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©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Hepatitis C virus NS5A region mutation in chronic hepatitis C genotype 1 patients who are non-responders to two or more treatments and its relationship with response to a new treatment
Paloma Muñoz de Rueda, José Manuel Fuentes Rodríguez, Rosa Quiles Pérez, Ana Gila Medina, Ana Belén Martín Álvarez, Jorge Casado Ruíz, Angeles Ruíz Extremera, Javier Salmerón
Paloma Muñoz de Rueda, José Manuel Fuentes Rodríguez, Rosa Quiles Pérez, Jorge Casado Ruíz, Javier Salmerón, Ana Belén Martín Alvarez, Ángeles Ruíz Extremera, Research Support Unit, San Cecilio University Hospital of Granada, 18014 Granada, Spain
Paloma Muñoz de Rueda, Rosa Quiles Pérez, Javier Salmerón, Ana Belén Martín Alvarez, Jorge Casado, Ángeles Ruíz Extremera, Instituto de Investigación Biosanitaria, 18012 Granada, Spain
Paloma Muñoz de Rueda, Rosa Quiles Pérez, Ana Gila Medina, Javier Salmerón, Ángeles Ruíz Extremera, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
Paloma Muñoz de Rueda, Rosa Quiles Pérez, Ana Gila Medina, Ana Belén Martín Álvarez, Jorge Casado Ruíz, Javier Salmerón, Unit for Clinical Management of Digestive Diseases, San Cecilio University Hospital of Granada, 18014 Granada, Spain
Javier Salmerón, Ángeles Ruíz Extremera, Granada University, 18010 Granada, Spain
Author contributions: Salmerón J contributed to planning and conducting the study and collecting and interpreting the data; Muñoz de Rueda P, Fuentes Rodríguez JM and Quiles Pérez R contributed to collecting and interpreting the data and drafting the manuscript; Gila Medina A, Martín Álvarez AB, Casado Ruíz J and Ruíz Extremera Á contributed to collecting the data; and Muñoz de Rueda P contributed to the biostatistical analysis.
Supported by “Consejería de Salud de la Junta de Andalucía”, No. PI0137/07; and “Instituto de Salud Carlos III”, No. FIS-Intrasalud PI010/717.
Institutional review board statement: The study was reviewed and approved by the Andalusian Coordinating Committee for Biomedical Research Ethics.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrolment.
Conflict-of-interest statement: The authors have no potential conflicts of interest to disclose.
Data sharing statement: A technical appendix, statistical codes and datasets are available from the corresponding author at rosa-quiles@hotmail.com. Informed consent for data sharing was obtained from the participants as the presented data are anonymized and the risk of identification is very low. 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: Dr. Rosa Quiles Pérez, CIBERehd Researcher, Research Support Unit, University Hospital San Cecilio of Granada, Dr/ Olóriz 16, 18012 Granada, Spain.
rosa-quiles@hotmail.com
Telephone: +34-95-8023655 Fax: +34-95-8023434
Received: January 13, 2017
Peer-review started: January 14, 2017
First decision: February 9, 2017
Revised: February 24, 2017
Accepted: March 4, 2017
Article in press: March 6, 2017
Published online: July 7, 2017
Processing time: 175 Days and 17.1 Hours
AIM
To determine the number of mutations in the NS5A region of the hepatitis C virus (HCV) and its relationship to the response to antiviral therapy in patients with chronic hepatitis C genotype 1 who are non-responders to two or more treatments.
METHODS
Sequences within HCV NS5A [PKR binding domain (PKRBD) and the interferon-sensitivity-determining region (ISDR)] were analysed via direct sequencing in a selected cohort of 72 patients, with a total of 201 treatments [interferon-alpha (IFN-α), n = 49; IFN-α + ribavirin (RBV), n = 75; pegylated (peg) IFN-α + RBV, n = 47; first-generation direct-acting antivirals (DAAs), n = 13; and second-generation DAAs, n = 17]. Of these, 48/201 achieved a sustained virological response (SVR) and 153/201 achieved no virological response (NVR).
RESULTS
For both regions, treatments resulting in SVR were associated with more baseline mutations than were treatments resulting in NVR (SVR vs NVR; PKRBD: 5.82 ± 3 vs 4.86 ± 2 mutations, P = 0.045; ISDR: 2.65 ± 2 vs 1.51 ± 1.7 mutations, P = 0.005). A decrease or no change in the number of mutations over time between treatments in the PKRBD or ISDR, as shown by sequencing, was associated with patients who usually failed to respond to treatment (PKRBD, P = 0.02; ISDR, P = 0.001). Moreover, patients showing a post-treatment baseline viral load > 600000 IU/mL and increased ISDR mutations with respect to the previous treatment were 9.21 times more likely to achieve SVR (P = 0.001).
CONCLUSION
The obtained results show that among patients who have shown no response to two or more antiviral treatments, the likelihood of achieving SVR increases with the genetic variability in the ISDR region (≥ 2 mutations or number of substitutions from the HCV-J and HCV-1 prototype), especially when the viral load is greater than 600000 IU/mL.
Core tip: To the best of our knowledge, this study is the first to evaluate the change in the number of mutations of the hepatitis C virus (HCV) NS5A region in patients with chronic hepatitis C genotype 1 and who were non-responders to two or more treatments over a period of two decades. The number of mutations in the HCV NS5A region was identified as an independent predictor of a sustained virological response regardless of the interferon-containing regimen or direct-acting antiviral-containing interferon-free protocol applied.
