Retrospective Cohort Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 14, 2021; 27(18): 2177-2192
Published online May 14, 2021. doi: 10.3748/wjg.v27.i18.2177
Factors influencing the failure of interferon-free therapy for chronic hepatitis C: Data from the Polish EpiTer-2 cohort study
Ewa Janczewska, Mateusz Franciszek Kołek, Beata Lorenc, Jakub Klapaczyński, Magdalena Tudrujek-Zdunek, Marek Sitko, Włodzimierz Mazur, Dorota Zarębska-Michaluk, Iwona Buczyńska, Dorota Dybowska, Agnieszka Czauż-Andrzejuk, Hanna Berak, Rafał Krygier, Jerzy Jaroszewicz, Jolanta Citko, Anna Piekarska, Beata Dobracka, Łukasz Socha, Zbigniew Deroń, Łukasz Laurans, Jolanta Białkowska-Warzecha, Olga Tronina, Brygida Adamek, Krzysztof Tomasiewicz, Krzysztof Simon, Malgorzata Pawłowska, Waldemar Halota, Robert Flisiak
Ewa Janczewska, Brygida Adamek, Department of Basic Medical Sciences, The School of Health Sciences in Bytom, Medical University of Silesia, Bytom 41-902, Poland
Mateusz Franciszek Kołek, Department of Animal Physiology, Faculty of Biology, University of Warsaw, Warszawa 02-096, Poland
Beata Lorenc, Pomeranian Center of Infectious Diseases, Medical University Gdańsk, Gdańsk 80-214, Poland
Jakub Klapaczyński, Department of Internal Medicine and Hepatology, Central Clinical Hospital of the Ministry of Internal Affairs and Administration, Warszawa 02-507, Poland
Magdalena Tudrujek-Zdunek, Krzysztof Tomasiewicz, Department of Infectious Diseases, Medical University of Lublin, Lublin 20-081, Poland
Marek Sitko, Department of Infectious and Tropical Diseases, Jagiellonian University, Kraków 30-688, Poland
Włodzimierz Mazur, Clinical Department of Infectious Diseases, Medical University of Silesia in Katowice, Chorzów 41-500, Poland
Dorota Zarębska-Michaluk, Department of Infectious Diseases, Jan Kochanowski University Kielce, Kielce 25-369, Poland
Iwona Buczyńska, Krzysztof Simon, Department of Infectious Diseases and Hepatology, Medical University Wrocław, Wrocław 51-149, Poland
Dorota Dybowska, Department of Infectious Diseases and Hepatology, Ludwik Rydygier Collegium Medicum in Bydgoszcz Faculty of Medicine Nicolaus Copernicus University in Toruń, Bydgoszcz 85-030, Poland
Agnieszka Czauż-Andrzejuk, Robert Flisiak, Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-540, Poland
Hanna Berak, One-Day Department, Hospital for Infectious Diseases in Warsaw, Warszawa 01-201, Poland
Rafał Krygier, Outpatient Clinic, State University of Applied Sciences in Konin, Konin 62-510, Poland
Jerzy Jaroszewicz, Department of Infectious Diseases and Hepatology, Medical University of Silesia in Katowice, Bytom 41-902, Poland
Jolanta Citko, Department of Medical Practice of Infections, Regional Hospital, Olsztyn 10-561, Poland
Anna Piekarska, Department of Infectious Diseases and Hepatology, Medical University of Łódź, Łódź 90-419, Poland
Beata Dobracka, MedicalSpec Center, Wrocław 53-428, Poland
Łukasz Socha, Łukasz Laurans, Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin 71-455, Poland
Zbigniew Deroń, Ward of Infectious Diseases and Hepatology, Biegański Regional Specialist Hospital, Łódź 91-347, Poland
Łukasz Laurans, Infectious and Liver Diseases Clinic, Multidisciplinary Regional Hospital, Gorzów Wielkopolski 66-400, Poland
Jolanta Białkowska-Warzecha, Department of Infectious and Liver Diseases, Medical University of Łódź, Łódź 91-347, Poland
Olga Tronina, Department of Transplantation Medicine, Nephrology, and Internal Diseases, Medical University of Warsaw, Warszawa 02-091, Poland
Malgorzata Pawłowska, Department of Paediatric Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Toruń, Bydgoszcz 85-030, Poland
Waldemar Halota, Department of Infectious Diseases and Hepatology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Faculty of Medicine, Nicolaus Copernicus University in Toruń, Bydgoszcz 85-030, Poland
