Clevudine for chronic hepatitis B: antiviral response, predictors of response, and development of myopathy

Abstract

Clevudine has been approved for the treatment of chronic hepatitis B (CHB) in South Korea. However, its long-term antiviral effect and safety awaits more study. The aim of this study was to evaluate antiviral efficacy, predictors of virologic response, and development of myopathy after clevudine therapy for CHB. The study included 102 nucleoside naïve CHB patients who had received clevudine for more than 6 months with good compliance. The median duration of clevudine treatment was 53 weeks (range, 25-90 weeks). A retrospective analysis of data retrieved from medical records was performed. The cumulative rate of virologic response [hepatitis B virus (HBV) DNA level <2000 copies/mL] at 48 weeks of clevudine therapy was 81%, and cumulative rate of clevudine resistance was 11% at 60 weeks of treatment. Independent predictors of virologic response to clevudine therapy were hepatitis B e antigen (HBeAg) negativity and rapid decrease of viral load during the early phase of treatment. The clevudine-related myopathy developed in 3.9% of patients, and was reversible after discontinuation of clevudine. Clevudine showed a potent antiviral response, and its effect was higher in HBeAg-negative patients, with rapid viral load reduction after therapy. However, long-term therapy for more than 1 year resulted in the development of considerable resistance and myopathy. Therefore, we should consider alternative antiviral agents if clevudine resistance or clevudine-induced myopathy is developed in patients on clevudine for the treatment of CHB.

Noncompetitive Inhibition of Hepatitis B Virus Reverse Transcriptase Protein Priming and DNA Synthesis by the Nucleoside Analog Clevudine

“…These results suggest that compounds with properties similar to those of clevudine are good candidates for combination therapy with currently approved NRTIs for HBV therapy. Efforts to develop clevudine in the United States were abandoned due to drug-related myopathy that occurred in a minority of patients (33). However, identification and development of compounds derived from or similar to clevudine, which retain the novel anti-HBV activity but lack the toxicity, may be useful in combination with approved NRTIs.…”

“…is a recently introduced NRTI approved for treatment of chronic HBV infections in South Korea (31)(32)(33)(34). Clevudine has the unnatural L-configuration and, compared to other NRTIs, has the unique ability to maintain suppression of HBV replication for an extended period of time (for at least 24 weeks) following drug withdrawal (35,36).…”

A comparison of 48-week treatment efficacy between clevudine and entecavir in treatment-naïve patients with chronic hepatitis B

“…In this study, two patients (3.4%) complained about proximal muscular weakness with corresponding elevation of muscle enzyme at 48th week, which disappeared after cessation of clevudine. The incidence of clevudine-associated myopathy was reported variable as 2.9-14.6% and almost always resolved after discontinuation [10,13,15,[24][25][26]. Although development of myopathy has been reported in other nucleos(t)ides analogs as well, such as lamivudine, adefovir, and tenofovir, the causal relationship was not elucidated [27].…”

Clevudine-induced viral response, associated with continued reduction of HBsAg titer, was durable after the withdrawal of therapy

“…However, the Korean FDA approved continued marketing based on the idea that the risk of infrequent and reversible adverse events was not greater than the advantage of continuing clevudine. Currently, the incidence of clevudine-associated myopathy is reported to vary from 2.9 to 14.6% [23][24][25].…”