2',3'-DIDEOXY-BETA-L-5-FLUOROCYTIDINE INHIBITS DUCK HEPATITIS-B VIRUSREVERSE TRANSCRIPTION AND SUPPRESSES VIRAL-DNA SYNTHESIS IN HEPATOCYTES, BOTH IN-VITRO AND IN-VIVO

beta-L-Nucleoside analogs represent a new class of potent antiviral ag ents with low cytotoxicity which provide nea hope in the therapy of ch ronic hepatitis B virus (HBV) infections. We evaluated the anti-HBV ac tivity of 2',3'-dideoxy-beta-L-5-fluorocytidine (beta-L-F-ddC), a beta -L-nucleoside analog derived from 2',3'-dideoxycytidine (ddC), in the duck HBV (DHBV) model. This compound was previously shown to inhibit H BV DNA synthesis in a stably transfected hepatoma cell line (F2215). U sing a cell-free system for the expression of an enzymatically active DHBV polymerase, we could demonstrate that the triphosphate form of be ta-L-F-ddC does inhibit hepadnavirus reverse transcription. In primary duck hepatocyte culture, beta-L-F-ddC showed a potent inhibitory effe ct on DHBV DNA synthesis which was concentration dependent. Although b eta-L-F-ddC was shown to be less active than ddC against the DHBV reve rse transcriptase in vitro, beta-L-F-ddC was a stronger inhibitor in h epatocytes. The oral administration of beta-L-F-ddC in experimentally infected ducklings showed that beta-L-F-ddC is a potent inhibitor of v iral replication in vivo, Short-term therapy could not prevent a rebou nd of viral replication after the drug was withdrawn. Preventive thera py with beta-L-F-ddC could delay the onset of viremia by only 1 day co mpared with the time to the onset of viremia in the control group. The in vivo inhibitory effect of beta-L-F-ddC was much stronger than that of ddC and was not associated with signs of toxicity. Our data show t hat beta-L-F-ddC inhibits hepadnavirus reverse transcription and is a strong inhibitor of viral replication both in vitro and in vivo.