Clevudine Induced Mitochondrial Myopathy

Clevudine was approved as an antiviral agent for hepatitis B virus, which showed marked, rapid inhibition of virus replication without significant toxicity. However, several studies have reported myopathy associated with clevudine therapy. Also, we experienced seven patients who suffered from myopathy during clevudine therapy. To characterize clevudine-induced myopathy, we collected previously reported cases of clevudine myopathy and analyzed all the cases including our cases. We searched electronic databases that were published in English or Korean using PubMed and KoreaMed. Ninety-five cases with clevudine myopathy, including our seven cases, were selected and analyzed for the demographic data, clinical features, and pathologic findings. The 95 patients with clevudine-induced myopathy comprised 52 women and 43 men aged 48.9 years (27–76 years). The patients received clevudine therapy for about 14.2 months (5–24 months) before the development of symptoms. Weakness mainly involved proximal extremities, especially in the lower extremities, and bulbar and neck weakness were observed in some cases (13.7%). Creatine kinase was elevated in the majority of patients (97.9%). Myopathic patterns on electromyography were observed in most patients examined (98.1%). Muscle biopsy presented patterns compatible with mitochondrial myopathy in the majority (90.2%). The weakness usually improved within about 3 months after the discontinuation of clevudine. Though clevudine has been known to be safe in a 6-month clinical trial, longer clevudine therapy for about 14 months may cause reversible mitochondrial myopathy. Careful clinical attention should be paid to patients with long-term clevudine therapy.

Management of Clevudine-Resistant Chronic Hepatitis B: A Multicenter Cohort Study

BACKGROUND/AIMS: Data are lacking regarding the management of chronic hepatitis B (CHB) with resistance to clevudine (CLV). This study evaluated the efficacy of different rescue therapies for CLV-resistant CHB. METHODS: Patients with CLV-resistant CHB were enrolled in the cohort, and all patients developed virologic breakthrough during CLV therapy and had confirmed-genotypic resistance to CLV (rtM204I mutation) before enrollment. RESULTS: Of the 107 patients, 12 received adefovir (ADV), 21 received a CLV plus ADV combination (CLV+ADV), 34 received a lamivudine plus ADV combination (LAM+ADV), and 40 received entecavir (ETV) therapy for 48 weeks. The CLV+ADV group had the lowest hepatitis B virus (HBV) DNA level (p<0.0001) and showed the greatest reduction of HBV DNA levels from baseline compared to all other groups (p=0.004) at week 48. HBV DNA was undetectable (<70 IU/mL) in 0%, 57.1%, 21.2%, and 27.5% (p=0.003) of the patients in each group, respectively, at week 48. At the end of the study, the mean alanine transaminase (ALT) level, rate of ALT normalization, and rate of hepatitis B envelope antigen loss or seroconversion did not differ between groups. CONCLUSIONS: CLV+ADV combination therapy in patients with CLV-resistant CHB more effectively suppresses HBV replication than ETV, ADV, or LAM+ADV therapy.

Efficacy of Entecavir Switching Therapy in Chronic Hepatitis B Patients with Clevudine-induced Myopathy / 대한소화기학회지

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.

Clinical and Pathological Features of Clevudine Induced Myopathy

BACKGROUND: Clevudine (Revovir(R)) is a recently introduced antiviral drug, and clinical trials have demonstrated its potent, sustained antiviral activity without specific adverse events. However, several studies have found severe myopathy during clevudine therapy. Our study aimed to summarize the clinical and pathological features of clevudine-induced myopathy. METHODS: We analyzed the demographic data, clinical features, and pathologic findings of 18 consecutive hepatitis-B patients who developed skeletal myopathy during clevudine therapy. RESULTS: The 18 patients comprised 11 women and 7 men aged 48.2+/-14.0 years (mean+/-standard deviation; range 28-74 years). Each of the 18 patients was treated with clevudine for at least 5 months (range 5-20 months) before the development of symptoms. In all patients the main symptom was proximal muscular weakness that progressed slowly over several months. Elevated creatine kinase and myopathic patterns on electromyography were found. Muscle biopsies revealed severe myonecrosis associated with numerous ragged red fibers and cytochrome-c-oxidase-negative fibers, mitochondrial proliferation, and predominant type-II fiber atrophy. The muscle weakness gradually improved within 20 weeks after discontinuation of clevudine. CONCLUSIONS: Clevudine therapy can induce myopathy associated with mitochondrial toxicity. Careful clinical and laboratory monitoring of the skeletal muscle dysfunction is required in patients receiving clevudine therapy.

