Emerging tools in the changing landscape of chronic hepatitis B management

ABSTRACT

Introduction: The availability of a preventative vaccine, interferon, and nucleos(t)ide analogs have provided progress in the control of chronic hepatitis B (CHB). Despite this, it remains a major contributor to global morbidity and mortality. Developments in our understanding of the pathogenesis of CHB and the emergence of new therapies are paving the way, as we move toward HBV cure.

Areas covered: We performed bibliographical searches of online databases to review the literature regarding conventional disease phases of CHB. We provide the latest evidence challenging the perception of the natural history of CHB, noting that previously considered quiescent disease phases may not represent benign disease states devoid of progression. We explore the use of potential novel immunological and viral tools which should enhance disease stratification and management decisions in the coming years. Finally, we discuss the timing of treatment and how this could be initiated earlier to improve treatment outcomes, preventing sequelae of chronic infection.

Expert opinion: The treatment paradigm in CHB is set to change with multiple novel agents in early phase clinical trials with the aim of a functional cure. An improved understanding of disease pathogenesis and the timing of treatment will be critical to the success of new therapies.

KEYWORDS:

• Hepatitis B virus
• immune response
• viral factors
• treatment
• disease progression

Article highlights

• CHB is traditionally perceived to progress through four distinct disease phases; eAg-positive chronic infection, eAg-positive chronic hepatitis, eAg-negative chronic infection and eAg-negative chronic hepatitis (formerly labeled as immune tolerant, immune active/clearance, immune control, and immune escape, respectively)

• There is now greater recognition that the ‘immune tolerant’ disease phase is not a benign disease state, as these patients demonstrate an immune response, which is more robust than that observed in their adult counterparts, meriting more stringent assessment and follow-up.

• There is a misconception that ‘inactive carrier’ patients do not require rigorous follow-up; however, studies have shown that these patients have an immune phenotype of partial exhaustion, which progresses with age.

• In addition to HBV DNA, HBeAg and HBsAg, there are now novel quantitative markers that can be measured in the blood, including hepatitis B core-related antigen (HBcrAg) and HBV RNA. These markers may be better surrogates of intrahepatic viral activity and for longitudinal monitoring purposes in those patients undergoing treatment.

• There is a growing debate in the field around the timing of treatment with emerging data suggesting that early treatment in CHB may prevent liver inflammation and reduce the risk of cancer development.

• The majority of novel agents, entering the clinical trial pipeline, are likely to be used in conjunction with current antiviral agents, thus increasing the treatment candidacy pool is likely to accelerate the HBV cure program.

Declaration of interest

PTF Kennedy has collaborative grant funding from Gilead Sciences, participates on the advisory boards of and provides consultancy to Gilead Sciences, Janssen, GSK and Immunocore and is an investigator for industry-led trials with Gilead Sciences, Janssen, Spring Bank Pharmaceuticals, Roche, Alere, and Assembly Biosciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by an NIHR Academic Clinical Lectureship, an Academy of Medical Sciences Starter Grant and Seedcorn funding from the Rosetrees Charity awarded to U S Gill, Barts Charity Large Project grants (723/1795 and MGU/0406) and an NIHR Research for patient benefit award (PB-PG-0614-34087) to PTF Kennedy.