Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management

Abstract

Even though an approved vaccine for hepatitis B virus (HBV) is available and widely used, over 257 million individuals worldwide are living with chronic hepatitis B (CHB) who require monitoring of treatment response, viral activity, and disease progression to reduce their risk of HBV-related liver disease. There is currently a lack of predictive markers to guide clinical management and to allow treatment cessation with reduced risk of viral reactivation. Novel HBV biomarkers are in development in an effort to improve the management of people living with CHB, to predict disease outcomes of CHB, and further understand the natural history of HBV. This review focuses on novel HBV biomarkers and their use in the clinical setting, including the description of and methodology for quantification of serum HBV RNA, hepatitis B core-related antigen (HBcrAg), quantitative hepatitis B surface antigen (qHBsAg), including ultrasensitive HBsAg detection, quantitative anti-hepatitis B core antigen (qAHBc), and detection of HBV nucleic acid-related antigen (HBV-NRAg). The utility of these biomarkers in treatment-naïve and treated CHB patients in several clinical situations is further discussed. Novel HBV biomarkers have been observed to provide critical clinical information and show promise for improving patient management and our understanding of the natural history of HBV.

Keywords: HBcrAg; NRAg; biomarker; hepatitis B virus; pgRNA; qHBsAg; quantitative anti-HBc; serum HBV RNA.

Figure 1

Overview of the HBV infection and replication cycle. Infecting virion particles are transported to the hepatocyte nucleus to release the relaxed circular partially double-stranded DNA genome, associated with the viral polymerase, into the nucleus. The genome is repaired and converted into cccDNA, which is the template for viral mRNA synthesis. The viral transcripts are translated following transport to the cytoplasm. The three surface antigen proteins are membrane specific and compose the viral envelope in conjunction with host lipid. Within the cytoplasm, pregenomic RNA (pgRNA) is encapsidated together with newly expressed polymerase protein within spontaneously formed capsid particles composed of core protein, to form the viral replication complex. pgRNA also serves as the template for the expression of the polymerase and core proteins. The HBV biomarkers discussed in this review, other than qAHBc, which is produced following the humoral immune response to core antigen, are shown within their expression pathways and their component parts. Note that HBsAg is detectable from replicative and non-replicative virion particles, as well as subviral particles and HBsAg expressed from HBV DNA integrated into host genomic DNA.