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 107- to 108-fold, down to levels as low as 102 to 103 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.

Comparison of renal safety and efficacy of telbivudine, entecavir and tenofovir treatment in chronic hepatitis B patients: real world experience

“…Furthermore, real-world studies 2 showed no major changes in renal function in TDF-naïve CHB patients [9][10][11][12][13][14] . In 3 contrast to TDF, nucleoside analogs including ETV and LdT did not show renal 4 toxicity at supranormal doses in rat studies 5,15 . It has been shown that the estimated 5 Glomerular Filtration Rate (eGFR) in CHB patients was increased via an unknown 6 mechanism after LdT treatment 16 .…”

“…TDF is an acyclic nucleotide 14 analogue structurally similar to adefovir (ADV), which has been shown to be 15 nephrotoxic 3,4 . Nephrotoxicity with TDF has been demonstrated, including increases 16 in serum creatinine and blood urea nitrogen, decrease in serum phosphate, and 17 glycosuria, proteinuria, and phosphaturia 5 . In HIV-infected patients, TDF therapy 18 has been associated with a modest decline in serum creatinine clearance; cessation M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT of TDF may help to normalize creatinine clearance 6,7 .…”

Entecavir: A new treatment option for chronic hepatitis B

“…At month 3, serum viral load dropped by 7-8 log 10 copies/mL down to 100-1000 copies/mL. Eventually, viraemia levels returned to pre-treatment levels, as observed with other antiviral agents administered for short duration of time (Genovesi et al, 1998). This was followed by a prolonged study of entecavir administration for 14-36 months which showed a prolonged suppression of viral replication including suppression of viral load, a decline in cccDNA levels and expression of viral antigens in the liver of infected animals (Colonno et al, 2001).…”

Current options for the therapy of chronic hepatitis B infection

“…In the woodchuck model, entecavir treatment showed remarkable reduction in the level of woodchuck hepatitis virus DNA without being associated with toxicities in an animal model [28]. A phase I trial in healthy subjects indicates good bioavailability of entecavir after oral absortion and a single daily dose of 5 mg should give plasma concentrations of drug above the effective concentration 50% value against HBV for 24 hours [29].…”