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World J Hepatol. Sep 27, 2018; 10(9): 595-602
Published online Sep 27, 2018. doi: 10.4254/wjh.v10.i9.595
Hepatocellular carcinoma occurrence in DAA-treated hepatitis C virus patients: Correlated or incidental? A brief review
Eleni Gigi, Vasileios I Lagopoulos, Eleni Bekiari
Eleni Gigi, Eleni Bekiari, 2nd Internal Medicine Department, Aristotle University Medical School, Hippokrateio General Hospital, Thessaloniki 54642, Greece
Vasileios I Lagopoulos, 5th Surgical Department, Aristotle University Medical School, Hippokrateio General Hospital, Thessaloniki 54642, Greece
Author contributions: All authors equally contributed to conception and design of the study, literature review and analysis. Gigi E and Lagopoulos VI composed the core of the manuscript and performed additional research, critical revision and editing; final review was equally managed by all authors; all authors approved the final version of the manuscript.
Conflict-of-interest statement: No potential conflicts of interest. No financial support.
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:
Correspondence to: Eleni Gigi, MD, PhD, Academic Research, Assistant Professor, Hepatology Unit, 2nd Internal Medicine Department, Aristotle University Medical School, Hippokrateio General Hospital, Konstantinoupoleos 49, Thessaloniki 54642, Greece.
Telephone: +30-2313-312263 Fax: +30-2310-992794
Received: March 30, 2018
Peer-review started: March 30, 2018
First decision: May 11, 2018
Revised: May 25, 2018
Accepted: June 30, 2018
Article in press: June 30, 2018
Published online: September 27, 2018

Hepatitis C virus (HCV) chronic infection induces liver fibrosis and cirrhosis but is also responsible for a significant portion of hepatocellular carcinoma (HCC) occurrence. Since it was recognized as a causative factor of chronic hepatitis, there have been multiple efforts towards viral eradication, leading to the first-generation HCV treatment that was based on interferon (IFN)-αand its analogs, mainly PEGylated interferon-α (PEG IFNα). Sustained virological response (SVR), defined as the absence of detectable RNA of HCV in blood serum for at least 24 wk after discontinuing the treatment, was accepted as a marker of viral clearance and was achieved in approximately one-half of patients treated with PEG IFNα regimens. Further research on the molecular biology of HCV gave rise to a new generation of drugs, the so-called direct antiviral agents (DAAs). DAA regimens, as implied by their name, interfere with the HCV genome or its products and have high SVR rates, over 90%, after just 12 wk of per os treatment. Although there are no questions about their efficacy or their universality, as they lack the contraindication for advanced liver disease that marks PEG IFNα, some reports of undesired oncologic outcomes after DAA treatment raised suspicions about possible interference of this treatment in HCC development. The purpose of the present review is to investigate the validity of these concerns based on recent clinical studies, summarize the mechanisms of action of DAAs and survey the updated data on HCV-induced liver carcinogenesis.

Keywords: Hepatocellular carcinoma, Hepatitis C virus infection, Direct antiviral agents, Liver carcinogenesis, advanced fibrosis, Hepatitis C virus-induced cancer sequence, Sustained virological response

Core tip: Inability to reach sustained virological response (SVR) and cirrhosis are independent prognostic factors for developing hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) patients from the interferon (IFN) era. DAAs offer significantly better SVR rates. The first data regarding HCC occurrence after direct antiviral agent (DAA) treatment are similar to the data from patients who achieved SVR under IFN treatment. Some reports on early HCC occurrence or recurrence after DAA treatment are probably due to selection bias, as they were not reproduced in large comparative studies. DAAs can eradicate HCV, but they cannot terminate HCV-induced premalignant processes once triggered.