Long-term therapy with clevudine for chronic hepatitis B can be associated with myopathy characterized by depletion of mitochondrial DNA

Abstract

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 clevudineinduced 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. Conclusion: 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. (HEPATOLOGY 2009; 49:2080-2086 H epatitis B virus (HBV) is the leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. As carriers of HBV serve as reservoirs for vertical and horizontal transmissions, the prevalence of carriers and the number of acute and chronic liver diseases place HBV infection among the most frequent and important transmissible diseases of the hepatobiliary system. Appropriate therapeutic agents are required in order to prevent its irreversible sequelae.Currently, the use of oral antiviral drugs is considered a milestone of chronic hepatitis B therapy. The majority of these are nucleoside and nucleotide analogues that interfere primarily with viral replication by inhibition of the viral DNA polymerase. However, their therapeutic effects are limited because of the development of drug resistance, 1,2 relapse following cessation of treatment, 3,4 and possible toxicity. 5 Mitochondrial cytotoxicity is a wellknown side effect of nucleoside analogues and is most frequently associated with therapy using nucleoside re-

Mitochondrial myopathies caused by prolonged use of telbivudine

“…5,6,9,10 And our study shows that telbivudine is not an exception from antiviral-induced mitochondrial toxicity. This nucleoside analogue-related cellular toxicity is related to decreased mtDNA content (Fig.…”

“…3,4 Previous pathological studies have shown that the myopathy associated with nucleoside/nucleotide analogues is mostly due to the mitochondrial toxicity. 5,6 However, previous pathological reports on telbivudine-induced myopathy did not clearly reveal the evidence of mitochondrial toxicity. 7,8 Here, we showed that the myopathy induced by prolonged use of telbivudine is a mitochondrial myopathy caused by disturbed replication of mitochondrial DNA.…”

“…Genomic DNA was isolated from frozen skeletal muscles as previously described. 5 Information on the primer sequences for target and reference amplifications, and compositions and reactions of Q-PCR are available on request. After the 50 cycles, a melting curve analysis (55-95°C) was performed to confirm product specificity.…”

Clinical and Virological Responses to Clevudine Therapy of Hepatocelluar Carcinoma Patients with Chronic Hepatitis B

“…9,12,13,24,25 However, severa l hepatitis B patients develop myopathy during long-term clevudine therapy. 26,27 Moreover, long-term clevudine therapy induces depletion of mitochondrial DNA and leads to mitochondrial myopathy associated with myonecrosis. 26 In our study, one CHI/HCC (1.9%) patient discontinued clevudine treatment due to symptomatic myopathy.…”

“…26,27 Moreover, long-term clevudine therapy induces depletion of mitochondrial DNA and leads to mitochondrial myopathy associated with myonecrosis. 26 In our study, one CHI/HCC (1.9%) patient discontinued clevudine treatment due to symptomatic myopathy. His clinical symptoms subsequently improved after clevudine withdrawal, and no residual symptoms remained.…”