Hepatitis B virus variants in patients receiving lamivudine treatment withbreakthrough hepatitis evaluated by serial viral loads and full-length viral sequences

Both viral loads and genome variations have been implicated in the pathogen esis of acute exacerbation of chronic hepatitis B. Hepatitis B exacerbation in patients receiving lamivudine treatment represented a unique setting to clarify their importance. Three organ recipients with posttransplantation hepatitis B exacerbation and 3 patients with chronic hepatitis B were studi ed. All received lamivudine treatment and their alanine aminotransferase (A LT) levels and hepatitis B virus (HBV) loads were regularly followed. Full- length genomic sequences before and during lamivudine treatment were determ ined in patients who had breakthrough of serum HBV DNA or elevation of seru m ALT. Breakthrough of serum HBV DNA occurred after 6 to 15 months of lamiv udine treatment in all. A rapid increase of viral load accompanying the eme rgence of tyrosine-methionine-aspartate-aspartate (YMDD) variant was follow ed by hepatitis B exacerbation in each patient. The mean number of nucleoti de and amino acid substitutions per genome pair was equivalent in immunosup pressed or immunocompetent patients (6.3 vs. 6.3 for nucleotide, P > .05; 6 .0 vs. 6.7 for amino acid, P > .05). Changes of nucleotide and amino acid b eyond the YMDD motif were distributed along the whole HBV genome but none o ccurred within the known B-cell epitopes and human leukocyte antigen class I- or II-restricted T-cell epitopes. Our results suggest that a resurgence of viral load rather than changes of the known immunogenic viral epitopes i s more closely associated with the development of hepatitis B exacerbation after the emergence of YMDD variants in patients receiving lamivudine treat ment.