Potent Efficacy of Entecavir (BMS-200475) in a Duck Model of Hepatitis B Virus Replication

Abstract

The ability of entecavir (ETV) to inhibit Duck hepatitis B virus (DHBV) infection in duck hepatocytes and ducklings was examined using lamivudine (3TC) as a comparator drug. ETV exhibited antiviral activity (50% effective concentration [EC 50 ], 0.13 nM) in DHBV-infected duck hepatocytes that was >1,000-fold more potent than that of 3TC (EC 50 , 138 nM). A 21-day treatment of ducklings with 1 mg of ETV per kg of body weight per day by oral gavage resulted in a mean reduction of log 10 3.1 in serum DHBV DNA levels. Daily treatment with 0.1 mg of ETV/kg was nearly as effective, achieving an average viral DNA level decrease of log 10 2.1. Reducing the daily dose of ETV to only 0.01 mg/kg resulted in an average viral DNA level decrease of log 10 0.97. Daily treatment with 25 mg of 3TC/kg resulted in an average viral DNA level decrease of log 10 0.66, compared to the log 10 0.20 drop seen for ducklings given the vehicle alone. ETV was also more effective in decreasing the DHBV DNA levels in duck livers after 21 days of treatment, causing average drops of log 10 1.41, log 10 0.76, and log 10 0.26 for dose levels of 1.0, 0.1, and 0.01 mg/kg, respectively, compared to a decrease of log 10 0.06 for 3TC at a dose level of 25 mg/kg. Levels of viral covalently closed circular DNA in the treatment group receiving 1 mg of ETV/kg were reduced compared to those in the vehicle-treated group. ETV and 3TC were both well tolerated in all treated animals. These results show that ETV is a highly potent and effective antiviral in the DHBV duck model. Hepatitis B virus (HBV), a small DNA virus that replicates through an RNA intermediate, is a leading cause of chronic hepatitis. The World Health Organization estimated in 1996 that 350 million people were persistently infected with the virus worldwide (8). Despite the availability of an effective vaccine against HBV, the prevalence of chronic infection has not significantly decreased (2). Persons with chronic hepatitis B not only suffer the wide range of symptoms associated with hepatitis but are at significant risk for the development of cirrhosis and/or primary hepatocellular carcinoma. Chronic carriers of HBV, moreover, constitute a reservoir for new infections.Therapy currently consists of treatment with alpha interferon, which is associated with several undesirable side effects and variable, sometimes low, response rates (3), and treatment with lamivudine (3TC), a pyrimidine dideoxynucleoside (reviewed in reference 5). While effective in reducing viral load, 3TC treatment leads to resistance in both immunocompromised and immunocompetent patients with chronic HBV infections who receive the compound for extended periods (1, 6, 9). Consequently, there is an urgent need for new anti-HBV agents that are both safe and effective.A number of compounds, most of which are nucleoside analogs that inhibit HBV polymerase and thereby interfere with replication, are currently under investigation for use in the chemotherapy of chronic HBV infection (for reviews, see references 3, 10, and 19). One ...

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