Efficacy of the carbocyclic 2'-deoxyguanosine nucleoside BMS-200475 in the woodchuck model of hepatitis B virus infection.

Abstract

Daily oral treatment with the cyclopentyl 2'-deoxyguanosine nucleoside BMS-200475 at doses ranging from 0.02 to 0.5 mg/kg of body weight for 1 to 3 months effectively reduced the level of woodchuck hepatitis virus (WHV) viremia in chronically infected woodchucks as measured by reductions in serum WHV DNA levels and endogenous hepadnaviral polymerase activity. Within 4 weeks of daily therapy with 0.5 or 0.1 mg of BMS-200475 per kg, endogenous viral polymerase levels in serum were reduced about 1,000-fold compared to pretreatment levels. Serum WHV DNA levels determined by a dot blot hybridization technique were comparably decreased in these treated animals. In the 3-month study, the sera of animals that had undetectable levels of WHV DNA by the dot blot technique were further analyzed by a highly sensitive semiquantitative PCR assay. The results indicate that BMS-200475 therapy reduced mean WHV titers by 10(7)- to 10(8)-fold, down to levels as low as 10(2) to 10(3) virions/ml of serum. Southern blot hybridization analysis of liver biopsy samples taken from animals during and after BMS-200475 treatment showed remarkable reductions in the levels of WHV DNA replicative intermediates and in the levels of covalently closed circular viral DNA. WHV viremia in BMS-200475-treated WHV carriers eventually returned to pretreatment levels after therapy was stopped. These results indicate that BMS-200475 should be evaluated in clinical trials for the therapy of chronic human hepatitis B virus infections.

• Authors: E V Genovesi, L Lamb, I Medina, D Taylor, M Seifer, S Innaimo, R J Colonno, D N Standring, J M Clark
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 42 Issue 12 Pg. 3209-17 (Dec 1998) ISSN: 0066-4804 [Print] United States
• PMID: 9835516 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• DNA, Viral
• entecavir
• Deoxyguanosine

Topics

• Animals
• Antiviral Agents (administration & dosage, therapeutic use)
• DNA, Viral (blood, metabolism)
• Deoxyguanosine (administration & dosage, analogs & derivatives, therapeutic use)
• Hepatitis B (drug therapy, virology)
• Hepatitis B Virus, Woodchuck (metabolism)
• Liver (metabolism, virology)
• Marmota
• Polymerase Chain Reaction
• Time Factors