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Antimicrobial Agents and Chemotherapy, September 2009, p. 3803-3814, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00263-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Profound Antiviral Effect of Oral Administration of MIV-210 on Chronic Hepadnaviral Infection in a Woodchuck Model of Hepatitis B{triangledown}

Tomasz I. Michalak,1 Hong Zhang,2* Norma D. Churchill,1 Torbjörn Larsson,2 Nils-Gunnar Johansson,2 and Bo Öberg2,3

Molecular Virology and Hepatology Research Group, Faculty of Medicine, The Health Sciences Centre, Memorial University, St. John's, Newfoundland A1B 3V6, Canada,1 Medivir AB, Lunastigen 7, S-141 44, Huddinge,2 MTC, Karolinska Institute, S-171 77, Stockholm, Sweden3

Received 24 February 2009/ Returned for modification 25 March 2009/ Accepted 24 June 2009

MIV-210 is a prodrug of 3'-fluoro-2',3'-dideoxyguanosine with high oral bioavailability in humans and potent activity against hepatitis B virus (HBV). Woodchucks infected with woodchuck hepatitis virus (WHV) represent an accurate model of HBV infection that is utilized for evaluation of the efficacy and safety of novel anti-HBV agents. Oral administration of MIV-210 at 20 or 60 mg/kg of body weight/day induced a rapid virological response in chronically infected woodchucks, reducing serum WHV DNA levels by 4.75 log10 and 5.72 log10, respectively, in 2 weeks. A progressive decline in WHV viremia occurred throughout the 10-week therapy, giving final reductions of 7.23 log10 and 7.68 log10 in the 20- and 60-mg/kg/day groups, respectively. Further, a daily dose of 10 mg/kg decreased the serum WHV load 400-fold after 4 weeks of treatment, and a dose of 5 mg/kg/day was sufficient to maintain this antiviral effect during the following 6-week period. MIV-210 at 20 or 60 mg/kg/day reduced the liver WHV DNA load 200- to 2,500-fold from pretreatment levels and, importantly, led to a 2.0 log10 drop in the hepatic content of WHV covalently closed circular DNA. The treatment with 60 mg/kg/day was well tolerated. Liver biopsy specimens obtained after the 10-week treatment with 20 or 60 mg/kg/day and after the 10-week follow-up showed hepatocyte and mitochondrial ultrastructures comparable to those in the placebo-treated group. It was concluded that MIV-210 is highly effective against chronic WHV infection. These findings, together with the previously demonstrated inhibitory activity of MIV-210 against lamivudine-, adefovir-, and entecavir-resistant HBV variants, make MIV-210 a highly valuable candidate for further testing as an agent against chronic hepatitis B.

* Corresponding author. Mailing address: Medivir AB, P.O. Box 1086, SE-141 22, Huddinge, Sweden. Phone: 46 8 54683161. Fax: 46 8 54683199. E-mail: hong.zhang{at}medivir.se

{triangledown} Published ahead of print on 29 June 2009.

Antimicrobial Agents and Chemotherapy, September 2009, p. 3803-3814, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00263-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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