Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. May 18, 2015; 7(8): 1064-1073
Published online May 18, 2015. doi: 10.4254/wjh.v7.i8.1064
Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues
Irene Rapti, Stephanos Hadziyannis
Irene Rapti, Stephanos Hadziyannis, Liver Unit and its Molecular Biology Laboratory, National and Kapodistrian University of Athens, Evgenidion Hospital of Athens, 15669 Athens, Greece
Irene Rapti, Athens Medical Center, National and Kapodistrian University of Athens, Evgenidion Hospital of Athens, 15669 Athens, Greece
Author contributions: Both authors contributed to this manuscript.
Conflict-of-interest: None.
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: Stephanos Hadziyannis, Emeritus Professor of Medicine and Hepatology, Liver Unit and its Molecular Biology Laboratory, National and Kapodistrian University of Athens, Evgenidion Hospital of Athens, 4 Dirrachiou Str., 15669 Athens, Greece. hadziyannis@ath.forthnet.gr
Telephone: +30-21-06516807 Fax: +30-21-06543299
Received: December 26, 2014
Peer-review started: December 30, 2014
First decision: January 20, 2015
Revised: March 3, 2015
Accepted: March 16, 2015
Article in press: March 18, 2015
Published online: May 18, 2015
Processing time: 144 Days and 15.3 Hours
Abstract

Hepatocellular carcinoma (HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus (HBV) infection (CHB) is the most important etiologic factor of this tumor, accounting for the development of more than 50% of the cases in the world. Primary prevention of HCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N° 204 (update of July 2014) globally there exists a large pool of > 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed.

Keywords: Chronic hepatitis B; Cirrhosis; Hepatocellular carcinoma; Hepatitis B virus; Treatment; Interferon; Lamivudine; Adefovir; Entecavir; Tenofovir; Virological remission; Nucleos(t)ide analogues

Core tip: Hepatocellular carcinoma (HCC) represents a major health problem worldwide. It develops on the grounds of chronic liver disease, with chronic hepatitis B virus infection (CHB) being responsible for more than 50% of HCC worldwide. Currently, the vast majority of patients with CHB are being treated with nucleos(t)ide analogues, which have changed the natural history of the disease, reducing at a considerable extent its long-term consequences. However, although the risk of HCC has also been reduced, it has not been eliminated even after HBsAg loss or seroconversion. Therefore, constant surveillance, according to guidelines should never be omitted, unless new more potent treatment options are identified.