State-of-the-art and emerging antivirals for chronic hepatitis B infection

ABSTRACT

Introduction

Current treatment options for chronic hepatitis B virus (HBV) infection cannot achieve functional cure [hepatitis B surface antigen (HBsAg) loss]; therefore, new approaches are under investigation. This review summarizes the most promising approaches in emerging antivirals against HBV, after search in Medline (2016–2022) and European and American liver meetings (2019–2022).

Areas covered

Classes of antivirals include entry inhibitors (bulevirtide), capsid assembly modulators (CAMs), translation inhibitors [small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs)], and HBsAg secretion inhibitors [nucleic acid polymers (NAPs)]. Bulevirtide has good efficacy in hepatitis B and D coinfection, but there is limited data in HBV monoinfection. CAMs profoundly reduce serum HBV DNA/RNA levels, but have minimal effects on antigen levels. siRNAs and ASOs mostly reduce HBsAg levels, but small proportions of patients reach HBsAg seroclearance. NAPs reduce serum HBV DNA and especially HBsAg levels offering substantial HBsAg seroconversion rates, but having limited data over a long period. Combinations of agents of different classes are starting to be evaluated.

Expert opinion

Continued efforts are required in order to address many unanswered questions about the optimal combined regimens of finite duration which will be safe and well tolerated achieving functional cure in a substantial proportion of chronic HBV patients.

KEYWORDS:

• functional cure
• nucleoside
• nucleotide
• entry inhibitor
• capsid assembly modulator
• small interfering RNA
• antisense oligonucleotide
• nucleic acid polymer
• cccDNA

Article highlights

• Current HBV agents cannot achieve HBsAg loss and therefore new agents and strategies are under investigation.

• Antivirals, the most popular new class of HBV agents, include entry inhibitors (mainly bulevirtide), capsid assembly modulators (CAMs), translation inhibitors [small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs)] and inhibitors of HBsAg secretion [nucleic acid polymers (NAPs)].

• There are limited data on bulevirtide in HBV monoinfection, while CAMs reduce serum HBV DNA/RNA levels, but have minimal effects on HBV antigens levels.

• siRNAs and ASOs reduce mostly HBsAg levels without achieving high HBsAg seroclearance rates so far, while the existing limited data for NAPs suggest that they can reduce serum HBV DNA and mainly HBsAg levels offering substantial rates of HBsAg seroconversion.

• Combination of agents of different classes are just starting to be evaluated and thus continued research is required for the development of safe and effective regimens of finite duration which will achieve functional cure in a substantial proportion of chronic HBV patients.

Declaration of interest

G Papatheodoridis has served as advisor/lecturer for AbbVie, Amgen, Dicerna, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck Sharp & Dohme, Novo Nordisk, Roche and Takeda and has received research grants from AbbVie and Gilead. 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.

Author contributions

M Papatheodoridi: literature search and interpretation of data; drafting of the initial manuscript; approval of the final version of the manuscript.

GV Papatheodoridis: conception and design of the review; interpretation of data; revision of the initial manuscript; approval of the final version of the manuscript.

Additional information

Funding

This paper was not funded.