Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: A longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline

doi:10.1016/j.jhep.2005.03.018

Journal of Hepatology

Volume 43, Issue 3, September 2005, Pages 411-417

https://doi.org/10.1016/j.jhep.2005.03.018 Get rights and content

Background/Aims

Longitudinal studies on the relationship between hepatitis B virus (HBV) genotypes and reactivation of hepatitis B and progression to cirrhosis were very rare.

Methods

Liver biochemistry, virological markers and ultrasound were monitored in 202 hepatitis B e antigen (HBeAg)-positive patients with normal alanine aminotransferase (ALT) at baseline for 3–20 (average 10.8) years, and the outcome was correlated with HBV genotypes.

Results

There were 150 genotype B and 52 genotype C patients. Hepatitis activity during the HBeAg-positive phase showed no significant difference. However, genotype B was associated with a significantly earlier and higher rate of HBeAg seroconversion. HBeAg seroconversion correlated with age at entry for genotype B and with ALT levels for genotype C. Reactivation of hepatitis B was significantly more common in genotype C patients. Five genotype B and 10 genotype C patients progressed to cirrhosis. Multivariate analysis revealed that genotype C (P=0.03) and reactivation of hepatitis B (P=0.0004) were independent factor predictive of cirrhosis.

Conclusions

Rate and factors of HBeAg seroconversion, and rate of reactivation of hepatitis B differed between genotype B and genotype C patients. Genotype C and reactivation of hepatitis B were associated with increased risk of cirrhosis.

Introduction

There are eight genotypes of hepatitis B virus (HBV) designated A to H based on greater than 8% nucleotide variation over the entire genome [1]. The eight genotypes of HBV show a distinct geographical distribution. The prevalent genotypes in Asia are genotypes B and C [2]. HBV genotypes may influence the course of disease. Studies of the Asian patients revealed that, compared to genotype B, genotype C is associated with a higher prevalence of hepatitis B e antigen (HBeAg), higher serum levels of HBV DNA, higher histological activities, more severe acute exacerbation, a lower rate of spontaneous HBeAg seroconversion, and a higher rate of cirrhosis and hepatocellular carcinoma [3], [4], [5], [6], [7], [8], [9], [10], [11]. However, other studies have shown controversial results: there was no significant difference in spontaneous HBeAg seroconversion rate between genotype B and genotype C [12], [13]; the frequency of acute exacerbation showed no significant difference between genotype B and genotype C [12], [14]; severe icteric acute exacerbation was associated with genotype B rather than genotype C [15], [16]; and the distribution of genotype B and genotype C showed no significant difference between different stage of chronic liver disease [12], [15]. The reason for these controversies remains unknown. Furthermore, it has been shown that reactivation of hepatitis B is a major risk factor for progression to cirrhosis [17], [18]. However, the relationship between HBV genotypes and reactivation of hepatitis B and progression to cirrhosis has been rarely explored in longitudinal studies.

The natural history of chronic HBV infection can be divided into three phases: immune tolerance (HBeAg positive and normal alanine aminotransferase [ALT]), immune clearance (HBeAg positive and elevated ALT), and residual phases (hepatitis B e antibody [anti-HBe] positive and normal ALT) [19], [20], [21]. Previous studies on the natural course of chronic HBV infection usually included patients with chronic hepatitis B. Most of these studies were reported from tertiary medical centers and likely enrolled patients with more severe or protracted course. A longitudinal study beginning at the early phase of infection may minimize the referral bias inherent to many natural history studies [18]. In this study, the impact of HBV genotype on the natural course of chronic HBV infection was studied in 202 HBeAg-positive patients with normal ALT at baseline.

Section snippets

Patients

From 1982 to 2000, asymptomatic adults incidentally identified as hepatitis B surface antigen (HBsAg) carriers during blood donation or health test were recruited into the present study if they fulfilled the following criteria: (1) HBeAg positive by radioimmunoassay with counts per minute/cut-off value ratios >2.0, normal ALT (<40 U/l), no evidence of cirrhosis or hepatocellular carcinoma based on the clinical ground and ultrasound examination, and no concomitant hepatitis C or D virus infection

Clinical characteristics at baseline and during follow up

Of the 206 study patients, 150 had genotype B and 52 had genotype C, while four had HBV genotypes unclassified and were excluded from analysis. Table 1 compares the clinical characteristics at baseline and during follow up between genotype B and genotype C patients.

ALT levels returned to normal in all patients after HBeAg seroconversion. During a median follow up of 5–6 years, reactivation of hepatitis B, defined as elevation of ALT accompanied by reappearance of HBV DNA [median (range)

Discussion

The present study had two unique features. First, the subjects recruited in this study were HBeAg-positive patients with normal ALT at baseline. By the contrast, most previous studies have included patients with chronic hepatitis B and were reported from tertiary medical centers, where patients are likely to have a more severe or protracted course. Second, the followed up duration was long up to 20 years (mean 11 years) that enabled us to delineate the rate of reactivation of hepatitis B and

Acknowledgements

This study was supported by a grant from National Science of Council, Taiwan, ROC.

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Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: A longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline

Background/Aims

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Clinical characteristics at baseline and during follow up

Discussion

Acknowledgements

Gastroenterology

Hepatology

Hepatology

Hepatology

Gastroenterology

Hepatology

Am J Med

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

J Hepatol

Gastroenterology

Hepatitis B virus genotypes: comparison of genotyping methods

Rev Med Virol

Hepatitis B viral genotypes: clinical relevance and molecular characteristics

J Gastroenterol Hepatol

Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers

J Infect Dis