Deletions in the hepatitis B virus core gene may influence the clinical outcome in hepatitis B e antigen-positive asymptomatic healthy carriers.

To address the significance of mutations within the hepatitis B virus (HBV) core gene in chronic HBV infection, we followed prospectively HBe-antigen-positive asymptomatic healthy carriers, documented the onset of their disease based on serum alanine transaminase (ALT) concentrations, and analyzed sequentially serum samples from a quiescent phase through to an active phase of the chronic infection. In three female carriers, the first flare-up was documented during the follow-up period. Serial analysis by polymerase chain reaction, cloning, and sequencing of the HBV precore/core open reading frame genome demonstrated that clones with core gene deletions emerged during the quiescent phase and persisted subsequently during the active phase in two patients, who failed to seroconvert to anti-HBe and had persistently increased ALT levels despite interferon (IFN) therapy. The deletions were various, overlapping, and located in the mid-core region ranging from amino acid (aa) position 64 to 128. The remaining patient, who seroconverted with IFN therapy, did not have a core-gene-deletion HBV variant during follow-up, but had aa substitutions clustered in some restricted core regions. Two control asymptomatic carriers, who had no change in biochemical or virologic markers over a 15- to 19-year period, had no core-gene-deletion variants and few aa changes. These findings indicate that the mid-portion of the core gene is subject to deletion even during the quiescent phase. Thus, the immunologic interaction between the host and virus may occur insidiously, and the emergence of a core-gene-deletion HBV variant during the quiescent phase may be involved in the onset of hepatitis and the subsequent outcome of chronic infection.