Special ArticleMyopathy and neuropathy associated with nucleos(t)ide analog therapy for hepatitis B☆
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.