毒（HCV）的比例显著偏高。肝脏是HCV感染的主要靶器官，同时也是药物代谢的核心器官。美沙酮维持治疗（MMT）是阿片类药物依赖的主要治疗方案。HCV感染可能影响美沙酮代谢，但相关研究尚少。本研究旨在验证这一假说：在台湾的美沙酮维持治疗队列中，HCV可能影响美沙酮剂量及其血浆代谢物浓度。 研究方法 本研究共招募366名美沙酮维持治疗患者。检测了受试者血浆乙型肝炎病毒（HBV）、HCV、人类免疫缺陷病毒（HIV）抗体（Ab）水平，肝脏天冬氨酸氨基转移酶（AST）与丙氨酸氨基转移酶（ALT）水平，美沙酮及其代谢物2-亚乙基-1,5-二甲基-3,3-二苯基吡咯烷（EDDP）水平，同时检测了尿吗啡浓度并进行苯丙胺筛查。 研究结果 本队列中共有352名受试者拥有HCV检测记录，其中95%的血浆抗HCV抗体呈阳性。抗HCV抗体阳性受试者的肝脏功能指标AST（威尔科克森秩和检验（Wilcoxon Rank-Sum test），P=0.02）、ALT（威尔科克森秩和检验（Wilcoxon Rank-Sum test），P=0.04）、血浆美沙酮浓度（威尔科克森秩和检验（Wilcoxon Rank-Sum test），P=0.043）以及美沙酮R对映体（R-enantiomer）浓度（威尔科克森秩和检验（Wilcoxon Rank-Sum test），P=0.032）均显著高于抗HCV抗体阴性患者，而S-EDDP/美沙酮剂量比则无此组间差异。在单因素回归分析（univariate regression analysis）与多因素回归分析（multivariate regression analysis）中，HCV水平与美沙酮剂量（标准化回归系数分别为14.65、14.13；P值分别为0.029、0.03）及S-EDDP/美沙酮剂量比（标准化回归系数分别为-0.41、-0.40；P值分别为0.00084、0.002）显著相关。 研究结论 本初步研究结果表明，HCV可能影响美沙酮维持治疗患者的美沙酮剂量及血浆S-EDDP/美沙酮剂量比。