Retrospective Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2019; 25(40): 6094-6106
Published online Oct 28, 2019. doi: 10.3748/wjg.v25.i40.6094
Sustained virologic response to direct-acting antiviral agents predicts better outcomes in hepatitis C virus-infected patients: A retrospective study
GianLuca Colussi, Debora Donnini, Rosario Francesco Brizzi, Silvia Maier, Luca Valenti, Cristiana Catena, Alessandro Cavarape, Leonardo Alberto Sechi, Giorgio Soardo
GianLuca Colussi, Debora Donnini, Rosario Francesco Brizzi, Silvia Maier, Luca Valenti, Cristiana Catena, Alessandro Cavarape, Leonardo Alberto Sechi, Giorgio Soardo, Department of Medicine, University of Udine, Udine 33100, Italy
Author contributions: Colussi G, Donnini D, Sechi LA and Soardo G contributed to study conception and design; Donnini D, Brizzi RF and Maier S contributed to data acquisition; Colussi G, Catena C, Valenti L, Cavarape A and Sechi LA contributed to analysis and interpretation of data; Colussi G, Donnini D, Brizzi RF and Catena C contributed to drafting the article; Maier S, Valenti L, Cavarape A and Sechi LA contributed to making critical revisions of the manuscript; all authors contribute to final approval of the version of the manuscript.
Institutional review board statement: This study was approved by the Institutional Review Board of the University of Udine.
Informed consent statement: According to the Italian law on retrospective studies and the Italian Data Protection Authority, all involved person, whenever reachable or alive, gave their informed consent to use their data. Any details that might disclose the identity of the subjects under study has been omitted or anonymized.
Conflict-of-interest statement: Authors do not have any conflict-of-interest to disclose.
STROBE statement: Authors have read the STROBE Statement-checklist of items and the manuscript was prepared and revised accordingly.
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/
Corresponding author: Giorgio Soardo, MD, Associate Professor, Department of Medicine, University of Udine, 1st floor, Building n.8, Piazzale Santa Maria della Misericordia 1, Udine 33100, Italy. giorgio.soardo@uniud.it
Telephone: +39-432-559490 Fax: +39-432-559490
Received: June 17, 2019
Peer-review started: June 17, 2019
First decision: July 21, 2019
Revised: August 9, 2019
Accepted: September 9, 2019
Article in press: September 9, 2019
Published online: October 28, 2019
Processing time: 134 Days and 23.6 Hours
ARTICLE HIGHLIGHTS
Research background

Direct-acting antiviral agents (DAAs) are extremely effective in eradicating hepatitis C virus (HCV) in chronically infected patients. However, the protective role of a sustained virologic response (SVR) achieved by second- and third-generation DAAs against the onset of hepatocellular carcinoma (HCC) and mortality is less well established.

Research motivation

The main topic of this study was to establish the effectiveness of new generations of DAAs to induce SVR and to prevent HCC development or mortality in HCV-infected patients. These patients were characterized by an elevated risk for HCC because of their advanced or complicated liver disease. The strength of this study was the use of a multi-state Cox-Markov model. This model permitted us to explore more deeply the relationships of baseline variables with events in each different disease state. This last approach is not possible with a classical survival Cox model.

Research objectives

The aim of this study was to examine HCC occurrence or death from any cause in a retrospective-prospective study of patients treated with DAAs and to identify potential predictors of SVR achievement and HCC development.

Research methods

The patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy. The study was conducted using 380 patients (age: 60 ± 13 years, 224 males, 32% with cirrhosis) treated with DAAs with or without SVR (95/5%), with a median follow up of 58 wk (interquartile range: 38-117). The baseline anthropometric features, HCV viral load, severity of liver disease, presence of extra-hepatic complications, coinfection with HIV and/or HBV, alcohol consumption, previous interferon use, alpha-fetoprotein levels, and renal function were considered to be confounders. Survival analysis was conducted using a classical Cox model and a more advanced Cox-Markov multi-state model that considered SVR as a time-dependent variable that can influence the probability of the outcome.

Research results

The incidence rates of HCC in patients with and without SVR were 1.3 and 59 per 100 person-years, respectively (incidence rate ratio: 44, 95%CI: 15-136, P < 0.001). Considering the combined endpoint of HCC or death from any cause, the hazard ratio (HR) for SVR patients was 0.070 (95%CI: 0.025-0.194, P < 0.001). Other independent predictors of HCC or death were low HCV viremia (HR: 0.808, P = 0.030), low platelet count (HR: 0.910, P = 0.041), and presence of mixed cryoglobulinemia (HR: 3.460, P = 0.044). Considering SVR in a multi-state model, independent predictors of SVR achievement were the absence of cirrhosis (HR: 0.521, P < 0.001) and high platelet count (HR: 1.019, P = 0.026). Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR (HR: 5.982, P = 0.028 and HR: 5.633, P = 0.047, respectively).

Research conclusions

Treatment with DAAs is very effective in inducing SVR and protecting against HCC or death. A residual risk for HCC persists in patients with advanced liver disease or disease complicated by extra-hepatic manifestations, such as mixed cryoglobulinemia and renal failure.

Research perspectives

New generations of DAAs should be recommended to treat all patients with HCV infection independently of the status of their liver disease or the presence of extra-hepatic manifestations. Further studies are needed to define a better strategy to treat HCV-infected patients with more advanced or complicated liver disease.