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Baseline hepatitis C virus resistance-associated substitutions present at frequencies lower than 15% may be clinically significant

Authors Perales C, Chen Q, Soria ME, Gregori J, Garcia-Cehic D, Nieto-Aponte L, Castells L, Imaz A, Llorens-Revull M, Domingo E, Buti M, Esteban JI, Rodriguez-Frias F, Quer J

Received 25 April 2018

Accepted for publication 10 August 2018

Published 8 November 2018 Volume 2018:11 Pages 2207—2210


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Eric Nulens

Celia Perales,1,2,* Qian Chen,1,2,* Maria Eugenia Soria,1 Josep Gregori,1–3 Damir Garcia-Cehic,1,2 Leonardo Nieto-Aponte,4 Lluis Castells,1,2 Arkaitz Imaz,5 Meritxell Llorens-Revull,1 Esteban Domingo,2,6 Maria Buti,1,2,7 Juan Ignacio Esteban,1,2,7 Francisco Rodriguez-Frias,2,4,7 Josep Quer1,2,7

1Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Internal Medicine Department, Vall d’Hebron Institut of Research (VHIR)- Vall d’Hebron University Hospital(HUVH), 08035, Barcelona, Spain; 2Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029, Madrid, Spain; 3Roche Diagnostics SL, Sant Cugat del Vallès, 08174, Barcelona, Spain; 4Liver Pathology Unit, Department of Biochemistry and Microbiology, HUVH, 08035, Barcelona, Spain; 5HIV and STD Unit, Infectious Diseases Department, Bellvitge University Hospital-Bellvitge Biomedical Research Institut (IDIBELL), Hospitalet de Llobregat, 08907, Barcelona, Spain; 6Virology and Microbiology Department, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Campus de Cantoblanco, 28049, Madrid, Spain; 7Medicine Department. Autonomous University of Barcelona, Bellaterra, 08193, Barcelona, Spain

*These authors contributed equally to this work

Background: Controversy is ongoing about whether a minority mutant present at frequencies below 15% may be clinically relevant and should be considered to guide treatment.
Resistance-associated substitution (RAS) studies were performed in patients before and at failure of antiviral treatments using Next-generation hepatitis C virus (HCV) sequencing (NGS).
We have found two patients with genotype 1a infection having RAS in 3.5%–7.1% of the viral population at baseline that were selected during ledipasvir + sofosbuvir treatment. Co-selection of RAS located in a region not directly affected by the antiviral treatment also occurred. This observation calls into question, the recommendations to guide RAS-based direct-acting antiviral (DAA) treatment only when RAS are present in >15% of the sequences generated.
Our results suggests that RAS study should include all three HCV DAA target proteins and minority mutants should be considered as clinically relevant.

HCV, minority mutants, NGS, antiviral resistance

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