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 HB e-antigen-positive asymptomatic healthy carriers, documented the onset of their disease based on serum alanine transaminase (ALT) concentrat ions, and analyzed sequentially serum samples from a quiescent phase t hrough to an active phase of the chronic infection. In three female ca rriers, 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 c lones with core gene deletions emerged during the quiescent phase and persisted subsequently during the active phase in two patients, who fa iled to seroconvert to anti-HBe and had persistently increased ALT lev els despite interferon (IFN) therapy. The deletions were various, over lapping, and located in the mid-core region ranging from amino acid (a a) position 64 to 128. The remaining patient, who seroconverted with I FN therapy, did not have a core-gene-deletion HBV variant during follo w-up, but had aa substitutions clustered in some restricted core regio ns. Two control asymptomatic carriers, who had no change in biochemica l 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 q uiescent phase. Thus, the immunologic interaction between the host and virus may occur insidiously, and the emergence of a core-gene-deletio n HBV variant during the quiescent phase may be involved in the onset of hepatitis and the subsequent outcome of chronic infection. (C) 1998 Wiley-Liss, Inc.