Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B.
ABSTRACT Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n=182) or placebo (n=61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P<0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P<0.0001). ALT normalization in the clevudine group was well maintained during post-treatment follow-up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. CONCLUSION: A 24-week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg-positive chronic hepatitis B.
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ABSTRACT: Treatment predictors are important tools for the management of therapy in patients with chronic hepatitis B and C virus (HBV, HCV) infection. In chronic hepatitis B, several pretreatment parameters have been identified for prediction of virologic response to interferon alfa-based antiviral therapies or treatment with polymerase inhibitors. In interferon alfa and pegylated interferon alfa-treated patients, low baseline HBV DNA concentrations, HBV genotype A (B), and high baseline ALT levels are significantly associated with treatment response. In patients treated with nucleos(t)ide analogues, low baseline HBV DNA but not viral genotype is positively associated with virologic response. During treatment the best predictor of response is HBV DNA kinetics. Early viral suppression is associated with favourable virologic response and reduced risk for subsequent resistance mutations. For the current standard treatment with pegylated interferon alfa and ribavirin in patients with chronic hepatitis C, infection with HCV genotypes 2 and 3, baseline viral load below 400,000-800,000 IU/ml, Asian and Caucasian ethnicity, younger age, low GGT levels, absence of advanced fibrosis/cirrhosis, and absence of steatosis in the liver have been identified as independent pretreatment predictors of a sustained virologic response. After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of sustained virologic response independent of HCV genotype.Journal of Hepatology 11/2008; 49(4):634-51. DOI:10.1016/j.jhep.2008.07.013 · 10.40 Impact Factor
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ABSTRACT: Despite the significant successes in the area of anti-HBV agents, resistance and cross-resistance against available therapeutics are the major hurdles in drug discovery. The present investigation is to understand the molecular basis of drug resistance conferred by the B and C domain mutations of HBV-polymerase on the binding affinity of five anti-HBV agents [lamivudine (3TC, 1), adefovir (ADV, 2), entecavir (ETV, 3), telbivudine (LdT, 4) and clevudine (l-FMAU, 5)]. In this regard, homology modeled structure of HBV-polymerase was used for minimization, conformational search and induced fit docking followed by binding energy calculation on wild-type as well as on mutant HBV-polymerases (L180M, M204V, M204I, L180M+M204V, L180M-M204I). Our studies suggest a significant correlation between the fold resistances and the binding affinity of anti-HBV nucleosides. The binding mode studies reveals that the domain C residue M204 is closely associated with sugar/pseudosugar ring positioning in the active site. The positioning of oxathiolane ring of 3TC (1) is plausible due the induced fit orientation of the M204 residue in wild-type, and further mutation of M204 to V204 or I204 reduces the final binding affinity which leads to the drug resistance. The domain B residue L180 is not directly close ( approximately 6A) to the nucleoside/nucleoside analogs, but indirectly associated with other active-site hydrophobic residues such as A87, F88, P177 and M204. These five hydrophobic residues can directly affect on the incoming nucleoside analogs in terms of its association and interaction that can alter the final binding affinity. There was no sugar ring shifting observed in the case of adefovir (2) and entecavir (3), and the position of sugar ring of 2 and 3 is found similar to the sugar position of natural substrate dATP and dGTP, respectively. The exocyclic double bond of entecavir (3) occupied in the backside hydrophobic pocket (made by residues A87, F88, P177, L180 and M204), which enhances the overall binding affinity. The active site binding of LdT (4) and l-FMAU (5) showed backward shifting along with upward movement without enforcing M204 residue and this significant different binding mode makes these molecules as polymerase inhibitors, without being incorporated into the growing HBV-DNA chain. Structural results conferred by these l- and d-nucleosides, explored the molecular basis of drug resistance which can be utilized for future anti-HBV drug discovery.Antiviral research 09/2008; 80(3):339-53. DOI:10.1016/j.antiviral.2008.07.010 · 3.43 Impact Factor
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ABSTRACT: Chronic Hepatitis B, were considered in the development of these guidelines.3-7 The recommendations suggest pre- ferred approaches to the diagnostic, therapeutic, and pre- ventive aspects of care. They are intended to be flexible. Specific recommendations are based on relevant pub- lished information. In an attempt to characterize the qual- ity of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a category to be assigned and reported with each recommendation (Table 1). These guidelines may be updated periodically as new information becomes available.