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

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

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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 Mock Neck Pullover 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.Methods: 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).Results: 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.Conclusion: Our results suggests that RAS study should include Brake Flywheel all three HCV DAA target proteins and minority mutants should be considered as clinically relevant.Keywords: HCV, minority mutants, NGS, antiviral resistance.