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Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2021; 27(21): 2727-2757
Published online Jun 7, 2021. doi: 10.3748/wjg.v27.i21.2727
Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure
Efthymios P Tsounis, Evanthia Tourkochristou, Athanasia Mouzaki, Christos Triantos
Efthymios P Tsounis, Evanthia Tourkochristou, Christos Triantos, Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
Athanasia Mouzaki, Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
Author contributions: Tsounis PE and Tourkochristou E have contributed equally to this work; Tsounis PE and Tourkochristou E were responsible for the literature review and analysis, for drafting the manuscript and interpreting the data; Mouzaki A and Triantos C were responsible for the revision of the manuscript for important intellectual content; all authors provided final approval for the submitted version of the manuscript.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Christos Triantos, FAASLD, MD, Assistant Professor, Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, D. Stamatopoulou 4, Rio, Patras 26504, Greece. chtriantos@hotmail.com
Received: January 20, 2021
Peer-review started: January 20, 2021
First decision: February 9, 2021
Revised: February 23, 2021
Accepted: April 13, 2021
Article in press: April 13, 2021
Published online: June 7, 2021
Processing time: 126 Days and 23.6 Hours
Abstract

Hepatitis B virus (HBV) infection, although preventable by vaccination, remains a global health problem and a major cause of chronic liver disease. Although current treatment strategies suppress viral replication very efficiently, the optimal endpoint of hepatitis B surface antigen (HBsAg) clearance is rarely achieved. Moreover, the thorny problems of persistent chromatin-like covalently closed circular DNA and the presence of integrated HBV DNA in the host genome are ignored. Therefore, the scientific community has focused on developing innovative therapeutic approaches to achieve a functional cure of HBV, defined as undetectable HBV DNA and HBsAg loss over a limited treatment period. A deeper understanding of the HBV life cycle has led to the introduction of novel direct-acting antivirals that exert their function through multiple mechanisms, including inhibition of viral entry, transcriptional silencing, epigenetic manipulation, interference with capsid assembly, and disruption of HBsAg release. In parallel, another category of new drugs aims to restore dysregulated immune function in chronic hepatitis B accompanied by lethargic cellular and humoral responses. Stimulation of innate immunity by pattern-recognition receptor agonists leads to upregulation of antiviral cytokine expression and appears to contribute to HBV containment. Immune checkpoint inhibitors and adoptive transfer of genetically engineered T cells are breakthrough technologies currently being explored that may elicit potent HBV-specific T-cell responses. In addition, several clinical trials are attempting to clarify the role of therapeutic vaccination in this setting. Ultimately, it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs. This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.

Keywords: Chronic hepatitis B; Functional cure; Direct-acting antivirals; Gene silencing; Immunotherapy; Therapeutic vaccination

Core Tip: Despite preventive vaccination and effective antiviral drugs, approximately 300 million people worldwide are at risk of liver-related morbidity and mortality from hepatitis B virus (HBV) infection. In the search for more effective strategies, research has focused on two broad categories of therapeutic intervention. First, direct-acting antivirals that interrupt various stages of the HBV life cycle are yielding promising results in clinical trials that show suppression of the HBV antigen load. Second, the need to address depleted immune responses and revive the tolerogenic liver microenvironment has brought immunotherapies to the forefront. It is likely that an upcoming treatment that combines agents from both classes will achieve HBV elimination.