Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation
AuthorBock, CT; Tillmann, HL; Torresi, J; Klempnauer, J; Locarnini, S; Manns, MP; Trautwein, C
PublisherW B SAUNDERS CO
University of Melbourne Author/sTorresi, Joseph
AffiliationMedicine - Royal Melbourne And Western Hospitals
Document TypeJournal Article
CitationsBock, CT; Tillmann, HL; Torresi, J; Klempnauer, J; Locarnini, S; Manns, MP; Trautwein, C, Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation, GASTROENTEROLOGY, 2002, 122 (2), pp. 264 - 273
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C1 - Journal Articles Refereed
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.
KeywordsMedical Virology ; Clinical Pharmacology and Therapeutics; Infectious Diseases
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