Clevudine is highly efficacious in HBeAg(-) chronic hepatitis B patients with a sustained antiviral effect after cessation of therapy

Abstract

Background: Clevudine is a pyrimidine analogue with potent anti-HBV activityin vitro. In woodchucks infected with woodchuck hepatitis virus, clevudine produced a potent and sustained viral suppression accompanied by significant reduction of cccDNA. In a phase II clinical study, clevudine produced a potent and sustained viral suppression after a 12-week dosing period.

Aims and Methods: A multicenter, randomized, double-blind phase III clinical trial to evaluate the safety and efficacy of clevudine 30mg once a day for 24 weeks and the durable antiviral response for 24 weeks after cessation of dosing in HBeAg(-) chronic hepatitis B patients. Eligible patients were HBeAg(-) chronic hepatitis B patients with HBV DNA levels >= 5 log10 copies/mL and alanine aminotransferase(ALT) levels between 1.2 and 15 times that of the upper limit of normal. A total of 86 patients were randomized (3:1) to receive clevudine 30 mg (n=63) or placebo (n=23) once a day for 24 weeks. Patients were followed post-treatment for additional 24 weeks.

Results: Median HBV DNA levels at baseline were 6.92 and 6.37 log10 copies/mL, and the median changes in HBV DNA levels from baseline were – 4.25 and – 0.48 log10 copies/mL at the end of the 24-week treatment period in clevudine and placebo groups, respectively (p<0.0001). Post-treatment antiviral activity was sustained with –3.11 log10 reduction at week 24 off therapy in clevudine group compared with -0.66 log10 reduction in placebo group(p<0.0001). Serum HBV DNA levels were below the lower limit of detection (300 copies/mL) by Amplicor PCR assay in 92.1 % and 0% at week 24, 47.5% and 4.8% at week 34, and 16.4% and 0% at week 48 in clevudine and placebo groups, respectively. Viral breakthrough was not observed during the entire dosing period. A statistically significant difference was observed in the proportion of patients with normal ALT levels in clevudine group (74.6%) compared with placebo group (33.3%) at Week 24. The ALT normalization rates further increased in clevudine group after the cessation of therapy up to 86.7% at week 34 and then slightly decreased thereafter to 70.5% at week 48. Clevudine was well tolerated throughout the course of the study with the incidence of adverse events similar between the clevudine and placebo groups.

Conclusions: Twenty four weeks dosing with clevudine 30mg QD was well tolerated and showed potent antiviral activity against HBV with a sustained viral suppression and normalization of aminotransferase levels at week 24 off therapy in HBeAg(-) chronic hepatitis B patients.