The role of Hepatitis B virus X gene on the natural history of hepatitis B virus infection
Date Issued
2016
Date
2016
Author(s)
Chang, Kai-Chi
Abstract
Abstract Backgrounds and Aims Chronic hepatitis B virus (HBV) infection is a world-wide health problem. Persistent HBV infection is often associated with chronic liver disease and may lead to liver cirrhosis and hepatocellular carcinoma (HCC). HBV infections were mostly acquired in the infancy and early childhood through the route of mother-to-infant transmission, especially in endemic areas such as Taiwan. Children with HBV infection often remained asymptomatic at their young age, and their immune tolerance phases may last 2 decades or longer. The mechanism of HBV to evade or overwhelm the human innate immune system, and to keep a state of relative hypo-responsiveness to HBV in children still remained largely unclear. Recently, HBx gene, which was one of the four HBV functional genes, had been reported to be involved in the host immune abrogation. However, the relationship between HBx mutation and either the persistence or the ending of immune tolerance was unknown. The impacts of HBx mutation on long term natural course of chronic HBV infection remained to be elucidated, particularly in children. We aim to investigate prognostic value of mutant HBx gene on the natural history of HBV infection from childhood to adult life. Materials and Methods Patients were recruited from long term prospective chronic HBV carrier cohort, which was conducted in Pediatric department of National Taiwan University Hospital. They received evaluations periodically including history taking and physical examinations. Liver enzymes, HBV markers (HBsAg, HBeAg, Anti-HBe, Anti-HBs, Anti-HBc), AFP, DNA quantitation, and HBV genotyping were also assessed. The blood samplings collected at initial time of enrollment were examined for HBx gene. We analyze the sequences of HBx genes and tried to find the mutations. We attempt to elucidate the correlations between HBx gene mutations and the lasting or ending of immune tolerance phase. Results A total of 155 children (105 males) were followed for 23.4± 6.7 years with initial age of 8.9± 4.5 years. Genotype B accounted for 77.4% of all patients according to sequence findings. One hundred and ten patients had breakthrough immune tolerance phase and 81 patients achieved HBe seroconversion. HBx gene mutations of V44G/L, A66T, R87G, N118T, I127V had highest frequencies. In Kaplan-Meier survival analysis, genotype B and mutants of R87V, N118T, and I127V in HBx gene had significantly higher cumulative proportion of breakthrough of immune tolerance phase (log rank test, p<0.001, p=0.017, 0.044, and 0.001, respectively). In multivariate analysis, we found that mutation of I127V in HBx gene was an independent favorable factor to predict earlier breakthrough of immune tolerance phase, with a statistically significant value (hazard ratio 2.07, 95% CI 1.11-3.85, p=0.022) Conclusions In chronic HBV infection, patients with I127V mutation in HBx gene had higher potential to breakthrough the immune tolerance phase.
Subjects
Chronic hepatitis B infection
hepatitis B X gene
immune tolerance phase
type I interferon
MAVS protein
SDGs
Type
thesis
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