Origin of serum hepatitis B virus in acute exacerbation: Comparison with HBV in the liver and from other exacerbation

Acute exacerbation (AE) of chronic hepatitis B is usually preceded by reemergence or increase of hepatitis B virus (HBV) in the serum. To investigate the origin of the reemergence or increase, we compared the identity of the serum viral genome to that in the liver and in previous AE by full-length sequencing. The full-length viral genome and extent of quasispecies were obtained from serum and liver biopsy specimens at the same time from 9 subjects with hepatitis B exacerbation (group I). Composition of viral quasispecies was compared by the genetic diversity and the average number of nucleotide substitutions within and between different viral sources. Another 2 patients with repeated AEs (group II) were also enrolled, and their serial serum alanine aminotransferase, HBV DNA levels and full-length sequences were determined. In all group I patients, serum viral genome was identical to that in the liver. The genetic diversity and the average number of nucleotide difference were also comparable between serum and liver tissue. In 2 group II patients, the viral variant that emerged after previous AE was not identical to that caused by the subsequent AE. Dominant viral strains for serial AEs in a single patient did not show a sequential evolution, but presented as a horizontal selection of a minor population from the original viral pool. In conclusion, the findings suggest that viral strain in serum reflects the intrahepatic strain of the AE. Random reactivation of the original HBV pool, rather than a sequential evolution of one strain, also contributes to the onset of repeated AE.