Profound suppression of hepatitis B virus replication with lamivudine

The therapeutic goats in chronic hepatitis B are to prevent or decrease cir rhosis and hepatocellular carcinoma in patients with pre-cirrhotic or early cirrhotic disease and to stabilise patients with end-stage cirrhosis. Lami vudine is an oral nucleoside analogue that suppresses hepatitis B virus (HB V) replication, and so may achieve both these treatment objectives. The act ive 5'-triphosphate metabolite of lamivudine has two modes of viral suppres sion. First, it mimics deoxycytidine triphosphate and is incorporated into newly synthesised HBV DNA to cause chain termination. Second, it demonstrat es competitive inhibition of viral DNA-dependent and RNA-dependent DNA poly merase activity (i.e., reverse transcriptase activity). Lamivudine may, the refore, act at four possible stages during HBV replication: reverse transcr iption of pre-genomic mRNA into nascent minus-strand DNA; formation of plus strand DNA from nascent minus-strand DNA; completion of double-stranded DN A; and formation of covalently closed circular DNA. In clinical studies, la mivudine therapy reduced serum HBV DNA and this was associated with signifi cant improvements in liver histology and significant and sustained enhancem ent of the proliferative CD4-mediated response to HBeAg and hepatitis B cor e antigen (HBcAg), and an increased frequency of HBeAg-specific T cells. HB V DNA concentrations often returned to pre-treatment values when therapy en ded prior to the loss of hepatitis B e antigen (HBeAg). Although the emerge nce of HBV variants with a mutation in the YMDD (tyrosine-methionine-aspart ate-aspartate) motif has been observed, such variants show reduced suscepti bility to lamivudine due to limited replication competence, and their emerg ence is not a signal to cease lamivudine therapy. In conclusion, viral supp ression with lamivudine offers a means of disease improvement and immunolog ical control in chronic hepatitis B. (C) 2000 Wiley-Liss, Inc.