IDENTIFICATION OF MORE THAN ONE MUTATION IN THE HEPATITIS-B VIRUS POLYMERASE GENE ARISING DURING PROLONGED LAMIVUDINE TREATMENT

Lamivudine has been shown to be a potent and nontoxic inhibitor of hep atitis B virus (HBV) replication in chronically infected patients. Dur ing prolonged treatment, drug resistance may develop, related to a mut ation of Met to Val or Ile in the YM552DD motif of the HBV DNA polymer ase gene. Analysis of the HBV DNA polymerase gene from 8 chronic hepat itis B patients with suspected resistance to lamivudine showed that in addition to a mutation in the YM552DD motif, a second mutation locate d in the B domain of this gene, a Leu(528)-to-Met(528) change, was con sistently and exclusively found in 4 patients showing the YV552DD moti f. This suggests a functional or structural relationship between these domains. Since the presence of both the YI552DD and YV552DD motif som etimes preceded the exclusive presence of the YV552DD motif, we conclu de that the YI552DD motif could occur as a temporal intermediate. Afte r cessation of therapy, the wild type sequences reemerged.