Mutational patterns of hepatitis B virus genome and clinical outcomes after emergence of drug-resistant variants during lamivudine therapy: analyses of the polymerase gene and full-length sequences.

It remains unclear whether mutational patterns of the hepatitis B virus (HBV) genome are associated with the development of severe hepatitis after the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) variants during lamivudine treatment. Thirty patients with chronic hepatitis B who had YMDD variants during lamivudine therapy and were followed up subsequently while receiving lamivudine alone for at least 6 months were examined retrospectively. The lamivudine resistant mutations in the HBV polymerase gene were detected by a line probe assay, and the full-length sequences of HBV DNA were determined in some patients. Between months 5 and 33 of therapy, mutations from methionine to isoleucine at rt204 (rtM204I) were detected in 18 patients, and mutations from methionine to valine at rt204 (rtM204V) were detected in 12. The rtM204V mutations were always accompanied by mutations from leucine to methionine at rt180 (rtL180M), while rtM204I mutations were not. Baseline characteristics, alanine aminotransferase (ALT) levels, and HBV DNA levels within 6 months after the emergence of YMDD variants did not differ significantly between patients with rtM204I alone and those with rtL180M/rtM204V. No specific mutation was identified on full-length sequence analysis in three patients with a hepatitis flare. During long term follow-up, the addition of rtL180M to rtM204I was found in four patients 7-31 months after detecting the change at rt204 and was linked to increased ALT levels. In conclusion, mutational patterns of HBV DNA at the time of emergence of YMDD variants were apparently unrelated to the clinical outcomes in Japanese patients with chronic hepatitis B during lamivudine therapy.