High degree of conservation in the hepatitis B virus core gene during the immune tolerant phase in perinatally acquired chronic hepatitis B virus infection

• Published in: Journal of hepatology Vol. 26; no. 3; pp. 508 - 516
• Main Authors: Bozkaya, Hakan, Akarca, Ulus S., Ayola, Brick, Lok, Anna S.F.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier B.V 01.03.1997; Elsevier
• Subjects: Adolescent; Adult; Base Sequence; Biological and medical sciences; Child; Child, Preschool; Chronic Disease; Consensus Sequence; Cross-Sectional Studies; DNA, Viral - analysis; Female; Gene Frequency; Genes, Viral; Hepatitis B - genetics; Hepatitis B - immunology; Hepatitis B - transmission; Hepatitis B core antigen; Hepatitis B Core Antigens - genetics; Hepatitis B e antigen seroconversion; Hepatitis B e Antigens - immunology; Hepatitis B virus - genetics; Hepatitis B virus - immunology; Hepatitis B virus core gene; Hepatitis B virus mutations; Human viral diseases; Humans; Infectious Disease Transmission, Vertical; Infectious diseases; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; Vertical transmission; Viral diseases; Viral hepatitis; Vertical transmission; Hepatitis B core antigen; Hepatitis B virus core gene; Hepatitis B e antigen seroconversion; Hepatitis B virus mutations; Human; Family study; Cell nucleus; Perinatal; Hepatic disease; Sequence; Mother to child transmission; Infection; Viral hepatitis B; Gene; Viral disease; Digestive diseases; Chinese; Mutation
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/S0168-8278(97)80415-1

Background: Mutations in the hepatitis B virus genome have been implicated in the persistence of hepatitis B virus infection and the pathogenesis of hepatitis B virus related liver disease. In view of the heterogeneity in published sequences, data from cross-sectional studies of unrelated subjects cannot differentiate true mutations from infections with variant sequences. Aims/Methods: We compared the hepatitis B virus core gene sequences of 42 HBsAg positive subjects from 11 Chinese families with those of the index patients (maternal carriers) to determine the frequency and rate of true hepatitis B virus core gene mutations in patients with chronic hepatitis B virus infection. Results: Completely identifical nucleotide sequences were present in all the family members and index patients in two families, suggesting that the hepatitis B virus core gene can be conserved for more than 20 years. The high degree of sequence conservation in these families is related to the young age of the subjects (mean 19.2±8.9 years), the fact that they were all HBeAg positive and that 75% of them had persistently normal aminotransferase levels. Longitudinal studies confirmed that mutations were rare in those who remained HBeAg positive with normal amino-transferase levels (immune tolerant phase), but significantly more common in HBeAg positive subjects who had elevated aminotransferase levels and in those who cleared HBeAg (immune clearance phase), the rates of nucleotide and amino acid changes were respectively: 0.28±0.12 vs 1.30±0.26/10 3 nt position/yr and 0.04±0.01 vs 0.18±0.5/10 2 codon/yr. Conclusions: Identical nucleotide differences could be found in the sequences of all the subjects in some families. These differences were more likely to be due to intra-familial transmission of stable variants. Sequence analysis based on comparisons with published sequences would have led to over-reporting of mutations. The hepatitis B virus core gene can remain highly conserved for more than two decades during the immune tolerant phase of perinatally acquired chronic hepatitis B virus infection. However, significant changes can occur within 2–3 years during the immune clearance phase.