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Antimicrobial Agents and Chemotherapy, June 2003, p. 1842-1852, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1842-1852.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Effects of Pyrimidine and Purine Analog Combinations in the Duck Hepatitis B Virus Infection Model

Béatrice Seignères,1 Perrine Martin,1 Bettina Werle,1 Olivier Schorr,1 Catherine Jamard,1 Laurence Rimsky,2 Christian Trépo,1 and Fabien Zoulim1*

INSERM Unit 271, 69003 Lyon, France,1 Triangle Pharmaceuticals, Durham, North Carolina2

Received 4 October 2002/ Returned for modification 20 December 2002/ Accepted 28 January 2003

To design new strategies of antiviral therapy for chronic hepatitis B, we have evaluated the antiviral activity of the combination of amdoxovir (DAPD), emtricitabine [(-)FTC], and clevudine (L-FMAU) in the duck hepatitis B virus (DHBV) model. Using their triphosphate (TP) derivatives in a cell-free system expressing a wild-type active DHBV reverse transcriptase (RT), the three dual combinations exhibited a greater additive inhibitory effect on viral minus-strand DNA synthesis than the single drugs, according to the Bliss independence model. Both dual combinations with DAPD TP were the most efficient while the triple combination increased the inhibitory effect on the DHBV RT activity in comparison with the dual association, however, without additive effect. Postinoculation treatment of experimentally infected primary duck hepatocytes showed that dual and triple combinations potently inhibited viral DNA synthesis during treatment but did not inhibit the reinitiation of viral DNA synthesis after treatment cessation. Preinoculation treatment with the same combinations exhibited antiviral effects on intracellular viral DNA replication, but it was unable to prevent the initial covalently closed circular DNA (cccDNA) formation. Short-term in vivo treatment in acutely infected ducklings showed that the dual combinations were more-potent inhibitors of virus production than the single treatments, with the L-FMAU and FTC combination being the most potent. A longer administration of L-FMAU and FTC for 4 weeks efficiently suppressed viremia and viral replication. However, no viral clearance from the liver was observed, suggesting that the enhanced antiviral effect of this combination was not sufficient for cccDNA suppression and HBV eradication from infected cells.

* Corresponding author. Mailing address: INSERM Unit 271, 151 cours Albert Thomas, 69003 Lyon, France. Phone: (33) 4 72 68 19 70. Fax: (33) 4 72 68 19 71. E-mail: zoulim{at}lyon.inserm.fr.

Antimicrobial Agents and Chemotherapy, June 2003, p. 1842-1852, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1842-1852.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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