Combination of HBIG and lamivudine‐resistant mutations: A formula for trouble?

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.