Transient emergence of hepatitis B variants in a patient with chronic hepatitis B resistant to lamivudine

Background: Lamivudine is a cytosine nucleoside analogue that inhibits hepatitis B virus replication. Resistance to lamivudine monotherapy has been reported in patients who received lamivudine to prevent recurrent hepatitis B virus infection after liver transplantation. No cases of resistance have been described in patients who did not clear HBV DNA during lamivudine therapy. Methods: We report the case of an adult patient with chronic HBeAg-positive hepatitis B who had a hepatitis flare during lamivudine therapy. The patient did not respond to lamivudine and, at 4 months of treatment, developed a significant serum alanine aminotransferase elevation. Alanine aminotransferase levels remained elevated for 4 months and returned to baseline spontaneously. Lamivudine therapy was administered for 1 year (52 weeks) and after withdrawal, alanine aminotransferase levels remained elevated. Results: Sequencing studies of HBV DNA at week 52 showed the emergence of a lamivudine-resistant variant associated with two point mutations in the hepatitis B virus polymerase gene: one mutation led to amino acid substitution of methionine to valine at residue 552, in the highly conserved tyrosine-methionine-aspartate-aspartate motif, part of the active site of the polymerase; the second mutation consisted of a substitution of leucine to methionine at residue 528. At week 54 of follow-up, both mutations were undetectable. Conclusion: This observation demonstrates the transient emergence of HBV variants in the course of therapy in a patient resistant to lamivudine therapy.