Clinical Significance of Precore and Core Promoter Mutations in Genotype D Hepatitis B-Related Chronic Liver Disease

Abstract

Background: Hepatitis B virus (HBV) infection is the most common cause of end-stage liver disease in Iran. More than 70% of cases are negative for the hepatitis B e antigen (HBeAg) and have a long-term response to antiviral therapy, as well as a high relapse rate after discontinuing lamivudine or interferon. These features could be due, in part, to genetic variation of the HBV genome.

Materials and Methods: HBV-DNA from serum of 110 patients with chronic hepatitis B, some of whom were complicated by cirrhosis and hepatocellular carcinoma (HCC) was sequenced for basal core promoter and precore region. Twenty four of 110 patients were performed for full genomic analysis.

Results: In the first part of study all twenty four strains were classified into subgenotype D1, with 99% bootstrap values. In second part of study we showed that the HBeAg negative patients had a higher frequency of mutations at core promoter regions than HBeAg-positive patients (76.8% vs 26.6%). The frequencies of A1762T and G1764A mutations increased while the frequency of G1757A decreased with advance clinical stage of liver disease (p‹0.001). The double core promoter mutations T1762 /A1764 associated with G1757 conferred significantly higher and more frequent in patients with cirrhosis and HCC.

Conclusion: In Iran, all patients with chronic HBV, whether HBeAg positive or HBeAg negative, at the stage of cirrhosis and HCC were genotype D1. High frequency of mutations indicates the relation of antiviral pressure in Iranian population. The A1762T /G1764A double mutation of basal core promoter with A1757G polymorphism can major impacts on viral replication and severity of liver disease.