Emergence of the Precore Mutant Late in Chronic Hepatitis B Infection Correlates With the Severity of Liver Injury and Mutations in the Core Region

Maruyama, Toshiyuki; Mitsui, Hiroshi; Maekawa, Hisato; Yamada, Haruki; Hirayama, Miki; Iino, Shiro; Yasuda, Kiyomi; Koike, Kazuhiko; Kimura, Satoshi; Milich, David R.
October 2000
American Journal of Gastroenterology;Oct2000, Vol. 95 Issue 10, p2894
Academic Journal
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.


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