Evolution of Hepatitis B Virus Precore/Basal Core Promoter Gene
Evolution of Hepatitis B Virus Precore/Basal Core Promoter Gene
Aim: Lamivudine is effective in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, but the relapse rate after cessation of treatment is high. The evolution of viral genome may contribute to the viral replication under antiviral pressure of lamivudine. We therefore determined the evolution of hepatitis B virus (HBV) precore/basal core promoter and polymerase genes in HBeAg-positive chronic hepatitis B patient during lamivudine therapy.
Method: Thirteen patients with HBeAg-positive chronic hepatitis who had received short-term lamivudine therapy (mean, 30 weeks) during 1999-2001 were enrolled. The precore/basal core promoter region and polymerase gene were amplified and directly sequenced before, during and post lamivudine treatment.
Result: HBeAg loss or seroconversion occurred in 11, but eight relapsed after stopping therapy and five had reversion of HBeAg. Before treatment, basal core promoter mutation was found in 1. In the first 3 months of therapy, a rapid decline of serum HBV DNA level accompanied with basal core promoter mutation appeared in 11 of 13 patients (vs. before therapy; P=0.003). However, this mutant was replaced by wild-type virus in four of eight patients who relapsed after treatment. There was no significant change of precore sequences before and during therapy.
Conclusions: Lamivudine therapy may result in the rapid development of basal core promoter mutation of HBV, but this mutation may revert to wild type gradually after cessation of therapy.
Hepatitis B virus (HBV) is the major cause of acute and chronic liver diseases worldwide, and persistent HBV infection is closely associated with the development of cirrhosis and hepatocellular carcinoma (HCC). Lamivudine is the first nucleoside analogue for the treatment of chronic active hepatitis B, which has been shown to increase hepatitis B e antigen (HBeAg) seroconversion and reduce progression of hepatic fibrosis. Nevertheless, the relapse rate is high after cessation of lamivudine therapy unless HBeAg seroconversion occurs.
HBV mutant strains selected during HBeAg seroconversion, which allow the persistence of viral replication after loss of HBeAg have been reported. Among these mutants, precore stop codon mutation (G1896A) that abolishes the synthesis of HBeAg has been extensively studied and may play a role in HBeAg-negative chronic hepatitis B. In addition, double mutations in the basal core promoter (A1762T and G1764A) are also demonstrated to reduce the synthesis of HBeAg by suppressing the transcription of precore mRNA in both HBeAg-positive and -negative patients. Our recent data further indicated that this mutation may increase the risk of HCC in HBV carriers. Nevertheless, little is known about whether these two mutants are being selected during antiviral therapy. The aim of this study was thus to determine the evolution of HBV precore/basal core promoter and polymerase genes in HBeAg-positive chronic hepatitis B patients during lamivudine therapy.
Aim: Lamivudine is effective in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, but the relapse rate after cessation of treatment is high. The evolution of viral genome may contribute to the viral replication under antiviral pressure of lamivudine. We therefore determined the evolution of hepatitis B virus (HBV) precore/basal core promoter and polymerase genes in HBeAg-positive chronic hepatitis B patient during lamivudine therapy.
Method: Thirteen patients with HBeAg-positive chronic hepatitis who had received short-term lamivudine therapy (mean, 30 weeks) during 1999-2001 were enrolled. The precore/basal core promoter region and polymerase gene were amplified and directly sequenced before, during and post lamivudine treatment.
Result: HBeAg loss or seroconversion occurred in 11, but eight relapsed after stopping therapy and five had reversion of HBeAg. Before treatment, basal core promoter mutation was found in 1. In the first 3 months of therapy, a rapid decline of serum HBV DNA level accompanied with basal core promoter mutation appeared in 11 of 13 patients (vs. before therapy; P=0.003). However, this mutant was replaced by wild-type virus in four of eight patients who relapsed after treatment. There was no significant change of precore sequences before and during therapy.
Conclusions: Lamivudine therapy may result in the rapid development of basal core promoter mutation of HBV, but this mutation may revert to wild type gradually after cessation of therapy.
Hepatitis B virus (HBV) is the major cause of acute and chronic liver diseases worldwide, and persistent HBV infection is closely associated with the development of cirrhosis and hepatocellular carcinoma (HCC). Lamivudine is the first nucleoside analogue for the treatment of chronic active hepatitis B, which has been shown to increase hepatitis B e antigen (HBeAg) seroconversion and reduce progression of hepatic fibrosis. Nevertheless, the relapse rate is high after cessation of lamivudine therapy unless HBeAg seroconversion occurs.
HBV mutant strains selected during HBeAg seroconversion, which allow the persistence of viral replication after loss of HBeAg have been reported. Among these mutants, precore stop codon mutation (G1896A) that abolishes the synthesis of HBeAg has been extensively studied and may play a role in HBeAg-negative chronic hepatitis B. In addition, double mutations in the basal core promoter (A1762T and G1764A) are also demonstrated to reduce the synthesis of HBeAg by suppressing the transcription of precore mRNA in both HBeAg-positive and -negative patients. Our recent data further indicated that this mutation may increase the risk of HCC in HBV carriers. Nevertheless, little is known about whether these two mutants are being selected during antiviral therapy. The aim of this study was thus to determine the evolution of HBV precore/basal core promoter and polymerase genes in HBeAg-positive chronic hepatitis B patients during lamivudine therapy.
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