LAMIVUDINE THERAPY OF WHV-INFECTED WOODCHUCKS

Hepatitis B viruses establish a chronic, productive, and noncytopathic infection of hepatocytes. Viral products are produced by transcriptio n from multiple copies (5-50) of covalently closed circular (ccc) vira l DNA. This cccDNA does not replicate, but can be replaced by DNA prec ursors that are synthesized in the cytoplasm. The present study was ca rried out to determine if long-term treatment with an inhibitor of vir al DNA synthesis would lead to loss of virus products, including cccDN A, from the liver of woodchucks chronically infected with woodchuck he patitis virus. Viral DNA synthesis was inhibited with the nucleoside a nalog, lamivudine (2'-deoxy-3'-thiacytidine). Lamivudine treatment pro duced a slow but progressive decline in viral titers in serum, to abou t 0.3% or less of the initial level. However, even after maintenance o f drug therapy for 3-12 months, >95% of the hepatocytes in most animal s were still infected. Significant declines in the percentage of infec ted hepatocytes and of intrahepatic cccDNA levels were observed in onl y three woodchucks, two in the group receiving lamivudine and one in t he placebo control group. Moreover, virus titers eventually rose in wo odchucks receiving lamivudine, suggesting that drug-resistant viruses began to spread through the liver starting at least as early as 9-12 m onths of treatment. Three types of mutation that may be associated wit h drug resistance were found at this time, in a region upstream of the YMDD motif in the active site of the viral reverse transcriptase. The YMDD motif itself remained unchanged. Not unexpectedly, the lamivudin e therapy did not have a impact on development of liver cancer. (C) 19 98 Academic Press.