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Antimicrobial Agents and Chemotherapy, January 2000, p. 111-122, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Characterization of the Antiviral Effect of 2',3'-Dideoxy-2', 3'-Didehydro-beta -L-5-Fluorocytidine in the Duck Hepatitis B Virus Infection Model

Franck Le Guerhier,1 Christian Pichoud,1 Sylviane Guerret,2 Michèle Chevallier,2 Catherine Jamard,1 Olivier Hantz,1 Xiu-Yan Li,3 Shu-Hui Chen,3 Ivan King,3 Christian Trépo,1 Yung-Chi Cheng,4 and Fabien Zoulim1,*

INSERM Unit 271, 69003 Lyon,1 and Department of Pathology, Marcel Mérieux Laboratory, 69007 Lyon,2 France; VION Pharmaceuticals Inc., New Haven, Connecticut 065113; and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 065204

Received 2 April 1999/Returned for modification 9 August 1999/Accepted 18 October 1999

A novel L-nucleoside analog of deoxycytidine, 2',3'-dideoxy-2',3'-didehydro-beta -L-5-fluorocytidine (beta -L-Fd4C), was recently shown to strongly inhibit hepatitis B virus (HBV) replication in the 2.2.15 cell line. Therefore, its antiviral activity was evaluated in the duck HBV (DHBV) infection model. Using a cell-free system for the expression of the DHBV polymerase, beta -L-Fd4C-TP exhibited a concentration-dependent inhibition of dCTP incorporation into viral minus-strand DNA with a 50% inhibitory concentration of 0.2 µM which was lower than that of other tested deoxycytidine analogs, i.e., lamivudine-TP, ddC-TP, and beta -L-FddC-TP. Further analysis showed that beta -L-Fd4C-TP is likely to be a competitive inhibitor of dCTP incorporation and to cause premature DNA chain termination. In primary duck hepatocyte cultures infected in vitro, beta -L-Fd4C administration exhibited a long-lasting inhibitory effect on viral DNA synthesis but could not clear viral covalently closed circular DNA (CCC DNA). Results of short-term antiviral treatment in experimentally infected ducklings showed that beta -L-Fd4C exhibited the most potent antiviral effect, followed by beta -L-FddC, lamivudine, and ddC. Longer administration of beta -L-Fd4C induced a sustained suppression of viremia (>95% of controls) and of viral DNA synthesis within the liver. However, the persistence of trace amounts of viral CCC DNA detected only by PCR was associated with a recurrence of viral replication after drug withdrawal. In parallel, beta -L-Fd4C treatment suppressed viral antigen expression within the liver and decreased intrahepatic inflammation and was not associated with any sign of toxicity. Our data, therefore, demonstrate that in the duck model of HBV infection, beta -L-Fd4C is a potent inhibitor of DHBV reverse transcriptase activity in vitro and suppresses viral replication in the liver in vivo.

* 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}lyon151.inserm.fr.

Antimicrobial Agents and Chemotherapy, January 2000, p. 111-122, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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