Editorial
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jul 28, 2016; 8(21): 863-873
Published online Jul 28, 2016. doi: 10.4254/wjh.v8.i21.863
New horizon for radical cure of chronic hepatitis B virus infection
Kazuto Tajiri, Yukihiro Shimizu
Kazuto Tajiri, the Third Department of Internal Medicine, Toyama University Hospital, Toyama 930-0194, Japan
Yukihiro Shimizu, Gastroenterology Center, Nanto Municipal Hospital, Toyama 932-0211, Japan
Author contributions: Tajiri K and Shimizu Y wrote this paper; Shimizu Y conducted this work.
Conflict-of-interest statement: Tajiri K and Shimizu Y declare there is no conflict of interest related to this publication.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
Correspondence to: Yukihiro Shimizu, MD, PhD, Gastroenterology Center, Nanto Municipal Hospital, 938 Inami, Toyama 932-0211, Japan. rsf14240@nifty.com
Telephone: +81-76-3821475 Fax: +81-76-3821853
Received: March 27, 2016
Peer-review started: March 28, 2016
First decision: May 17, 2016
Revised: May 28, 2016
Accepted: June 27, 2016
Article in press: June 29, 2016
Published online: July 28, 2016
Abstract

About 250 to 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and about 700000 patients per year die of HBV-related cirrhosis or hepatocellular carcinoma (HCC). Several anti-viral agents, such as interferon and nucleos(t)ide analogues (NAs), have been used to treat this disease. NAs especially have been shown to strongly suppress HBV replication, slowing the progression to cirrhosis and the development of HCC. However, reactivation of HBV replication often occurs after cessation of treatment, because NAs alone cannot completely remove covalently-closed circular DNA (cccDNA), the template of HBV replication, from the nuclei of hepatocytes. Anti-HBV immune responses, in conjunction with interferon-γ and tumor necrosis factor-α, were found to eliminate cccDNA, but complete eradication of cccDNA by immune response alone is difficult, as shown in patients who recover from acute HBV infection but often show long-term persistence of small amounts of HBV-DNA in the blood. Several new drugs interfering with the life cycle of HBV in hepatocytes have been developed, with drugs targeting cccDNA theoretically the most effective for radical cure of chronic HBV infection. However, the safety of these drugs should be extensively examined before application to patients, and combinations of several approaches may be necessary for radical cure of chronic HBV infection.

Keywords: Covalently-closed circular DNA, Genome editing technology, Immune response, Immunotherapy, Program death-1, Interferon-γ, Tumor necrosis factor-α

Core tip: Among the agents used to treat chronic hepatitis B virus (HBV) infection are nucleos(t)ide analogues, which have been shown to strongly suppress HBV replication. HBV replication, however, may be reactivated after cessation of treatment, because complete removal of covalently-closed circular DNA (cccDNA) from hepatocyte nuclei is extremely difficult. Immune responses have been shown to destroy cccDNA, but immune response alone is insufficient for complete eradication of template DNA. Several drugs were recently developed to block the HBV life cycle in hepatocytes, with drugs targeting cccDNA being, at least theoretically, the most effective for radical cure of chronic HBV infection. The safety of these agents should be extensively examined before their use in patients. Combinations of two or more classes of agent may be necessary for radical cure of chronic HBV infection.