Evolution of the hepatitis B virus gene during chronic infection in seven patients

We analyzed the evolution of the precore/core gene of hepatitis B virus (HBV) over a period of 6 to 11 years in seven patients with chronic HBV infection, who exhibited a variety of clinical features. Sequence analysis revealed the following results: (1) HBeAg to anti‐HBe seroconversion was correlated roughly with the occurrence of precore‐defective mutants, and several years appeared to be required for complete replacement of wild types by mutants; (2) core gene mutations preceded precore‐defective mutations and tended to increase with time, although not cumulatively. They occurred not only during serum alanine aminotransferase (ALT) elevations but also after ALT returned to normal; (3) ALT fluctuations appeared to subside with complete replacement of the wild type by the mutant type and/or substantial accumulation of core gene mutations; (4) unexpectedly, the anti‐HBe‐positive “healthy” carrier was found to harbor the wild type precore gene, as did the HBeAg‐positive “healthy” carrier; however, the core gene of the former evolved at a rapid rate; and (5) a partial deletion was recognized in the core gene at the onset of fatal hepatic failure in one patient. Thus, the precore/core mutation was closely related with the clinical features in the patients. © 1994 Wiley‐Liss, Inc.