Seok Jung Im, Lee Dong Kuck, Lee Chang Hyeong, Park Min Su, Kim Sun Young, Kim Hyang-Sook, Jo Hee-Young, Lee Chang Hun, Kim Dae-Seong
Department of Neurology, School of Medicine, Catholic University of Daegu, Daegu, South Korea.
Hepatology. 2009 Jun;49(6):2080-6. doi: 10.1002/hep.22959.
Clevudine (Revovir), a pyrimidine nucleoside analogue, is a recently introduced antiviral drug. Clinical trials have demonstrated potent, sustained antiviral activity against hepatitis B virus without specific adverse events. The lack of cytotoxicity and absence of an effect on mitochondrial function have been considered the reasons for the fewer adverse events. However, it came to our attention that several hepatitis B patients developed myopathy during clevudine therapy. Our study was aimed to analyze the clinical and pathological features of patients with clevudine-induced myopathy with some consideration of its pathogenetic mechanism. Seven hepatitis B patients who developed severe skeletal myopathy during clevudine therapy were examined in this study. The demographic data, clinical features, pathological findings, and molecular studies of these patients were analyzed with speculation about the underlying pathogenic mechanisms. All seven patients were treated with clevudine for more than 8 months (8-13 months). In all, the main symptom was slowly progressive proximal muscular weakness over several months. A markedly elevated creatine kinase level and myopathic patterns on electromyography were found. Muscle biopsies revealed severe myonecrosis associated with numerous ragged red fibers, cytochrome c oxidase-negative fibers, and predominant type II fiber atrophy. Molecular studies using quantitative polymerase chain reaction showed a depletion of the mitochondrial DNA in the patients' skeletal muscle.
To the best of our knowledge, this is the first report of myopathy associated with clevudine therapy. This study has clearly shown that long-term clevudine therapy can induce the depletion of mitochondrial DNA and lead to mitochondrial myopathy associated with myonecrosis. Careful clinical and laboratory attention should be paid to patients on long-term clevudine therapy for this skeletal muscle dysfunction.
克来夫定（Revovir），一种嘧啶核苷类似物，是最近引入的一种抗病毒药物。临床试验已证明其对乙型肝炎病毒具有强效、持续的抗病毒活性，且无特定不良事件。缺乏细胞毒性以及对线粒体功能无影响被认为是不良事件较少的原因。然而，我们注意到有几位乙型肝炎患者在克来夫定治疗期间出现了肌病。我们的研究旨在分析克来夫定诱导的肌病患者的临床和病理特征，并对其发病机制进行一些探讨。本研究检查了7例在克来夫定治疗期间出现严重骨骼肌病的乙型肝炎患者。分析了这些患者的人口统计学数据、临床特征、病理结果和分子研究，并推测了潜在的致病机制。所有7例患者均接受克来夫定治疗超过8个月（8 - 13个月）。总体而言，主要症状是数月来缓慢进展的近端肌肉无力。发现肌酸激酶水平显著升高，肌电图显示肌病模式。肌肉活检显示严重的肌坏死，伴有大量破碎红纤维、细胞色素c氧化酶阴性纤维以及主要的II型纤维萎缩。使用定量聚合酶链反应的分子研究表明患者骨骼肌中线粒体DNA减少。
据我们所知，这是关于克来夫定治疗相关肌病的首次报告。本研究清楚地表明，长期克来夫定治疗可导致线粒体DNA减少，并导致与肌坏死相关的线粒体肌病。对于接受长期克来夫定治疗的患者，应密切关注其骨骼肌功能障碍，进行仔细的临床和实验室检查。
