viruses Review Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management Alicia Vachon 1,2 and Carla Osiowy 1,2, *   Citation: Vachon, A.; Osiowy, C. Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management. Viruses 2021, 13, 951. https:// doi.org/10.3390/v13060951 Academic Editor: Carla S. Coffin Received: 29 April 2021 Accepted: 18 May 2021 Published: 21 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; vachona@myumanitoba.ca 2 National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3R2, Canada * Correspondence: carla.osiowy@canada.ca 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: hepatitis B virus; biomarker; qHBsAg; serum HBV RNA; pgRNA; quantitative anti-HBc; HBcrAg; NRAg 1. Introduction It is estimated that over 257 million people are chronically infected with hepatitis B virus (HBV) worldwide and over 880,000 annual deaths are the result of hepatitis B-related outcomes such as hepatocellular carcinoma (HCC) and liver cirrhosis [1]. Although child- hood vaccination programs have been operational since the 1990s, a significant number of individuals worldwide live with the life-changing disease that is hepatitis B and there- fore require monitoring of treatment response, viral activity, and disease progression to minimize their imminent risk of developing HBV-related liver disease. While qualitative detection of traditional markers such as HBV DNA, HBV e antigen (HBeAg), HBV surface antigen (HBsAg), and antibody to the HBV core antigen (AHBc) are used in monitoring of acute or chronic hepatitis B, these markers have limitations in predicting clinical outcomes of disease or antiviral treatment. Quantification of intrahepatic covalently closed circular DNA (cccDNA) is the gold standard for gaining a full understanding of HBV replicative and transcriptional activity; however, invasive procedures and a lack of standardization prevent this as a routine prognostic HBV biomarker. Quantification of novel and tradi- tional serum HBV markers is being investigated as a surrogate of cccDNA, not only to circumvent the need for a liver biopsy to measure viral transcriptional activity, but also to provide additional information on the state of disease, allow for more refined guidance in the clinical management of hepatitis B, and improve our understanding of HBV natural history. Methods to detect and quantify novel serum markers of HBV have been developed Viruses 2021, 13, 951. https://doi.org/10.3390/v13060951 https://www.mdpi.com/journal/viruses