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Background/aims: Clevudine is a potent antiviral agent against HBV. However, long-term clevudine therapy may cause myopathy. This study was carried out to identify the efficacy of entecavir switching therapy in chronic hepatitis B patients experiencing clevudine-induced myopathy., Methods: One hundred forty six patients with chronic hepatitis B treated with 30 mg of clevudine per day for 73 weeks (range, 36-132 weeks) were enrolled. Among them, clevudine-induced myopathy occurred in 21 patients (14.4%) which was diagnosed if the patients had symptoms related to myopathy with concurrent CK and AST elevation. All the patients who were diagnosed as clevudine-induced myopathy stopped the therapy, and 17 patients (81%) were switched to entecavir 0.5 mg., Results: The patients with clevudine-induced myopathy were switched to entecavir 0.5 mg for median 68 weeks, and all of them showed disappearance of clinical myopathic symptoms and normalization of CK and AST level within median 2.2 months. Eight patients (47%) were HBeAg positive before entecavir treatment, and HBeAg seroconversion was achieved in 2 patients (25%). HBV DNA level was elevated in 3 patients (17.6%) at the time when the patients were diagnosed as myopathy, all of them achieved virological response with entecavir switching therapy. ALT level was elevated in 3 patients (17.6%) before entecavir treatment, all of them showed normalization of ALT level. During entecavir therapy, genotypic resistance to entecavir or virological breakthrough was not noted., Conclusions: In chronic hepatitis B patients experiencing clevudine-induced myopathy, switching to entecavir 0.5 mg per day showed a resolution of myopathy and adequate viral suppression.

Background/aims: clevudine is a potent antiviral agent that has demonstrated efficacy in patients with chronic hepatitis B. This study compared the efficacy of clevudine (C), entecavir (E) and lamivudine (L) in treatment-naive patient with HBeAg-positive chronic hepatitis B., Methods: a total of 146 treatment-naive patients with HBeAg-positive chronic hepatitis B received clevudine, entecavir or lamivudine. C group (n=39) received 30 mg of clevudine, E group (n=39) received 0.5 mg of entecavir and L group (n=68) received 100 mg of lamivudine once a day for more than 48 weeks. The efficacy analysis estimated the mean changes of the HBV DNA levels as a virologic response, the normalization of the ALT levels (less than 35 IU/L) as a biochemical response and loss of HBeAg or seroconversion as a serologic response. The serum HBV DNA level was quantified by hybrid capture and real-time PCR assay., Results: before the administration of clevudine, entecavir and lamivudine, the mean HBV DNA and ALT levels and the gender and age were well balanced among the three groups (p>0.05). For the virologic response at 48 weeks, the mean changes of the HBV DNA levels from baseline of the C, E and L groups were -3.8+/-2.2, -4.5+/-1.9 and -2.5+/-2.1 log copies/mL. C and E group showed superior antiviral activity compared to that of L group (p<0.0001), but no significant differences in antiviral response were noted between C and E groups. For the biochemical response at 48 weeks, the normalization of the ALT levels (less than 35 IU/L) among the C, E and L groups was 82%, 74% and 71%, respectively (p=0.46). The rates of undetectable serum HBV DNA (less than 300 copies/mL) of the C, E and L groups were 39%, 69% and 27%, respectively (p<0.0001). For the serologic response at 48 weeks, the loss of HBeAg was 13%, 31% and 24% and the seroconversion was 10%, 23% and 17%, respectively. There was no difference of efficacy among the three groups regarding ALT normalization or serologic response (p>0.05). Viral breakthrough in C group was noted at 24 weeks (5%) and 48 weeks (21%), but no biochemical breakthrough was noted. The elevation of the serum CK level was noted in only 1 patient of group C at 48 weeks (2.56%) after therapy. For the patients without or with liver cirrhosis (LC), C and E group showed superior antiviral activity compared to that of the L group, but the antiviral activity was more effective in non- LC group than LC group (p<0.0001 vs p=0.036)., Conclusions: clevudine therapy compared with lamivudine for 48 weeks showed significantly potent antiviral efficacy in treatment-naive patients with HBeAg-positive chronic hepatitis B, and especially in the non-LC patients. However, the antiviral efficacy of clevudine was similar to that of entecavir even though taking into account relatively short follow up period and retrospective study.

Background/aims: Clevudine is a nucleoside analogue that exhibits potent and sustained antiviral effects as a 24-week therapy for chronic hepatitis B (CHB). This study evaluated the efficacy and viral resistance of a 48-week course of clevudine treatment for CHB., Methods: Data on patients with CHB and detectable serum hepatitis B virus (HBV) DNA who were treated with clevudine for 48 weeks or longer were collected retrospectively for this study. Patients who had taken lamivudine within the 3 years prior to this study were excluded. Serum HBV DNA was measured by polymerase chain reaction hybridization (lower detection limit=316 copies/mL). Serum HBV DNA and biochemical data were analyzed at weeks 24 and 48. Developments of viral breakthrough and resistance to the antiviral drug were also monitored., Results: Data from 74 patients (mean age 44 years; M:F=54:20; HBeAg-positive, 47; HBeAg-negative, 27) were included in this study. Ten patients had experienced previous lamivudine treatment. Median HBV DNA at baseline was 6.49 log(10) copies/mL. Median serum HBV DNA reductions from baseline at week 48 were -4.34 log(10) copies/mL (HBeAg-positive, -4.84 log(10) copies/mL; HBeAg-negative, -3.74 log(10) copies/mL). At week 48, serum HBV DNA was not detected in 83.8% of the patients (HBeAg-positive, 76.6%; HBeAg-negative, 96.3%). Normalization of serum alanine aminotransferase levels was achieved in 84.7% of the patients. Viral breakthrough and antiviral resistance developed in two patients at week 48. The development of antiviral resistance was associated with the presence of previous lamivudine treatment and cirrhosis., Conclusion: A 48-week course of clevudine therapy was highly effective in patients with CHB. The risk of development of resistance to clevudine was increased in patients with previous exposure to lamivudine and cirrhosis.

