Getting to HBV cure—Will new biomarkers help?

The natural history and response to therapy in chronic hepatitis B (CHB) infection have been defined by a combination of serological and virological biomarkers along with liver biochemistry and/or histology. A number of novel biomarkers, including HBV RNA, hepatitis B core-related antigen, hepatitis B core antigen, and quantitative HBsAg, have been developed and evaluated in different clinical settings. Novel immunological biomarkers have also been studied but have been less well characterized. In addition to providing insights into HBV biology, these novel biomarkers may significantly aid in the design, development, and assessment of novel antiviral strategies aiming for the cure of chronic hepatitis B. Biomarkers can be used to confirm the mechanism of action or target engagement of a novel agent but also may be used for patient selection for trials and clinical use. Ideally, biomarkers can be used to more accurately define stages of chronic hepatitis B, particularly degrees of virological control. In this review, the serological, virological, and immunological biomarkers are described with a focus on how they can be used to guide the development of HBV cure strategies. New terminology is proposed for clinical endpoints, including sustained control to replace the concept of partial cure and resolved chronic infection to replace functional cure, reserving the term cure for clearance or silencing of all covalently closed circular DNA and integrated HBV DNA.