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Antimicrobial Agents and Chemotherapy, January 2002, p. 82-88, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.82-88.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Patricia L. Marion,1,2* Felix H. Salazar,2 Mark A. Winters,2 and Richard J. Colonno3

Division of Gastroenterology, Stanford University School of Medicine, Stanford, California 94305-5187,1 Hepadnavirus Testing, Inc., Mountain View, California 94043-1757,2 Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 064923

Received 19 March 2001/ Returned for modification 23 May 2001/ Accepted 1 October 2001

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 [EC50], 0.13 nM) in DHBV-infected duck hepatocytes that was >1,000-fold more potent than that of 3TC (EC50, 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 log10 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 log10 2.1. Reducing the daily dose of ETV to only 0.01 mg/kg resulted in an average viral DNA level decrease of log10 0.97. Daily treatment with 25 mg of 3TC/kg resulted in an average viral DNA level decrease of log10 0.66, compared to the log10 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 log10 1.41, log10 0.76, and log10 0.26 for dose levels of 1.0, 0.1, and 0.01 mg/kg, respectively, compared to a decrease of log10 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.

* Corresponding author. Mailing address: Center for Clinical Sciences Research, Room 3115, 269 Campus Dr., Stanford University, Stanford, CA 94305-5187. Phone: (650) 964-1865. Fax: (650) 725-5488. E-mail: pmarion{at}stanford.edu.

Antimicrobial Agents and Chemotherapy, January 2002, p. 82-88, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.82-88.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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