Author contributions: Janczewska E and Flisiak R conceived the study design; Janczewska E, Lorenc B, Klapaczyński J, Tudrujek-Zdunek M, Sitko M, Mazur W, Zarębska-Michaluk D, Buczyńska I, Dybowska D, Czauż-Andrzejuk A, Berak H, Krygier R, Jaroszewicz J, Citko J, Piekarska A, Dobracka B, Socha Ł, Deroń Z, Laurans Ł, Białkowska-Warzecha J, Tronina O, Adamek B, Tomasiewicz K, Simon K, Pawłowska M, Halota W and Flisiak R acquired the data; Janczewska E and Kołek MF analyzed and interpreted the data; Kołek MF performed statistical analysis, Janczewska E drafted the manuscript; Janczewska E, Kołek MF, Lorenc B, Klapaczyński J, Tudrujek-Zdunek M, Sitko M, Mazur W, Zarębska-Michaluk D, Buczyńska I, Dybowska D, Czauż-Andrzejuk A, Berak H, Krygier R, Jaroszewicz J, Citko J, Piekarska A, Dobracka B, Socha Ł, Deroń Z, Laurans Ł, Białkowska-Warzecha J, Tronina O, Adamek B, Tomasiewicz K, Simon K, Pawłowska M, Halota W and Flisiak R made critical revisions related to important intellectual content of the manuscript and approved the final version of the manuscript.
Institutional review board statement: Patients participating in the study were not exposed to any experimental interventions, nor did the study intervene with the clinical management of the patient. The study only collected information from patient records. The data were originally collected to assess treatment efficacy and safety in individual patients, not for scientific purposes. Hence, the treating physicians did not obtain approval from the ethics committee. According to local law (Pharmaceutical Law of 6th September 2001, art. 37al), non-interventional studies do not require ethics committee approval.
Informed consent statement: All study participants provided informed consent for treatment and the processing of personal data.
Conflict-of-interest statement: Janczewska E has acted as a speaker and/or advisor for AbbVie, Gilead, MSD, Ipsen, and has received funding for clinical trials from AbbVie, Allergan, BMS, Celgene, Cymabay, Dr Falk Pharma, Exelixis, GSK, and MSD. Jakub Klapaczyński has acted as a speaker for Gilead and AbbVie. Mazur W has acted as a speaker and/or advisor for AbbVie, Gilead, Merck, and has received funding for clinical trials from AbbVie, Gilead, and Janssen. Zarębska-Michaluk D has acted as a speaker for AbbVie and Gilead. Dybowska D has received funding for participation in the conference: from AbbVie. Czauż-Andrzejuk A has received funding for clinical trials from AbbVie and Merck. Berak H has acted as a speaker and/or advisor for Gilead, Abbvie, and MSD. Krygier R has acted as a consultant for AbbVie and Gilead. Jaroszewicz J has acted as a speaker and/or advisor for AbbVie, Gilead, Merck, Roche, Alfasigma, MSD, Gilead and PRO.MED. CS. Piekarska A has acted as a speaker and/or advisor for AbbVie, Gilead, Merck, and Roche. Socha Ł has acted as a consultant for BMS. Brygida Adamek has acted as a speaker for AbbVie, Gilead, and MSD. Tomasiewicz K has acted as a speaker and/or advisor AbbVie, Alfa Wasserman, BMS, Gilead, Janssen, Merck, Roche, and has received funding for clinical trials from AbbVie, BMS, Gilead, Janssen, Merck, and Roche. Simon K has acted as a speaker and/or advisor: AbbVie, Gilead, Merck, Alfa-Wassermann, Novartis, Lilly, Bayer, and has received funding for clinical trials from: AbbVie, Allergan, Bayer, EISAI, Gilead, Intercept, Pfizer. Pawłowska M has acted as a speaker and/or advisor for AbbVie, Gilead, Merck, Roche and has received funding for clinical trials from AbbVie, Gilead, and Roche. Halota W has acted as a speaker and/or advisor for AbbVie, BMS, Gilead, Janssen, Merck, Roche, and has received funding for clinical trials from AbbVie, Gilead, and Roche. Flisiak R has acted as a speaker and/or advisor, and has received funding for clinical trials from AbbVie, Gilead, Merck, and Roche. Lorenc B, Kołek MF, Tudrujek-Zdunek M, Sitko M, Buczyńska I, Citko J, Dobracka B, Deroń Z, Laurans Ł, Białkowska-Warzecha J and Tronina O have no conflict of interest to declare.
Data sharing statement: The original anonymous dataset is available on request from the corresponding author at ejanczewska@sum.edu.pl.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
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: Ewa Janczewska, DSc, MD, PhD, Adjunct Professor, Department of Basic Medical Sciences, The School of Health Sciences in Bytom, Medical University of Silesia, Piekarska 18, Bytom 41-902, Poland. ejanczewska@sum.edu.pl
Received: January 26, 2021
Peer-review started: January 26, 2021
First decision: February 27, 2021
Revised: March 13, 2021
Accepted: April 20, 2021
Article in press: April 20, 2021
Published online: May 14, 2021
Processing time: 103 Days and 14.8 Hours
Abstract
BACKGROUND