Backgrounds/aims: Clevudine is an effective antiviral nucleoside analogue, but there are few data regarding its long-term effects, resistance, and safety. The aim of this study was to evaluate the long-term clinical efficacy of clevudine over a 1-year treatment period in nucleos(t)ide-naive and lamivudine-experienced chronic hepatitis B patients., Methods: Nucleos(t)ide-naive (group A, n=196) and lamivudine-experienced (serum hepatitis B virus, HBV DNA >2,000 copies/mL without resistant mutants at the start of clevudine therapy, group B, n=75) patients were included in this study. Basic clinical characteristics including age, sex, the presence of cirrhosis, laboratory data, and hepatitis B surface antigen (HBeAg) positivity were similar between the two groups. Pretreatment serum levels of HBV DNA were 7.4 and 6.6 log(10) copies/mL (P<0.001). The mean treatment duration was 8 months for both groups (range for group A: 3-21 months; range for group B: 3-20 months). Genotypic analysis for resistant mutations in the reverse transcriptase of HBV was performed after viral breakthrough., Results: After 1 year of therapy, 75.0% and 51.9% of groups A and B, respectively, had HBV DNA levels of <2,000 copies/mL (P=0.032), and HBeAg seroconversion rates were 16.9% and 16.7%, respectively. The rates of viral breakthrough at 1 year were 10.0% (8/80) and 44.4% (12/27), respectively (P<0.001). Proven sites of mutation of HBV DNA polymerase in naive patients were, for example, L80I, L180M, A181V/T, M204I and V207I. Ten patients complained of prominent fatigue and revealed elevated serum levels of aspartate aminotransferase (AST) and creatine phosphokinase (CPK). Two of these patients presented with severe myopathy from which they recovered completely after quitting clevudine., Conclusions: Clevudine is one of the recommended first-line medicines for the treatment of chronic hepatitis B, but it is not free from resistance, particularly in patients with a history of previous lamivudine treatment, but also in naive patients. Clevudine should be avoided in previously lamivudine-exposed patients. In addition, reelevation of serum AST and CPK levels is not a rare occurrence, and close observation and follow-up tests are essential.

Clevudine is a nucleoside analog of the unnatural beta-L configuration which has potent antiviral activity against hepatitis B virus (HBV). Clevudine is expected to have similar pattern of resistance profile as lamivudine. However, there was no report on the mutation associated with clevudine resistance in patients with chronic hepatitis B. We report a case of young male patient with chronic hepatitis B who presented with clevudine resistance. The patient had received lamivudine therapy for 5 months with reduced serum HBV DNA levels. Then, lamivudine was switched to clevudine monotherapy. After the 6 months of clevudine therapy, the patient developed virologic breakthrough (>1.0chi10(8) copies/mL) as well as biochemical breakthrough, which was associated with the presence of rtM204I plus rtL80I mutant. After switching from clevudine to adefovir, the viral load decreased with biochemical improvement.

Substantial progress has been made in the treatment of chronic hepatitis B during the past decade. Nucleos(t)ide analogues are now widely used due to their convenience, less side effects, and considerable response rates. However, development of antiviral resistance is a major problem being considered as the most important factor for the treatment failure. Viral breakthrough associated with selection of antiviral-resistant hepatitis B virus (HBV) is usually followed by biochemical breakthrough, clinical deterioration, and even progressive liver failure. Therefore, appropriate management of antiviral resistance is critical for improving treatment outcomes. Strategies for the management of antiviral-resistant chronic HBV infection are described herein considering recently published guidelines. Lamivudine/telbivudine resistance can be managed by adding adefovir. Switching to adefovir or entecavir is also a viable option. However, careful follow-up of viral load is mandatory to detect any primary or secondary treatment failure in case of sequential monotherapy. Interferon or peg-interferon therapy can also be considered in case of young patients with compensated liver disease. For adefovir resistance, lamivudine can be added, but adding or switching to entecavir is a more reasonable option. Likewise, adding or switching to adefovir can be considered for entecavir resistance. Adding or switching to tenofovir needs to be considered upon availability. Experiences for clevudine resistance are still lacking, and need to be studied further upon the isolation of clinically resistant strains. To avoid emergence of resistant mutations, antiviral therapy should be initiated after careful balance of risk and benefit, and the most potent antiviral agent with the lowest resistance rate should be selected.

Chronic hepatitis B (CHB) is a serious health problem in Korea. The natural history of chronic HBV infection has been divided into 4 phases: immune tolerance, immune clearance, inactive HBsAg carrier state and reactivation. During the phases of immune tolerance and inactive HBsAg carrier state, no treatment is required. Patients in the immune clearance or reactivation phases are candidates for therapy. In the last years, treatment effects of CHB have considerably improved. Several agents are currently approved for the treatment of CHB: interferon alpha, pegylated interferon alpha, lamivudine, adefovir, entecavir, telbivudine and clevudine in Korea. The treatment recommendations from the 2004 Korean Association for the Study of the Liver guideline on the management of CHB have been updated to incorporate new therapeutic options. What is uncertain is which agent or combination of agents is most effective, how long therapy should last, and which criteria should be used to start, continue, switch or stop therapy. Issues for consideration include efficacy, safety and incidences of resistance, and method of administration of antiviral therapy in treatment-naive patients.