A Prospective Study Characterizing Full-Length Hepatitis B Virus Genomes during Acute Exacerbation

Background and Aims: Hepatitis B virus (HBV) evolves rapidly in chronic hepatitis B patients and HBV variation may trigger acute exacerbation. To study this relationship, we investigated full-length viral sequences before, during and after the exacerbation. Methods: We prospectively collected 14 patients with hepatitis B exacerbation, either spontaneously (n=4), or after receiving various medical interventions (n=10), and followed their serum alanine aminotransferase (ALT) and HBV DNA levels monthly. Full- length HBV genomes at baseline, at the peak of serum viral load, at and after ALT peak, were obtained by polymerase chain reaction and sequenced, and compared. Replication activities of serial HBV variants were assayed by in vitro transfection. Results: An increase of serum viral load was observed in all exacerbations. Viral peak preceded ALT peak in 13 (93%) of the 14 patients. At virologic peak, 12 (86%) patients harbored viral genome identical to the corresponding baseline one. At and after ALT peak, 9 (64%) and 7 (50%) of the viral genomes remained identical to baseline one, respectively. Mean nucleotide change per genome was 0.2 at virologic peak, but increased to 4.4 and 8 .1 at and after ALT peak, respectively. The replication potential of the viral variant emerged during or after exacerbation was equivalent to that at baseline. Conclusions : Most exacerbations were preceded by an upsurge of serum HBV identical to the pre-existing HBV strain. After exacerbation, about half of the patients were repopulated by a different viral variant, that was likely a result of immune selection