Advances in determining new treatments for hepatitis B infection by utilizing existing and novel biomarkers

ABSTRACT

Introduction

Chronic hepatitis B (CHB) infection is a major global health threat and accounts for significant liver-related morbidity and mortality. An improved understanding of how hepatitis B virus (HBV) interacts with the host immune system allows the discovery of novel biomarkers and new treatment options. Viral biomarkers including hepatitis B surface antigen (HBsAg) and newer ones like HBV RNA and hepatitis B core-related antigen appear to be useful to select patients who are likely to benefit from cessation of long-term antiviral therapy. These markers can also help to confirm target engagement for novel compounds, and efficacy in HBsAg reduction and seroclearance is deemed essential as this is how the current treatment endpoint of functional cure is defined.

Areas covered

In this review, the authors discuss the current standard of care and the gaps between such standard and the ideal goals for treatment in CHB. The authors highlight novel viral and immunological biomarkers that are potentially useful to evaluate treatment response. Novel treatment approaches in relation to these novel biomarkers are also evaluated.

Expert opinion

Novel serum viral biomarkers and immunological markers are indispensable in the HBV functional cure program. These will likely become part of standard monitoring soon.

KEYWORDS:

• functional cure
• host immunity
• hepatitis B core-related antigen
• hepatitis B virus RNA
• quantitative hepatitis B surface antigen
• T cell exhaustion

Article highlights

• Chronic hepatitis B (CHB) infection is characterized by numerous perturbations in both the innate and adaptive immune system, contributed by chronic exposure to viral antigen.

• Nucleos(t)ide analogue (NUC) and pegylated interferon α (PEG-IFN α) could not fully reverse the dysfunctional immune system in CHB.

• Viral biomarkers including hepatitis B surface antigen (HBsAg) and transcriptional markers [(hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA)] are used to define functional cure and predict the probability of such following NUC discontinuation, respectively.

• A number of virus-directing and immunomodulatory therapies are being evaluated in clinical trials to help CHB patients achieve functional cure. Some of them have demonstrated potency in HBsAg suppression, which is sustainable.

• Restoration of virus-specific immunity could be observed in some novel compounds as evident by the assessment of immunological biomarkers.

• A good biomarker to prognosticate a flare following novel therapeutic approaches should be developed.

Declaration of interest

LY Mak is an advisory board member for Gilead Sciences. WK Seto received speaker’s fees from AstraZeneca and Mylan, is an advisory board member of CSL Behring, is an advisory board member and received speaker’s fees from AbbVie, and is an advisory board member, received speaker’s fees, and researching funding from Gilead Sciences. MF Yuen serves as advisor/consultant for AbbVie, Assembly Biosciences, Aligos Therapeutics, Arbutus Biopharma, Bristol Myer Squibb, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Merck Sharp and Dohme, Hoffmann-La Roche, and Springbank Pharmaceuticals, Vir Biotechnology and receives grant/research support from Assembly Biosciences, Aligos Therapeutics, Arrowhead Pharmaceuticals, Bristol Myer Squibb, Fujirebio Incorporation, Gilead Sciences, Immunocore, Merck Sharp and Dohme, Hoffmann-La Roche, Springbank Pharmaceuticals, and Sysmex Corporation. The remaining authors have no conflict of interests.

Reviewer disclosures

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

Additional information

Funding

This manuscript was not funded.