Mutations in the
DNA of the hepatitis B virus have been discovered and they may have clinical significance. A single
nucleotide substitution resulting in a
premature stop codon in the pre-core region of the
hepatitis B genome is the most common change. The
premature stop codon prevents the synthesis of
hepatitis B e antigen (
HBeAg), a virally encoded
protein normally secreted by hepatocytes. The mutant hepatitis B virus was initially discovered in patients who lacked
HBeAg in the serum yet had high levels of
hepatitis B viral DNA, a marker of active viral replication usually found in association with the continued presence of
HBeAg. Other studies demonstrated that the mutant forms were observed with increasing frequency during the successful conversion from
HBeAg positivity to anti-
hepatitis B e antibody (anti-HBe) positivity. The mutant form of hepatitis B virus was not identified in patients with stable
chronic hepatitis B who were positive for
HBeAg or in any patients with uncomplicated acute
hepatitis B, regardless of the presence of
HBeAg or anti-HBe. However, mutant hepatitis B virus was detected in patients with
fulminant hepatitis B who lacked both
HBeAg and anti-HBe. The lack of
HBeAg in the serum therefore may result in a more severe form of
acute disease. Together with experimental animal studies of the normal role of
HBeAg, these data suggest that serum
HBeAg may be associated with immunologic tolerance, whereas clearance of or lack of
HBeAg may be associated with an active immunologic response. Future studies are expected to clarify the role of mutant forms of hepatitis B virus in the natural history of
hepatitis B infection.