HIGH-DEGREE OF CONSERVATION IN THE HEPATITIS-B VIRUS CORE GENE DURINGTHE IMMUNE TOLERANT PHASE IN PERINATALLY ACQUIRED CHRONIC HEPATITIS-BVIRUS-INFECTION

Background: Mutations in the hepatitis B virus genome have been implic ated in the persistence of hepatitis B virus infection and the pathoge nesis of hepatitis B virus related liver disease, In view of the heter ogeneity 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 vir us core gene sequences of 42 HBsAg positive subjects from 11 Chinese f amilies with those of the index patients (maternal carriers) to determ ine the frequency and rate of true hepatitis B virus core gene mutatio ns in patients with chronic hepatitis B virus infection. Results: Comp letely identical nucleotide sequences were present in all the family m embers and index patients in two families, suggesting that the hepatit is 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 y oung 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 aminotrans ferase levels (immune tolerant phase), but significantly more common i n HBeAg positive subjects who had elevated aminotransferase levels and in those who cleared HBeAg (immune clearance phase), the rates of nuc leotide and amino acid changes were respectively: 0.28 +/- 0.12 vs 1.3 0 +/- 0.26/103 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 differen ces were more likely to be due to intra-familial transmission of stabl e variants, Sequence analysis based on comparisons with published sequ ences would have led to over-reporting of mutations, The hepatitis B v irus core gene can remain highly conserved for more than two decades d uring the immune tolerant phase of perinatally acquired chronic hepati tis B virus infection, However, significant changes can occur within 2 -3 years during the immune clearance phase.