Antiviral activity of beta-L-2 ',3 '-dideoxy-2 ',3 '-didehydro-5-fluorocytidine in woodchucks chronically infected with woodchuck hepatitis virus

The L-nucleoside analog beta -L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytid ine (beta -L-Fd4C) was first shown to exhibit potent activity against hepat itis B virus (HBV) in tissue culture and then to significantly inhibit vira l spread during acute infection in the duck HBV model (F. Le Guerhier et al ,, Antimicrob, Agents Chemother, 44:111-122, 2000), We have therefore exami ned its antiviral activity in a mammalian model of chronic HBV infection, t he woodchuck chronically infected with woodchuck hepatitis virus (WHV). Sid e-by-side comparison of beta -L-Fd4C and lamivudine administered intraperit oneally during short-term and long-term protocols demonstrated a more profo und inhibition of viremia in beta -L-Fd4C-treated groups. Moreover, beta -L -Fd4C induced a marked inhibition of intrahepatic viral DNA synthesis compa red with that induced by lamivudine, Nevertheless, covalently closed circul ar (CCC) DNA persistence explained the lack of clearance of infected hepato cytes expressing viral antigens and the relapse of WHV replication after dr ug withdrawal. Liver histology showed a decrease in the inflammatory activi ty of chronic hepatitis in woodchucks receiving beta -L-Fd4C, An electron m icroscopy study showed the absence of ultrastructural changes of hepatic mi tochondria, biliary canaliculi, and bile ducts, However, a loss of weight w as observed in all animals, whatever the treatment, as was a transient skin pigmentation in all woodchucks during beta -L-Fd4C treatment. There was no evidence that lamivudine or beta -L-Fd4C could prevent the development of hepatocellular carcinoma with the protocols used. These results indicate th at beta -L-Fd4C exhibits a more potent antiviral effect than lamivudine in the WHV model but was not able to eradicate CCC DNA and infected cells from the liver at the dosage and with the protocol used.