Emergence of the precore mutant late in chronic hepatitis B infection correlates with the severity of liver injury and mutations in the core region.
OBJECTIVE
The reason that precore negative mutants (e-minus DNA) gradually become predominant in some patients during chronic hepatitis B virus infection is not clear. Theoretically, as long as both e-plus and e-minus DNA share the same epitopes in the core region, HBcAg-specific cytotoxic T lymphocytes (CTLs) cannot distinguish between the target peptides expressed by e-plus and e-minus DNA. Therefore, e-minus DNA may be accompanied by additional mutations in the core region, which may affect cytotoxic T lymphocyte recognition. To examine this possibility, the sequences of the precore and the entire core region of the hepatitis B virus genome were analyzed from paired serum samples in CH-B patients who experienced HBeAg to anti-HBe seroconversion (SC).


METHODS
Patients were divided into two groups. Group A patients (n = 17) genome-converted to e-minus DNA in the precore region, which abolished HBeAg secretion within 3-4 yr after SC. Group B patients (n = 16) retained precore wild-type DNA for more than 3-4 yr after SC. To investigate the impact of the emergence of precore mutant type DNA on liver injury, alanine aminotransferase (ALT) levels were also examined.


RESULTS
ALT flares were more severe among patients in group A than in group B. The average mean ALT level during the HBeAg negative phase of chronic infection was 54 +/- 38 in group A and 28 +/- 24 in group B. The average maximal ALT level during the HBeAg negative phase was 235 +/- 249 in group A and 83 +/- 106 in group B. Furthermore, all 17 patients in group A developed new core mutants during genome conversion. The average number of mutations in the core gene was 0.9 +/- 1.2 before genome conversion (e-plus DNA dominant phase) and increased to 2.8 +/- 1.3 for the 3-4 yr during genome conversion (e-minus DNA dominant phase). In contrast, only 56% (nine of 16) of patients in group B developed new core mutations after the loss of HBeAg. The average number of mutations in the core gene was 1.8 +/- 1.3 before SC (HBeAg-positive and e-plus DNA dominant phase), and decreased to 1.1 +/- 1.1 for 3-4 yr after seroconversion (anti-HBe-positive and e-plus DNA dominant phase).


CONCLUSIONS
These data indicate that the emergence of a predominant precore negative genotype late in chronic hepatitis B virus infection is associated with the selection of additional mutations in the core gene, as well as with liver injury.
Maruyama
T
T
First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Mitsui
H
H
Maekawa
H
H
Yamada
H
H
Hirayama
M
M
Iino
S
S
Yasuda
K
K
Koike
K
K
Kimura
S
S
Milich
D R
DR
D000293:Adolescent; D000328:Adult; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D006510:Hepatitis B Antibodies / Q000097:blood; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics* / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000821:virology*; D006801:Humans; D008103:Liver Cirrhosis / Q000276:immunology / Q000821:virology*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D014758:Viral Core Proteins / Q000235:genetics* / Q000276:immunology; D014774:Virulence / Q000235:genetics
D006510:Hepatitis B Antibodies; D006513:Hepatitis B e Antigens; D014758:Viral Core Proteins