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

BACKGROUND/AIMS: The clinical effects of clevudine have been reported in patients with chronic hepatitis B virus infections (CHIs). In this investigation, we assessed whether clevudine induced biochemical and virological improvements in hepatocellular carcinoma (HCC) patients with CHI. METHODS: Fifty-four patients who received 30 mg clevudine for more than 24 weeks between 2007 and 2009 at the National Cancer Center Hospital, Korea, were enrolled. Among these cases, 39 had HCC (CHI/HCC group) and 15 did not (CHI group). RESULTS: In relation to the CHI group, the CHI/HCC group was older (55.5 years.) and had a higher liver cirrhosis rate (79.5%) (p0.05). Liver function was preserved with clevudine treatment in patients displaying response or stable disease under anti-cancer therapy. Four patients (7.4%) developed viral resistance during clevudine therapy. Among these, one was naive, and three had previously received antiviral therapy. One CHI/HCC patient (1.9%) discontinued clevudine treatment due to symptomatic myopathy. CONCLUSIONS: Our findings clearly indicate that clevudine has comparable antiviral and biochemical effects in patients with CHI and with CHI/HCC and preserves the underlying liver function in HBV-related HCC patients.

Comparison of entecavir and clevudine for treatment of chronic hepatitis B / 대한내과학회지

BACKGROUND/AIMS: Entecavir (ETV) and clevudine (CLV) are potent inhibitors of hepatitis B virus (HBV) DNA polymerase and have demonstrated clinical efficacy. No comparative study has reported on these two medications among patients with naive chronic hepatitis B (CHB). We assessed the clinical outcome of CHB patients treated with either ETV or CLV. METHODS: A nonrandomized comparative study was conducted retrospectively. The clinical results from treatments of either 0.5 mg ETV (n=56) or 30 mg CLV (n=45) were analyzed during a 1 year period. The median reduction in serum HBV DNA, undetectable HBV DNA, HBeAg seroconversion, and normalization of alanine transaminase (ALT) were compared between the two groups. RESULTS: After 1 year on antiviral therapy, the median reduction in serum HBV DNA from baseline to the endpoint was greater in patients in the ETV group than in those in the CLV (5.73 vs. 4.5 log copies/mL, p=0.009) group. ALT normalization occurred in 85.5% (47/55) of the ETV cases and 77.3% (34/40) of the CLV cases (p=0.215). HBV DNA was undetectable in 80.0% (44/55) of the ETV group and 78.0% (32/41) of the CLV group (p=0.505). HBeAg seroconversion occurred in 15.4% (6/39) of those administered ETV and in 14.3% (4/28) administered CLV (p=0.593). Within 12 months, a virological breakthrough was documented in three patients undergoing CLV treatment, and CLV-related myopathy developed in three other patients. CONCLUSIONS: ETV and CLV showed excellent antiviral effects in patients with CHB. ETV was superior for viral suppression and showed fewer side effects than CLV.

Forty-eight weeks treatment with clevudine 30 mg qd versus lamivudine 100 mg qd for chronic hepatitis B infection: a double-blind randomized study / 대한간학회지

BACKGROUND/AIMS: Clevudine is a pyrimidine analogue with potent activity against hepatitis B virus (HBV) replication in vitro. In a previous pivotal phase III clinical study, 24 weeks treatment with clevudine 30 mg has been shown to profoundly suppress HBV replication and normalize serum alanine aminotransferase level. METHODS: In this study, we compare the efficacy and safety of clevudine (30 mg daily) versus lamivudine (100 mg daily) for 48 weeks in treatment-naive chronic hepatitis B e antigen (HBeAg) positive patients. RESULTS: Ninety-two chronic HBeAg positive patients were randomized to receive clevudine 30 mg daily or lamivudine 100 mg daily in a 1:1 ratio. The clevudine group demonstrated greater viral suppression at week 48 when compared with the lamivudine group (median reduction: 4.27 vs. 3.17 log(10) copies/ml at week 48, p<0.0001). At week 48, serum HBV DNA level was below 300 copies/mL in 73% and 40% in the clevudine and lamivudine groups, respectively (p=0.001). HBeAg seroconversion occurred in 18% of patients in the clevudine group versus 12% in the lamivudine group at week 48. Lamivudine-resistant mutations were detected in 11 (24%) patients in the lamivudine group, who showed viral rebound during lamivudine therapy but no resistance was found in the clevudine group during 48-week treatment period. CONCLUSIONS: A 48-week dosing with clevudine 30 mg daily was superior to lamivudine 100 mg daily in suppressing HBV replication, with no emergence of viral breakthrough in patients with HBeAg positive chronic hepatits B.

