pyrimidinones and Muscular-Diseases

Successful treatment of chronic hepatitis B (CHB) often requires long-term oral nucleoside/nucleotide agents which can be associated with viral resistance, patient non-compliance and adverse effects. Telbivudine is one of the more potent options available, with a 6.5- to 6.6-log copies/ml hepatitis B DNA reduction at 12 weeks in an early viral kinetic study, a potency comparable to entecavir. It is also one of the few drugs in the treatment of CHB under FDA pregnancy Category B.. The efficacy and safety profile of telbivudine in compensated and decompensated CHB patients compared to other agents are discussed. Viral resistance, characteristic adverse effects including elevation in creatine kinase and peripheral neuropathy in telbivudine treatment are reviewed. Infrequent but significant adverse effects of other nucleoside/nucleotide analogs are highlighted.. Readers are provided the latest update on the clinical profile of long-term use of telbivudine.. Long-term telbivudine treatment offers effective viral suppression to CHB patients with certain baseline characteristics and on-treatment virologic response. Creatine kinase elevation is not a good predictor of muscle-related adverse effects with nucleoside/nucleotide analogs. But significant myopathy and neuropathy have been reported in a small number of patients receiving telbivudine.

Topics: Adult; Antiviral Agents; Biomarkers; Creatine Kinase; Double-Blind Method; Drug Resistance, Viral; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Isoenzymes; Male; Multicenter Studies as Topic; Muscular Diseases; Nucleosides; Peripheral Nervous System Diseases; Predictive Value of Tests; Pregnancy; Pregnancy Complications, Infectious; Pyrimidinones; Randomized Controlled Trials as Topic; Telbivudine; Thymidine

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.

Topics: Animals; Antiviral Agents; Arabinofuranosyluracil; Creatine Kinase; Drug Discovery; Early Termination of Clinical Trials; Hepatitis B, Chronic; Humans; Lamivudine; Mitochondrial Myopathies; Muscular Diseases; Nervous System Diseases; Nucleosides; Nucleotides; Pyrimidinones; Republic of Korea; Telbivudine; Thymidine

Topics: Adolescent; Adult; Aged; Antiviral Agents; Biomarkers, Pharmacological; Biotransformation; Clinical Trials, Phase III as Topic; Drug Resistance, Viral; Female; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Muscular Diseases; Nucleosides; Phosphorylation; Prodrugs; Pyrimidinones; Randomized Controlled Trials as Topic; Telbivudine; Thymidine; Virus Replication

Telbivudine (beta-l-2'-deoxythymidine) is an orally administered nucleoside analog drug approved for the treatment of patients with chronic hepatitis B since 2006. Initially, it was regarded as being generally well tolerated, with low adverse reaction profiles and no dose-limiting toxicity. Recently, with the result of the telbivudine worldwide phase III GLOBE trial and other clinical experiments, cases of myopathy and neuropathy have been reported undergoing long-term telbivudine treatments. Telbivudine-induced myopathy has been characterized by muscle pain, weakness and moderately elevated creatine kinase levels during treatments, although no severe adverse events have been observed. Rhabdomyolysis has not reported in any patient.

Topics: Acute Kidney Injury; Antiviral Agents; Fatal Outcome; Fibrosis; Hepatitis B; Humans; Male; Middle Aged; Muscular Diseases; Nucleosides; Pyrimidinones; Rhabdomyolysis; Telbivudine; Thymidine; Treatment Outcome

With the extensive use of telbivudine, more and more studies reported its association with creatine kinase (CK) elevations and myopathy. However, clinical features of these adverse effects were poorly understood. The aim of the present study was to investigate the clinical features and risk factors of CK elevations and myopathy associated with telbivudine. The serum CK levels of 200 patients who were treated with telbivudine for chronic hepatitis B (CHB) between January 2007 and July 2010 were monitored and analysed along with clinical manifestations. The 3-year cumulative incidence of CK elevations and myopathy was 84.3% and 5%, respectively. CK elevations occurred more frequently in men than in women, and patients aged ≤45 years and with negative HBeAg had higher incidence of CK elevations. There was no difference in CK elevations among patients with different HBV DNA levels. Male, younger age and HBeAg negativity were independent predictors of CK elevations by multivariate Cox regression analysis. There was no association between the occurrence of myopathy and variables including age, sex, HBeAg and HBV DNA. No risk factors of myopathy were identified. CK elevations usually occurred 21 months after starting treatment, and most patients resolved spontaneously without interruption of telbivudine therapy except three patients who had to switch to other agents. In conclusion, CK elevations are common adverse reactions associated with telbivudine therapy, while myopathy is rare. Male, younger age and HBeAg negativity might be risk factors of CK elevations.

Topics: Adolescent; Adult; Age Distribution; Aged; Antiviral Agents; Creatine Kinase; Female; Hepatitis B, Chronic; Humans; Incidence; Male; Middle Aged; Muscular Diseases; Nucleosides; Pyrimidinones; Risk Factors; Sex Distribution; Telbivudine; Thymidine; Young Adult

It is unknown if telbivudine causes muscle damage only in patients with pre-existing muscle pathology.. A 27 yo male of African origin received telbivudine for hepatitis B during 3 months. Three weeks after initiation of the drug he developed myalgia, and tiredness. Creatine-kinase increased from 278 U/l (n, <170 U/l) at baseline to 3243 U/l. Shortly after discontinuation of telbivudine muscle symptoms and hyper-CK-emia disappeared. The findings suggest that pre-existing muscle damage favored the myotoxic effect of telbivudine.. Telbivudine appears to cause accelerated muscle toxicity if given to patients who already have muscle damage. Patients under telbivudine should be closely monitored for muscular side effects and those with pre-existing muscle damage should not receive the drug.

Topics: Adult; Antiviral Agents; Creatine Kinase; Hepatitis B; Humans; Male; Muscle, Skeletal; Muscular Diseases; Nucleosides; Pyrimidinones; Telbivudine; Thymidine