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©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
Impact of hepatitis C virus core mutations on the response to interferon-based treatment in chronic hepatitis C
Camelia Sultana, Gabriela Oprişan, Monica Delia Teleman, Sorin Dinu, Cristiana Oprea, Mihai Voiculescu, Simona Ruta
Camelia Sultana, Simona Ruta, Virology Discipline, Carol Davila University of Medicine and Pharmacy, 030304 Bucharest, Romania
Camelia Sultana, Simona Ruta, Emergent Diseases Department, Stefan S. Nicolau Institute of Virology, 030304 Bucharest, Romania
Gabriela Oprişan, Faculty of Pharmacy, Titu Maiorescu University, 030304 Bucharest, Romania
Gabriela Oprişan, Sorin Dinu, Molecular Epidemiology Laboratory, NIRDMI Cantacuzino, 030304 Bucharest, Romania
Monica Delia Teleman, Department of Microbiology and Epidemiology, Carol Davila University of Medicine and Pharmacy, 030304 Bucharest, Romania
Cristiana Oprea, Victor Babeş Clinic of Infectious and Tropical Diseases, 030304 Bucharest, Romania
Mihai Voiculescu, Fundeni Institute, 030304 Bucharest, Romania
Author contributions: Sultana C, Oprişan G, Ruta S contributed to study conception and design; Oprea C and Voiculescu M contributed to patients recruitment and treatment and data acquisition; HepGen 88/2012 Project Team contributed to data acquisition; Sultana C, Oprişan G, Teleman MD, Dinu S and Ruta S contributed to virological testing, data analysis and interpretation, and drafted the manuscript; Sultana C and Ruta S wrote, edited and reviewed the final form of the manuscript; all authors approved the final form of the article.
Supported by PN-II-PT-PCCA-2011-3.2 Program, No. 88/2012; HepGen “Investigation of viral and host markers of non-response to anti-viral treatment in chronic hepatitis C” funded by the Romanian Ministry of Education and Research.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board IRB comitee of the “Stefan S. Nicolau” Institute of Virology, Bucharest, Romania.
Informed consent statement: All study participants provided informed written consent prior to study enrollment.
Conflict-of-interest statement: There are no conflicts of interest to report.
Data sharing statement: No additional data are available.
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: Simona Ruta, MD, PhD, Professor, Chair of Virology, Emergent Diseases Department, Stefan S. Nicolau Institute of Virology, 285 Mihai Bravu Bvd, 030304 Bucharest, Romania. simona@simonaruta.ro
Telephone: +40-213242590 Fax: +40-213242590
Received: June 24, 2016
Peer-review started: June 28, 2016
First decision: July 29, 2016
Revised: August 9, 2016
Accepted: August 23, 2016
Article in press: August 23, 2016
Published online: October 7, 2016
AIM
To determine whether hepatitis C virus (HCV) core substitutions play a role in the response to interferon-based treatment in Caucasian patients.
METHODS
One hundred eight HCV chronically infected patients initiating treatment with pegylated IFN plus ribavirin for 48 wk were tested for baseline substitutions at codons 70 and 91 of the viral core protein (BigDye Terminator vers.3.1, Applied Biosystems,) and for genetic polymorphisms in host IL28B gene rs12979860 (Custom TaqMan 5' allelic discrimination assay; Applied Biosystems).
RESULTS
Of the patients, all were infected with HCV genotype 1b, 44.4% had low baseline HCV viral load, and 37.9% had mild/moderate fibrosis. Only 38.9% achieved therapeutic success, defined as sustained virological response (SVR). Eighty-eight percent of the patients presented at least one substitution at core position 70 (R70Q/H) or/and position 91 (L91M). The favorable IL28B CC polymorphism was detected in only 17.6% of the patients. In the univariate analysis, young age (P < 0.001), urban residence (P = 0.004), IL28B CC genotype (P < 0.001), absence of core mutations (P = 0.005), achievement of rapid virologic response (P < 0.001) and early virological response (P < 0.001) were significantly correlated with SVR. A multivariate analysis revealed three independent predictors of therapeutic success: young age (P < 0.001), absence of core substitutions (P = 0.04) and IL28B CC genotype (P < 0.001); the model correctly classified 75.9% of SVR cases with a positive predictive value of 80.7%.
CONCLUSION
HCV core mutations can help distinguish between patients who can still benefit from the affordable IFN-based therapy from those who must be treated with DAAs to prevent the evolution towards end-stage liver disease.
Core tip: The high cost of the newly introduced direct acting antivirals precludes universal replacement of the suboptimal interferon-based therapy for chronic hepatitis C. Therefore, a series of host- and virus-related factors are used as prognostic markers of treatment response. In Asian patients, a newly described viral factor is represented by amino acid substitutions in the hepatitis C virus core protein at positions 70 and 91. The present study confirms that core substitutions are also found in Caucasian patients and, together with age and IL28B genotype, can be used as predictors of the outcome of interferon-based therapy.
