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Antimicrobial Agents and Chemotherapy, April 2001, p. 1065-1077, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1065-1077.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Antiviral Activity of -L-2',3'-Dideoxy-2',3'-Didehydro-5-Fluorocytidine in Woodchucks Chronically Infected with Woodchuck Hepatitis Virus

F. Le Guerhier,¹ C. Pichoud,¹ C. Jamard,¹ S. Guerret,² M. Chevallier,³ S. Peyrol,⁴ O. Hantz,¹ I. King,⁵ C. Trépo,¹ Y.-C. Cheng,⁶ and F. Zoulim^1,*

INSERM Unit 271, 69003 Lyon,¹ Biomaterials Laboratory, Faculty of Pharmacy² and Electron Microscopy Center of Laennec University School of Medicine,⁴ 69008 Lyon, and Department of Pathology, Marcel Mérieux Laboratory, 69007 Lyon,³ France; VION Pharmaceuticals Inc., New Haven, Connecticut 06511⁵; and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520⁶

Received 18 May 2000/Returned for modification 28 August 2000/Accepted 10 January 2001

The L-nucleoside analog -L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (-L-Fd4C) was first shown to exhibit potent activity against hepatitis B virus (HBV) in tissue culture and then to significantly inhibit viral spread during acute infection in the duck HBV model (F. Le Guerhier et al., Antimicrob. Agents Chemother. 44:111-122, 2000). We have therefore examined its antiviral activity in a mammalian model of chronic HBV infection, the woodchuck chronically infected with woodchuck hepatitis virus (WHV). Side-by-side comparison of -L-Fd4C and lamivudine administered intraperitoneally during short-term and long-term protocols demonstrated a more profound inhibition of viremia in -L-Fd4C-treated groups. Moreover, -L-Fd4C induced a marked inhibition of intrahepatic viral DNA synthesis compared with that induced by lamivudine. Nevertheless, covalently closed circular (CCC) DNA persistence explained the lack of clearance of infected hepatocytes expressing viral antigens and the relapse of WHV replication after drug withdrawal. Liver histology showed a decrease in the inflammatory activity of chronic hepatitis in woodchucks receiving -L-Fd4C. An electron microscopy study showed the absence of ultrastructural changes of hepatic mitochondria, biliary canaliculi, and bile ducts. However, a loss of weight was observed in all animals, whatever the treatment, as was a transient skin pigmentation in all woodchucks during -L-Fd4C treatment. There was no evidence that lamivudine or -L-Fd4C could prevent the development of hepatocellular carcinoma with the protocols used. These results indicate that -L-Fd4C exhibits a more potent antiviral effect than lamivudine in the WHV model but was not able to eradicate CCC DNA and infected cells from the liver at the dosage and with the protocol used.

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^* 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.

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Antimicrobial Agents and Chemotherapy, April 2001, p. 1065-1077, Vol. 45, No. 4
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.4.1065-1077.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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