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Antimicrobial Agents and Chemotherapy, July 2004, p. 2683-2692, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2683-2692.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Effect of a Combination of Clevudine and Emtricitabine with Adenovirus-Mediated Delivery of Gamma Interferon in the Woodchuck Model of Hepatitis B Virus Infection

A. C. Jacquard,1 M. Nassal,2 C. Pichoud,1 S. Ren,2 U. Schultz,2 S. Guerret,3 M. Chevallier,4 B. Werle,1 S. Peyrol,5 C. Jamard,1 L. T. Rimsky,6 C. Trepo,1 and F. Zoulim1*

INSERM U271,1 Biomaterials Laboratory, Faculty of Pharmacy,3 Pathology Department, Marcel Merieux Laboratory,4 Electron Microscopy Center, Laennec University School of Medicine, Lyon, France,5 University Hospital, Freiburg, Germany,2 Triangle Pharmaceuticals, Gilead Sciences, Durham, North Carolina6

Received 3 September 2003/ Returned for modification 4 November 2003/ Accepted 16 December 2003

Our aim was to evaluate the antiviral effect of a combination of two nucleoside reverse transcriptase inhibitors, emtricitabine (FTC) and clevudine (L-FMAU), with the addition of an adenovirus-driven delivery of recombinant gamma interferon (IFN-{gamma}) in the woodchuck model of hepatitis B virus infection. Six woodchuck hepatitis virus (WHV)-infected woodchucks received L-FMAU (10 mg/kg) plus FTC (30 mg/kg) intraperitoneally for 8 weeks; six other animals received in addition an intravenous injection of a recombinant adenovirus vector expressing woodchuck IFN-{gamma} (Ad-IFN) at weeks 4 and 8. In the control group, two animals received Ad-IFN alone, two received adenovirus vector expressing the green fluorescent protein reporter gene, and one remained untreated. In less than 2 weeks, all woodchucks that received L-FMAU plus FTC showed a rapid and marked inhibition of viral replication, with a 4-log10 drop in serum WHV DNA. In two animals, viremia remained suppressed for several months after the end of treatment. Similarly, a dramatic decrease in intrahepatic replicative intermediates of viral DNA was observed in the L-FMAU/FTC-treated groups. The additional administration of Ad-IFN led to increased inflammation in the liver but did not enhance the antiviral effect of the L-FMAU/FTC combination. In conclusion, therapies combining L-FMAU and FTC in WHV-infected woodchucks resulted in a potent and sustained antihepadnaviral effect both in the liver and in the blood circulation. However, no extra benefit of adding IFN-{gamma} gene transduction to the L-FMAU/FTC combination could be detected.

* Corresponding author. Mailing address: INSERM U271, 151 Cours Albert Thomas, 69003 Lyon, France. Phone: (33) 4726-91870. Fax: (33) 4726-81971. E-mail: zoulim{at}lyon.inserm.fr.

Antimicrobial Agents and Chemotherapy, July 2004, p. 2683-2692, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2683-2692.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dusheiko, G, Antonakopoulos, N (2008). Current treatment of hepatitis B. Gut 57: 105-124 [Full Text]  
  • Lim, S. G., Krastev, Z., Ng, T. M., Mechkov, G., Kotzev, I. A., Chan, S., Mondou, E., Snow, A., Sorbel, J., Rousseau, F., for the FTCB-204 Study Group, (2006). Randomized, Double-Blind Study of Emtricitabine (FTC) plus Clevudine versus FTC Alone in Treatment of Chronic Hepatitis B.. Antimicrob. Agents Chemother. 50: 1642-1648 [Abstract] [Full Text]  
  • Zoulim, F. (2005). Combination of nucleoside analogues in the treatment of chronic hepatitis B virus infection: lesson from experimental models. J Antimicrob Chemother 55: 608-611 [Abstract] [Full Text]  


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