Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation.


Journal Article

BACKGROUND & AIMS: Lamivudine has become a main therapeutic option for treating hepatitis B virus (HBV) infection. Although drug resistance develops, the clinical course after selection of antiviral-resistant HBV mutants seems to be benign. However, we observed a severe clinical course of hepatitis B infection in several liver transplant recipients after the emergence of lamivudine resistance. This was associated with high viral load in the blood. METHODS: In this report, we characterize the molecular mechanisms underlying drug-dependent enhanced replication of particular lamivudine-resistant HBV mutants selected in these patients, which were associated with sudden onset of liver failure. RESULTS: The clinical course was characterized by a sudden rise in serum bilirubin, prothrombin time, and transaminase. HBV sequence analysis of these patients revealed both mutations in the "a-determinant" of the envelope and the YMDD (tyrosine, methionine, aspartate, aspartate) motif (domain C) of the polymerase protein. Transfection experiments with replication competent vectors indicated that the "a-determinant" changes were not associated with resistance, whereas mutations in the YMDD motif conferred resistance to lamivudine. More importantly, combinations of mutations in the "a-determinant" and the YMDD motif in patients with a severe hepatitis were not only resistant to lamivudine treatment, but showed enhanced replication in vitro in the presence of lamivudine. This observation was confirmed in separate laboratories. CONCLUSIONS: Severe and fatal hepatitis B infection can occur during lamivudine therapy and may be associated with certain HBV mutants selected during sequential nucleoside and HBIg treatment. The lamivudine-enhanced replication shown by these mutants suggests that continuation of therapy with lamivudine could be deleterious in some patients.

Full Text

Cited Authors

  • Bock, C-T; Tillmann, HL; Torresi, J; Klempnauer, J; Locarnini, S; Manns, MP; Trautwein, C

Published Date

  • February 2002

Published In

Volume / Issue

  • 122 / 2

Start / End Page

  • 264 - 273

PubMed ID

  • 11832441

Pubmed Central ID

  • 11832441

International Standard Serial Number (ISSN)

  • 0016-5085

Digital Object Identifier (DOI)

  • 10.1053/gast.2002.31015


  • eng

Conference Location

  • United States