The treatment of woodchuck hepatitis virus infections with 1-(2'-deoxy-2'-fluoro-4-D-arabinofuranosyl)-5-iodocytosine (FIAC) and 1-(2'-deoxy-2'-fluoro-4-D-arabinofuranosyl)-5-methyluracil (FMAU), given intraperitoneally, caused complete and permanent decrease of serum virus endogenous DNA polymerase and viral DNA in all treated woodchucks but was associated with severe toxicity. By contrast 1-(2'-deoxy-2'-fluoro-l-D-arabinofuranosyl)-5-ethyluracil (FEAU) induced a sustained, although less dramatic, decrease of viral replication without apparent toxic effect. FEAU was also effective when given orally. However, in both cases this inhibitory effect was transient. (7) is often associated with chronic hepatitis leading to liver cirrhosis and hepatocellular carcinoma. So far none of the current treatments, including vidarabine (11, 15), acyclovir (16), alpha interferon (3), and immunomodulatory compounds (18), have been able to satisfy the clinical needs. The discovery of HBV-related animal viruses designated hepadnavirus (8) in woodchucks, ground squirrels, and Pekin ducks offers new possibilities to test potential anti-HBV agents (10,(12)(13)(14). Among the three animal hepadnaviruses, the woodchuck hepatitis virus (WHV) is the most closely related to HBV (6). The natural courses of WHV and HBV chronic hepatitis are comparable, especially progression to hepatocellular carcinoma (5). Thus we investigated in vivo in the woodchuck model the antiviral activity of three compounds of the family of 2'-fluoro-substituted arabinosyl pyrimidine analogs (4)
Hepatitis B virus (HBV) infection, and 1-(2'-deoxy-2'-fluoro-i-D-arabinofuranosyl)-5-ethyluracil (FEAU). Indeed, the triphosphate derivatives of these compounds, known as antiherpetic agents, specifically inhibit the viral DNA polymerases of HBV and WHV in vitro (9). FIAC, FMAU, and FEAU were synthesized in the laboratory of organic chemistry of the Memorial Sloan-Kettering Cancer Center. Adenine arabinoside monophosphate (araAMP) was supplied by the Warner Lambert Co. Woodchucks chronically infected with WHV were obtained from our breeding colony initially established from animals imported from Pennsylvania. WHV replication was followed by the detection of WHV DNA polymerase activity in serum by using virus pelleted by ultracentrifugation through a sucrose cushion and by the detection of WHV DNA in serum by the hybridization spot test of Cova et al. (2). The relative amount of WHV DNA in serum was estimated as previously described (2). Forty-six WHV chronic carrier woodchucks were involved in two independent experiments. These animals were divided into two groups: one group of high replicators with WHV endogenous DNA polymerase * Corresponding author. activity higher than 1,000 cpm and the other group including moderate and low replicators (500 to 1,000 and <500 cpm, respectively). Generally, high replicators were younger (age range, 1 to 2 years); conversely, moderate and especially low replicators were older (3 to 4 years of age). In many cases, we observed that lower le...
