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

doi:10.1128/AAC.44.1.111-122.2000

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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 recentlyshown to strongly inhibit hepatitis B virus (HBV) replicationin the 2.2.15 cell line. Therefore, its antiviral activity wasevaluated in the duck HBV (DHBV) infection model. Using a cell-freesystem for the expression of the DHBV polymerase, $beta$ -L-Fd4C-TPexhibited a concentration-dependent inhibition of dCTP incorporationinto viral minus-strand DNA with a 50% inhibitory concentrationof 0.2 µM which was lower than that of other tested deoxycytidineanalogs, i.e., lamivudine-TP, ddC-TP, and $beta$ -L-FddC-TP. Furtheranalysis showed that $beta$ -L-Fd4C-TP is likely to be a competitiveinhibitor of dCTP incorporation and to cause premature DNA chaintermination. In primary duck hepatocyte cultures infected in vitro, $beta$ -L-Fd4C administration exhibited a long-lasting inhibitory effecton viral DNA synthesis but could not clear viral covalently closedcircular DNA (CCC DNA). Results of short-term antiviral treatmentin experimentally infected ducklings showed that $beta$ -L-Fd4C exhibitedthe most potent antiviral effect, followed by $beta$ -L-FddC, lamivudine,and ddC. Longer administration of $beta$ -L-Fd4C induced a sustainedsuppression of viremia (>95% of controls) and of viral DNA synthesiswithin the liver. However, the persistence of trace amounts ofviral CCC DNA detected only by PCR was associated with a recurrenceof viral replication after drug withdrawal. In parallel, $beta$ -L-Fd4Ctreatment suppressed viral antigen expression within the liverand decreased intrahepatic inflammation and was not associatedwith any sign of toxicity. Our data, therefore, demonstrate thatin the duck model of HBV infection, $beta$ -L-Fd4C is a potent inhibitorof DHBV reverse transcriptase activity in vitro and suppressesviral replication in the liver invivo.

^* Corresponding author. Mailing address: INSERM Unit 271, 151 cours Albert Thomas, 69003 Lyon, France. Phone: (33) 4 72 68 1970. 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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Characterization of the Antiviral Effect of 2',3'-Dideoxy-2', 3'-Didehydro--L-5-Fluorocytidine in the Duck Hepatitis B Virus Infection Model

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