New Viral Biomarkers for Hepatitis B: Are We Able to Change Practice?

Christoph Höner zu Siederdissen; Benjamin Maasoumy; Markus Cornberg


J Viral Hepat. 2018;25(11):1226-1235. 

In This Article

Abstract and Introduction


The management of chronic hepatitis B virus (HBV) infection is challenged by its varying natural course and its stealthy nature. Not all HBV–infected patients will develop complications of infection; however, it is of utmost importance to identify patients who are at risk and require antiviral treatment and/or close surveillance. Hepatic inflammation and quantification of HBV DNA have guided treatment decisions in the last decade, and these guided interventions have been shown to reduce liver–related complications and death. Data on the quantification of additional HBV markers such as hepatitis B surface antigen (HBsAg), hepatitis B core–related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) have accumulated in recent years. Here, we review the current evidence of how to use these markers and discuss open issues that require additional research.


It is thought that 240 million people worldwide are chronically infected with the hepatitis B virus (HBV) accounting for around 600 000 deaths per year.[1,2] Importantly, the course of chronic HBV infection is commonly not clinically apparent and consequences such as hepatic decompensation and development of hepatocellular carcinoma (HCC), the main driver of death, usually occur only after decades of infection.

This is caused, in part, by the fact that chronic HBV infection is characterized by different phases, with varying consequences to the infected patients (Table 1). In case of ongoing hepatitis, treatment is required to prevent disease complications.[3] However, not all patients with chronic HBV infection will have disease progression. Some patients may even experience HBsAg loss with negative HBV DNA and no signs of inflammation in the liver, recently defined as functional cure.[4] But even in these patients, HBV DNA is still present as covalently closed circular DNA (cccDNA) in the hepatocytes and may lead to reactivation of infection under certain circumstances. Thus, functional cure may be considered as a 5th phase of infection (Table 1).

Given this variable nature of HBV infection, the natural course, but also treatment of HBV infection, needs to be monitored and has associated diagnostic challenges. Over time, several diagnostic markers have been utilized to help patients and physicians make the correct choices and improve the outcome of the disease. HBV DNA has emerged as the most important marker, and all major international guidelines base their treatment decisions on HBV DNA cut–offs.[3,5,6] Treatment decisions based on HBV DNA have been shown to lower the risk of hepatic decompensation, development of HCC and death.[3] However, the value of HBV DNA is limited in several settings, that is, a recent study has shown ongoing intrahepatic replication despite suppressed HBV DNA[7] and negativity for HBV DNA does not mean cure of HBV infection.

Numerous new therapeutic options aiming at functional or even complete cure of HBV infection are currently been investigated; therefore, diagnostic markers to assess the potential outcomes and risk are even more important.

We review here the current knowledge about older diagnostic markers such as HBV DNA and HBsAg, as well as the new markers HBV RNA, HBcrAg, HBs proteins (S–, M–, LHBs) and more. Is it time to change practice?