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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\u20107; weeks 2\u20104) or until target not detected. HCV\u2010RNA levels were determined by qPCR, and RASs were detected by deep sequencing. Sixty\u2010three (89%) patients achieved a sustained virological response (SVR), 7 (10%) relapsed, and 1 (1%) experienced a breakthrough. Almost all non\u2010SVR (7\/8, 88%) showed RASs either at baseline or relapse. High\u2010frequency 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\u2010days, before HCV\u2010RNA became undetectable. HCV\u2010RNA decay and genetic evolution of the quasispecies followed a similar pattern during the first hours of therapy in SVR and non\u2010SVR patients. In conclusion, the absence of early RASs selection and the similar dynamics of HCV kinetics and quasispecies in SVR and non\u2010SVR 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.<\/jats:p>","DOI":"10.1111\/jvh.12986","type":"journal-article","created":{"date-parts":[[2018,8,24]],"date-time":"2018-08-24T04:28:20Z","timestamp":1535084900000},"page":"1515-1525","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Hepatitis C virus early kinetics and resistance\u2010associated substitution dynamics during antiviral therapy with direct\u2010acting antivirals"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7055-7328","authenticated-orcid":false,"given":"Elena","family":"Perpi\u00f1\u00e1n","sequence":"first","affiliation":[{"name":"Liver Unit, Hospital Cl\u00ednic IDIBAPS CIBEREHD Universitat de Barcelona  Barcelona 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