Efficacy of the carbocyclic 2'-deoxyguanosine nucleoside BMS-200475 in the woodchuck model of hepatitis B virus infection.
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.
Genovesi
E V
EV
Pharmaceutical Research Institute, Bristol-Myers Squibb, Wallingford, Connecticut 06492, USA. eugenevvvgenovesi@ccmail.bms.com
Lamb
L
L
Medina
I
I
Taylor
D
D
Seifer
M
M
Innaimo
S
S
Colonno
R J
RJ
Standring
D N
DN
Clark
J M
JM
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood / Q000378:metabolism; D003849:Deoxyguanosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006509:Hepatitis B / Q000188:drug therapy* / Q000821:virology; D017919:Hepatitis B Virus, Woodchuck / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000821:virology; D008392:Marmota; D016133:Polymerase Chain Reaction; D013997:Time Factors; D006147:Guanine / Q000031:analogs & derivatives
D000998:Antiviral Agents; D004279:DNA, Viral; D003849:Deoxyguanosine; C413685:entecavir; D006147:Guanine