Serum HBV RNA quantification: useful for monitoring natural history of chronic hepatitis B infection

Abstract

Background: As an alternative biomarker of intrahepatic covalently closed circular DNA (cccDNA) transcriptional activity, hepatitis B virus (HBV) RNA may evolve during long-lasting virus-host interactions during chronic hepatitis B viral infection. The distribution pattern of serum HBV RNA levels in the natural course of chronic HBV infection remains unclear. The aim of this study was to evaluate the levels of HBV RNA during the natural course of CHB and the role in distinguishing the natural history of HBV infection.

Methods: A total of 291 treatment-naïve chronic HBV carriers were enrolled. Based on the clinical, biochemical, serological, and histological data as well as HBV DNA levels, patients were classified into the following four categories: the immune-tolerant phase (IT,n = 35), HBeAg-positive immune-active phase (EPIA,n = 121), inactive chronic hepatitis B(ICH,n = 77) and HBeAg-negative immune reactive hepatitis (ENH,n = 58) [corrected]. The parameters and distribution patterns of serum HBV RNA were evaluated in relation to viral replication status, immune phase, disease category and Child-Pugh class. The relationships between serum HBV RNA and other serum hepatitis B viral markers were also analyzed.

Results: Serum HBV RNA levels were significantly lower in the HBeAg-negative patients compared to those in the HBeAg-positive patients, with the lowest levels seen in inactive carriers. In HBeAg-negative patients, serum HBV RNA levels increased if there is reactivation to active hepatitis and showed obvious superiority for the combination of serum HBV DNA (cutoff>3.39 Log copies/mL) and HBsAg (cutoff>2.74 Log IU/mL) in discriminating between 'HBeAg-negative immune reactive' phase and inactive chronic hepatitis B phases of HBeAg-negative chronic HBV infection. Serum HBV RNA levels were positively correlated with serum HBV DNA and HBsAg levels in all chronic HBV-infected patients. A stratified analysis revealed that a correlation between serum HBV RNA and HBV DNA or HBsAg was present in HBeAg-positive patients; however, in HBeAg-negative patients, serum HBV RNA was positively correlated with HBV DNA only.

Conclusion: During the natural course of chronic HBV infection, serum HBV RNA levels vary. Serum HBV RNA can act as a biomarker to predict the natural history of disease in chronic hepatitis B patients. In treatment-naïve HBeAg-negative chronic HBV-infected individuals, serum HBV RNA shows superiority in differentiating the 'HBeAg-negative reactive' phase.

Keywords: Hepatitis B e antigen (HBeAg); Hepatitis B surface antigen (HBsAg); Hepatitis B virus (HBV); Natural history; Pregenomic RNA (pgRNA).

Fig. 1

Distribution of serum HBV RNA titers throughout the natural course of CHB. Median values with 95% confidence interval (of median) represented. IT, immune tolerant;EPIA, HBeAg-positive immune-active phase; ICH, Inactive chronic hepatitis B phase; ENH, HBeAg-negative chronic hepatitis B phase;CH,chronic hepatitis;LC, liver cirrhosis

Fig. 2

Correlation between serum HBV RNA titers and HBV DNA in various phases of CHB. IT, immune tolerant;EPIA, HBeAg-positive immune-active phase; ICH, Inactive chronic hepatitis B phase; ENH, HBeAg-negative chronic hepatitis B phase

Fig. 3

Receiver operating characteristic curve showing the diagnostic value of serum HBV RNA for HBeAg-positive status in chronic HBV infection and ‘aggressive HBeAg-negative CHB’ in HBeAg-negative chronic hepatitis B patients. A:serum HBV RNA level predicts HBeAg-positive CHB in chronic HBV-infected individuals; B:viral markers differentiate ‘aggressive HBeAg-negative CHB’ in HBeAg-negative chronic hepatitis B patients