The introduction of direct-acting antiviral drugs into clinical practice has revolutionized the treatment of chronic hepatitis C, making it highly effective and safe for patients. However, few researchers have analyzed the factors causing therapy failure in some patients.

AIM

To analyze factors influencing the failure of direct antiviral drugs in the large, multicenter EpiTer-2 cohort in a real-world setting.

METHODS

The study cohort consisted of patients with chronic hepatitis C treated at 22 Polish centers from 2016-2020. Data collected from the online EpiTer-2 database included the following: hepatitis C virus (HCV) genotype, stage of fibrosis, hematology and liver function parameters, Child-Turcotte-Pugh and Model for End-stage Liver Disease scores, prior antiviral therapy, concomitant diseases, and drugs used in relation to hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) coinfections. Adverse events observed during the treatment and follow-up period were reported. Both standard and machine learning methods were used for statistical analysis.

RESULTS

During analysis, 12614 patients with chronic hepatitis C were registered, of which 11938 (mean age: 52 years) had available sustained virologic response (SVR) data [11629 (97%) achieved SVR and 309 (3%) did not]. Most patients (78.1%) were infected with HCV genotype 1b. Liver cirrhosis was diagnosed in 2974 patients, while advanced fibrosis (F3) was diagnosed in 1717 patients. We included patients with features of hepatic failure at baseline [ascites in 142 (1.2%) and encephalopathy in 68 (0.6%) patients]. The most important host factors negatively influencing treatment efficacy were liver cirrhosis, clinical and laboratory features of liver failure, history of hepatocellular carcinoma, and higher body mass index. Among viral factors, genotype 3 and viral load also exerted an influence on treatment efficacy. Classical statistical analysis revealed that treatment ineffectiveness seemed to be influenced by the male sex, which was not confirmed by the multivariate analysis using the machine learning algorithm (random forest). Coinfection with HBV (including patients with on-treatment reactivation of HBV infection) or HIV, extrahepatic manifestations, and renal failure did not significantly affect the treatment efficacy.

CONCLUSION

In patients with advanced liver disease, individualized therapy (testing for resistance-associated variants and response-guided treatment) should be considered to maximize the chance of achieving SVR.

Keywords: Advanced liver disease; Chronic hepatitis C; Direct-acting antiviral drugs; Sustained virologic response; Interferon-free therapy; Antiviral therapy

Core Tip: We analyzed factors influencing the failure of direct-acting antiviral drugs (DAAs) in a large, multicenter EpiTer-2 cohort of patients treated across 22 centers. Our findings demonstrate that failure of DAA treatment occurred mainly in patients with liver cirrhosis and deterioration of liver function. Our machine learning analysis further revealed that older age and creatinine and hemoglobin levels also influenced treatment failure, as did viral factors such as genotype 3 and viral load. Thus, in patients with advanced liver disease, individualized therapy (testing for resistance-associated variants, response-guided treatment) should be considered to maximize the chance of achieving a sustained virologic response.