Hepatitis C virus early kinetics and resistance-associated substitution dynamics during antiviral therapy with direct-acting antivirals
Por:
Perpiñán E, Caro-Pérez N, García-González N, Gregori J, González P, Bartres C, Soria ME, Perales C, Lens S, Mariño Z, Londoño MC, Ariza X, Koutsoudakis G, Quer J, González-Candelas F, Forns X and Pérez-Del-Pulgar S
Publicada:
1 dic 2018
Ahead of Print:
23 ago 2018
Resumen:
The emergence of resistance-associated substitutions (RASs) can compromise the high efficacy of direct-acting antivirals (DAAs). Little is known about RASs selection at very early time points during DAA treatment. Therefore, we analyzed the potential emergence of RASs immediately after therapy initiation. Samples of 71 patients treated with different DAAs were collected at baseline, during therapy (hours 4 and 8; days 1-7; weeks 2-4) or until target not detected. HCV-RNA levels were determined by qPCR, and RASs were detected by deep sequencing. Sixty-three (89%) patients achieved a sustained virological response (SVR), 7 (10%) relapsed, and 1 (1%) experienced a breakthrough. Almost all non-SVR (7/8, 88%) showed RASs either at baseline or relapse. High-frequency RASs detected at baseline (Y93H and L159F+C316N) remained detectable at early time points during therapy and reappeared as most prevalent substitutions at relapse. Conversely, emergent RASs at relapse (Q80R, D168E/V, R155K and L31V) were not observed during the first hours-days, before HCV-RNA became undetectable. HCV-RNA decay and genetic evolution of the quasispecies followed a similar pattern during the first hours of therapy in SVR and non-SVR patients. In conclusion, the absence of early RASs selection and the similar dynamics of HCV kinetics and quasispecies in SVR and non-SVR patients after therapy initiation suggest that RASs selection may occur at later stages in the remaining reservoir, where viral populations persist hidden at very low replication levels. Nevertheless, we cannot completely exclude very early selection, when RASs are present below the sensitivity limit of deep sequencing.
Filiaciones:
Perpiñán E:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
Caro-Pérez N:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
:
Joint Research Unit Infección y Salud Pública, FISABIO-Universitat de València, I2SysBio, CIBERESP, Valencia, Spain
Gregori J:
Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Internal Medicine Department, Vall d'Hebron Institut Recerca (VHIR)-Hospital Universitari Vall d'Hebron (HUVH), CIBEREHD, Barcelona, Spain
Roche Diagnostics SL, Sant Cugat del Vallès, Barcelona, Spain
González P:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
Bartres C:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
Soria ME:
Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Internal Medicine Department, Vall d'Hebron Institut Recerca (VHIR)-Hospital Universitari Vall d'Hebron (HUVH), CIBEREHD, Barcelona, Spain
Perales C:
Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Internal Medicine Department, Vall d'Hebron Institut Recerca (VHIR)-Hospital Universitari Vall d'Hebron (HUVH), CIBEREHD, Barcelona, Spain
Lens S:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
Mariño Z:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
Londoño MC:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
Ariza X:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
Koutsoudakis G:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
Quer J:
Liver Unit, Liver Disease Laboratory-Viral Hepatitis, Internal Medicine Department, Vall d'Hebron Institut Recerca (VHIR)-Hospital Universitari Vall d'Hebron (HUVH), CIBEREHD, Barcelona, Spain
Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
:
Joint Research Unit Infección y Salud Pública, FISABIO-Universitat de València, I2SysBio, CIBERESP, Valencia, Spain
Forns X:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
Pérez-Del-Pulgar S:
Liver Unit, Hospital Clínic, IDIBAPS, CIBEREHD, Universitat de Barcelona, Barcelona, Spain
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