Entecavir (ETV) is a guanosine nucleoside analogue with potent antiviral efficacy in woodchucks chronically infected with woodchuck hepatitis virus. To explore the consequences of prolonged virus suppression, woodchucks received ETV orally for 8 weeks and then weekly for 12 months. Of the 6 animals withdrawn from therapy and monitored for an additional 28 months, 3 had a sustained antiviral response and had no evidence of hepatocellular carcinoma (HCC). Of the 6 animals that continued on a weekly ETV regimen for an additional 22 months, 4 exhibited serum viral DNA levels near the lower limit of detection for >2 years and had no evidence of HCC. Viral antigens and covalently closed circular DNA levels in liver samples were significantly reduced in all animals. ETV was well tolerated, and there was no evidence of resistant variants. On the basis of historical data, long-term ETV treatment appeared to significantly prolong the life of treated animals and delay the emergence of HCC.

ogy, genomic organization, and replication by means of reHepatitis B virus (HBV) has been demonstrated in bile verse transcription. 1,3 duct epithelial cells (BDEC) during chronic infection.The replication of human HBV has been extensively studThe persistence of virus in BDEC may play an important ied in hepatocytes, but comparatively less is known about role in disease pathogenesis, and may be at least partly HBV infection of nonparenchymal cells within the liver. Hepresponsible for the relapse phenomenon observed in adnaviral antigens have been shown in bile duct epithelial antiviral treatments using nucleoside analogues. The cells (BDEC) in both human 7,8 and animal 9,10 livers, but the aims of this study were to examine the morphological significance of these findings has not been fully determined. changes within the liver in the duck hepatitis B modelThe HBV life cycle is complex, and there is evidence that following bile duct ligation (BDL), and to assess the efit may vary depending on the cell type, such as lymphoid fect of biliary hyperplasia upon viral DNA and proteins.cells compared with hepatocytes. 11-15 Also, HBV replication Seven-day-old ducklings, congenitally infected with the appears to be cell-cycle dependent with enhanced viral repliduck hepatitis B virus (DHBV), were subject to BDL. The cation occurring in quiescent compared with proliferating hepathological and virological changes were then followed patocytes. 16 Recent studies have shown that HBV replication at 5, 10, 15, and 20 days after ligation. All results were is inversely correlated with cellular DNA synthesis with noncompared with age-matched unligated control birds cytolytic cell arrest resulting in increased viral expression. 1.3 days. The proliferated BDEC displayed immunohistoTherefore, the interaction of HBV with BDEC warrants more chemical features identical to resting BDEC. More than detailed investigation. The aim of the present study was to 50% of BDEC in unligated controls, and more than 46% characterize DHBV infection in BDEC of congenitally inof proliferated BDEC in ligated animals were positive fected animals, and to examine the effect of cell division on for DHBV DNA and structural proteins. The intensity of hepadnaviral proteins and DNA in proliferating BDEC using immunohistochemical staining and in situ hybridization immunohistochemistry and in situ hybridization, respecsignal in the BDEC was consistently greater than that tively. of the hepatocytes, both before and after BDL. BDL induces biliary hyperplasia in the duck model, and BDEC MATERIALS AND METHODS division does not reduce the viral burden in infected cells. (HEPATOLOGY 1997;25:463-469.)Animals and Experimental Strategy. One-day-old Pekin-Aylesbury ducklings, congenitally infected with an Australian strain of DHBV, were obtained from a commercial supplier.17 Viraemia was monitored by dot blot hybridization as previously described.9,18 Thirty-eight conInfection of Pekin-Aylesbury ducks with the duck hepatitis genitally infected ducklings aged between 7 and 9 ...

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