Clevudine induced diabetes mellitus in a patient with chronic hepatitis B / 대한내과학회지

Several studies have documented that various agents can induce diabetes mellitus, such as steroids, thiazides, anti-psychotic agents, and anti-viral agents. Many antiviral agents are also reported to impair insulin resistance and induce diabetes mellitus in patients infected with human immunodeficiency virus (HIV). However, there are no reports of diabetes mellitus induced by clevudine, one of the antiviral agents used to treat chronic hepatitis B virus (HBV) infection. We report a case of diabetes mellitus induced by clevudine in a patient with chronic hepatitis B.

Efficacy of Initial Treatment with Clevudine in Naive Patients with Chronic Hepatitis B

BACKGROUND/AIMS: Clevudine, a pyrimidine nucleoside analogue, has potent antiviral effects in patients with chronic viral hepatitis B (CHB). We report the efficacy of initial treatment with clevudine in naive patients with CHB living in Daejeon and Chungcheong Province, South Korea. METHODS: One hundred five adults with CHB were administered 30 mg of clevudine per day for an average of 51 weeks. We evaluated viral markers and liver biochemistry retrospectively every 3 months. RESULTS: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatitis B virus (HBV) DNA before the treatment were 184 +/- 188 IU/L, 150 +/- 138 IU/L, and 7.1 +/- 1.2 log copies/mL, respectively. Undetectable rates (< 60 IU/mL) of DNA were 36.2%, 68.9%, 83.6%, 76.2%, and 75.8% at 12, 24, 36, 48, and 60 weeks, respectively. Seroconversion rates were 9.1%, 13.6%, 24.6%, 26.5%, and 26.1% and ALT normalization rates were 64.5%, 78.1%, 87.9%, 90.0% at 12, 24, 36, and 48 weeks, respectively. Six patients (5.7%) had a viral breakthrough. CONCLUSIONS: Clevudine is a useful drug in the initial treatment of patients with CHB, with a potent antiviral effect and low incidence of viral breakthrough.

Treatment Efficacy of Clevudine, Entecavir and Lamivudine in Treatment-naive Patients with HBeAg-Positive Chronic Hepatitis B / 대한소화기학회지

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 (p0.05). 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.

Efficacy of 48-week clevudine therapy for chronic hepatitis B / 대한간학회지

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 log10 copies/mL. Median serum HBV DNA reductions from baseline at week 48 were -4.34 log10 copies/mL (HBeAg-positive, -4.84 log10 copies/mL; HBeAg-negative, -3.74 log10 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.

Clevudine therapy in patients with chronic hepatitis B / 대한간학회지

No abstract available.

Long-term clevudine therapy in nucleos(t)ide-naive and lamivudine-experienced patients with hepatitis B virus-related chronic liver diseases / 대한간학회지

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 log10 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.

Myopathy due to Chronic Clevudine Therapy: A Case Report

A 40-year-old man with chronic hepatitis B complained of progressive weakness of the proximal muscles and edema of both legs. He had been receiving long-term clevudine (nucleoside analogue reverse transcriptase inhibitor, NRTI) therapy for his hepatitis. The serum creatine kinase level was increased on the laboratory tests. His electromyography showed a generalized myopathic process. The muscle biopsy showed numerous ragged-red fibers, degenerating myofibers with variable sized cytoplasmic bodies, the prominence of type 1 fibers with type 2 fiber atrophy and an endomysial mononuclear cell infiltration. The electron microscopic examination revealed necrotic myofibers, including extremely dysmorphic mitochondria with extensive loss, blunting and focal clumping of the cristae and concentric cristae. Although clevudine is known to be a less cytotoxic agent among the various NRTIs, careful clinical attention should be paid to the patients who are receiving long-term clevudine therapy for the occurrence of myopathy.

Development of Clevudine Resistance after Switching from Lamivudine in a Patient with Chronic Hepatitis B / 대한소화기학회지

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 (>1.0x10(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.