Japanese Study Finds Entecavir (Baraclude) Is Effective and Well-tolerated in Treatment-naive Chronic Hepatitis B Patients

By Liz Highleyman

Entecavir (Baraclude)

Evidence continues to accumulate showing that the nucleoside analog drug entecavir (Baraclude) is an effective option for treatment of chronic hepatitis B virus (HBV) infection, including data from a Japanese study published in the February 2009 Journal of Gastroenterology and Hepatology.

Compared with lamivudine (Epivir-HBV), the earlier standard of care, entecavir has more than 300 times greater potency in vitro, inhibits all 3 steps of HBV DNA replication (priming of the HBV DNA polymerase, reverse transcription of negative-strand HBV DNA from messenger RNA, and synthesis of positive-strand HBV DNA), and has a higher barrier to development of drug resistance, authors Haruhiko Kobashi and colleagues noted as background.

In this double-blind multicenter study, the investigators evaluated the efficacy and safety of entecavir in 66 nucleoside-naive Japanese chronic hepatitis B patients. Eligible participants had active viral replication as evidenced by HBV DNA > 105 copies/mL, elevated serum ALT (1.3-10 times the upper limit of normal [ULN]), and compensated liver disease; HIV positive patients were excluded.

Participants were randomly assigned to receive 0.1 mg or 0.5 mg entecavir daily for 52 weeks. After 52 weeks of blinded dosing, they were given the option of enrolling in an entecavir rollover study.

At baseline, demographic and disease-related characteristics were similar in the 2 treatment arms. Approximately 80% in both groups were hepatitis B "e" antigen (HBeAg) positive, almost all had HBV genotype C, and the mean baseline HBV DNA level was about 7.5 log10 copies/mL.

The primary endpoint was the proportion of patients whose serum HBV DNA became undetectable (< 400 copies/mL) or decreased by at least 2 log10 copies/mL from baseline by week 48.

Results

All patients in both treatment groups achieved the primary efficacy endpoint at week 48.

81% of patients in the 0.1 mg entecavir arm and 68% in the 0.5 mg arm achieved undetectable HBV DNA by week 48 (not a statistically significant difference).

94% and 91% of patients in the 0.1 mg and 0.5 mg arms, respectively, achieved at least a 2 log10 drop in HBV DNA by week 4, and all did so by week 8.

Mean HBV DNA levels decreased by 4.49 and 4.84 log10 copies/mL from baseline, respectively, in the 0.1 mg and 0.5 mg arms.

Significant improvements in necroinflammation (by Knodell and New Inuyama classifications) were observed in both dose groups.

96% in the 0.1 mg arm and 94% in the 0.5 mg arm achieved ALT normalization by week 48.

Among patients who were HBeAg positive at baseline, 31% in the 0.1 mg arm and 30% in the 0.5 mg arm achieved HBeAg loss by week 48, and all of these experienced HBeAg seroconversion.

38% of patients in both groups had a "complete response" at week 48, defined as HBV DNA < 400 copies/mL plus ALT < 1.25 x ULN plus negative HBeAg if they started out HBeAg positive.

Among patients with available liver biopsy data, histological improvement (by Knodell classification) occurred in 72% in the 0.1 mg arm and 80% in the 0.5 mg arm, with mean changes in Knodell HAI scores of -3.2 and -4.6, respectively.

At week 48, the rtM204I mutation (associated with lamivudine resistance) was detected in 2 patients, but neither experienced virological breakthrough or ALT elevation.

Most adverse events were transient and classified as grade 1 or 2 (mild to moderate).

There were no clinically significant differences in adverse events across the 2 treatment arms.

No participants in either group discontinued due to adverse events.

These findings led the study authors to conclude, "In Japanese nucleoside-naive patients with chronic hepatitis B, 0.1 mg or 0.5 mg entecavir daily provided excellent efficacy and was well tolerated."

"The ultimate goal of chronic hepatitis B treatment is to arrest or reverse liver disease progression associated with HBV infection," the researchers wrote in their discussion. "Entecavir's demonstrated histological benefit after 1 year of treatment suggests that its potent viral suppression might also reduce the risk of progression to cirrhosis and end-stage liver disease among chronic hepatitis B patients."

"Entecavir's potent antiviral efficacy, good tolerability, and high barrier to resistance offer the potential for long-term treatment of chronic hepatitis B with the objective of halting or reversing liver disease progression," they added.

Okayama University Graduate School of Medicine, Okayama, Japan; Kagawa Prefectural Central Hospital, Kagawa, Japan; Kurashiki Central Hospital, Okayama, Japan; Chiba University, Chiba, Japan; Nihon University Itabashi Hospital, Tokyo, Japan; Kurume University, Fukuoka, Japan; University of Tokyo, Tokyo, Japan; Bristol-Myers Squibb Company, Research and Development, Tokyo, Japan.

2/10/09

Reference
H Kobashi, K Takaguchi, H Ikeda, and others. Efficacy and safety of entecavir in nucleoside-naive, chronic hepatitis B patients: Phase II clinical study in Japan. Journal of Gastroenterology and Hepatology 24(2): 255-261. February 2009. (Abstract).