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This study aimed to analyze the frequencies, genetic barriers, and evolutionary histories of naturally occurring resistance-associated variants (RAVs) in the six main HCV genotypes. A comprehensive analysis of up to 103 RAVs was performed in 2,901, 2,216, and 1,344 HCV isolates for the NS3, NS5A, and NS5B genes, respectively. We report significant intergenotypic differences in the frequencies of natural RAVs for these three HCV genes. In addition, we found a low genetic barrier for the generation of new RAVs, irrespective of the viral genotype. Furthermore, in 1,126 HCV genomes, including sequences spanning the three genes, haplotype analysis revealed a remarkably high frequency of viruses carrying more than one natural RAV to DAAs (53% of HCV-1a, 28.5% of HCV-1b, 67.1% of HCV-6, and 100% of genotype 2, 3, 4, and 5 haplotypes). With the exception of HCV-1a, the most prevalent haplotypes showed RAVs in at least two different viral genes. Finally, evolutionary analyses revealed that, while most natural RAVs appeared recently, others have been efficiently transmitted over time and cluster in well-supported clades. In summary, and despite the observed high efficacy of DAA-based regimens, we show that naturally occurring RAVs are common in all HCV genotypes and that there is an overall low genetic barrier for the selection of resistance mutations. There is a need for natural DAA resistance profiling specific for each HCV genotype.<\/jats:p>","DOI":"10.1128\/aac.02776-15","type":"journal-article","created":{"date-parts":[[2016,2,9]],"date-time":"2016-02-09T04:33:28Z","timestamp":1454992408000},"page":"2402-2416","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":46,"title":["Comprehensive Screening for Naturally Occurring Hepatitis C Virus Resistance to Direct-Acting Antivirals in the NS3, NS5A, and NS5B Genes in Worldwide Isolates of Viral Genotypes 1 to 6"],"prefix":"10.1128","volume":"60","author":[{"given":"Juan \u00c1ngel","family":"Pati\u00f1o-Galindo","sequence":"first","affiliation":[{"name":"Joint Unit in Infection and Health, FISABIO-Public Health\/Cavanilles Institute for Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain"},{"name":"CIBER-ESP (Centro de Investigaci\u00f3n Biom\u00e9dica en Epidemiolog\u00eda y Salud Publica), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karina","family":"Salvatierra","sequence":"additional","affiliation":[{"name":"Joint Unit in Genomics and Health, FISABIO-Public Health\/Cavanilles Institute for Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain"},{"name":"Virology Laboratory, Genomics and Health Area, FISABIO-Public Health, Generalitat Valenciana, Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Gonz\u00e1lez-Candelas","sequence":"additional","affiliation":[{"name":"Joint Unit in Infection and Health, FISABIO-Public Health\/Cavanilles Institute for Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain"},{"name":"CIBER-ESP (Centro de Investigaci\u00f3n Biom\u00e9dica en Epidemiolog\u00eda y Salud Publica), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F. 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