Elsevier

Journal of Hepatology

Volume 51, Issue 4, October 2009, Pages 787-791
Journal of Hepatology

Special Article
Myopathy and neuropathy associated with nucleos(t)ide analog therapy for hepatitis B

https://doi.org/10.1016/j.jhep.2009.06.011Get rights and content

The development of clevudine as a treatment for hepatitis B was terminated recently because of case reports of myopathy. In each case, the onset of symptoms occurred between 8 and 13 months after the initiation of treatment. Electromyography and muscle biopsy confirmed the presence of myonecrosis. One report also found evidence of mitochondrial toxicity. The delayed onset and the finding of mitochondrial damage are reminiscent of fialuridine toxicity. Telbivudine has also been reported to be associated with myopathy and neuropathy, particularly when used in combination with pegylated interferon. These findings serve as a sober reminder of the lack of data on long-term safety of nucleos(t)ide analogs for hepatitis B, the importance of balancing benefits versus risks before initiating treatment, and the need for more stringent post-marketing surveillance for drug toxicities.

Introduction

On April 20, 2009 Pharmasset Inc. announced that after a discussion with its independent Data Safety Monitoring Board and the Food and Drug Administration (FDA), the company decided to voluntarily terminate its phase III QUASH studies of clevudine for the treatment of chronic hepatitis B virus (HBV) infection [Pharmasset Inc. press release April 20, 2009]. Pharmasset indicated that the company became aware of a number of spontaneous serious adverse event reports and events of special interest in patients receiving clevudine as prescribed therapy for hepatitis B in South Korea. Although it is too early to know the full extent of the problem, at least 10 cases of myopathy have been reported in the QUASH studies with most cases having an onset of symptoms after roughly 1 year of therapy [personal communications, Michelle Berrey, Pharmasset Inc.]. A much larger number of cases have been reported to Bukwang (the company that markets clevudine in South Korea) from post-marketing surveillance studies as well as spontaneous reports submitted by physicians and consumers in South Korea where clevudine was approved in 2006 [personal communications, Michelle Berrey, Pharmasset Inc.]. While these reports are not available, two publications shed light on the onset, clinical manifestations, reversibility, and possible mechanisms of clevudine myopathy.

Section snippets

Clinical case reports

In this issue of the Journal, Kim et al. reported two patients developed muscle weakness of the legs after 11 and 12 months of clevudine therapy for hepatitis B [1]. Both patients had elevation in creatine kinase (CK) levels, electromyography (EMG) changes of myopathy and muscle biopsy findings of degenerating and necrotic myofibers infiltrated by macrophages. One patient had resolution of symptoms 1 month after clevudine withdrawal while the other patient had improvement in symptoms 2 months

Telbivudine

Myopathy and neuropathy have been reported in patients who received telbivudine treatment. In the worldwide phase III GLOBE trial, grade 3 or 4 elevation in CK levels was observed in 88 of 680 (12.9%) patients who received telbivudine and in 28 of 687 (4.1%) patients who received lamivudine for 104 weeks (p < 0.001) [21]. Myopathy, characterized by muscle pain and weakness and moderately elevated CK levels during treatment, was reported in 2 patients, both of whom had resolution of symptoms after

Long-term safety of nucleos(t)ide analog treatment for hepatitis B

The approval of 5 orally administered, well tolerated nucleos(t)ide analogs for hepatitis B in the past 10 years has stimulated enthusiasm for expanding the indications for treatment of hepatitis B. Some experts have argued that treatment should be initiated based on high serum HBV DNA levels alone and that treatment should be continued indefinitely to avoid post-treatment relapse or reactivation of hepatitis B. The withdrawal of clevudine from development is a sober reminder that while the

Monitoring of toxicities during drug development

The unfortunate situation with clevudine is a reminder of the difficulties in predicting drug-related adverse events. Although each new drug has to be rigorously tested in in-vitro and in animal toxicity studies, the ability of preclinical studies to predict toxicities in humans, particularly rare or idiosyncratic events, is low. Preclinical or phase I/II clinical studies may identify safety signals leading to the incorporation of monitoring and management plans in phase III trials that may

Conclusion

Substantial progress has been made in the treatment of hepatitis B in the past decade. The availability of well tolerated orally administered nucleos(t)ide analogs has prompted many experts to recommend expansion of treatment to patients with quiescent or minimally active liver disease. The case of clevudine myopathy is a sober reminder that the decision to initiate treatment should balance benefits against risks. Although the drug approval process is rigorous, toxicities may not be detected

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    R.D.F. declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. A.S.F.L. receives research support from Bristol-Myers Squibb, GlaxoSmithKline, Schering, Novartis and Gilead and serves as an advisor for Gilead, Pharamasset, Schering and Roche.

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