{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:40:17Z","timestamp":1767832817835,"version":"3.49.0"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Background: Approximately 71 million people are still in need of direct-acting antiviral agents (DAAs). To achieve the World Health Organization Hepatitis C elimination goals, insight into the prevalence and influence of resistance associated substitutions (RAS) is of importance. Collaboration is key since DAA failure is rare and real-life data are scattered. We have established a European collaboration, HepCare, to perform in-depth analysis regarding RAS prevalence, patterns, and multiclass occurrence. Methods: Data were extracted from the HepCare cohort of patients who previously failed DAA therapy. Geno\u2014and subtypes were provided by submitters and mostly based on in-house assays. They were reassessed using the Comet HCV subtyping tool. We considered RAS to be relevant if they were associated with DAA failure in vivo previously reported in literature. Results: We analyzed 938 patients who failed DAA therapy from ten different European countries. There were 239 genotypes (GT) 1a, 380 GT1b, 19 GT2c, 205 GT3a, 14 GT4a, and 68 GT4d infections. Several unusual subtypes (n = 15) (GT1b\/g\/l, GT3b, GT4k\/n\/r\/t) were present. RAS appeared in over 80% of failures and over a quarter had three or more RAS. Multiclass RAS varied over target region and genotype between 0\u201348%. RAS patterns such as the Q30R + L31M and Q30R + Y93H in GT1a, the L31V + Y93H and L31V + Y93H for GT1b, and A30K + L31M and A30K\/V + Y93H for GT3a all occurred with a prevalence below 5%. Conclusion: RAS occur frequently after DAA failures and follow a specific genotype and drug related pattern. Interpretation of the influence of RAS on retreatment is challenging due to various patterns, patients\u2019 characteristics, and previous treatment history. Moving towards HCV elimination, an ongoing resistance surveillance is essential to track the presence of RAS, RAS patterns and gather data for a re-treatment algorithm.<\/jats:p>","DOI":"10.3390\/v14010016","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T02:02:57Z","timestamp":1640224977000},"page":"16","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The European Prevalence of Resistance Associated Substitutions among Direct Acting Antiviral Failures"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8959-4671","authenticated-orcid":false,"given":"Stephanie","family":"Popping","sequence":"first","affiliation":[{"name":"Department of Viroscience, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Cento","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0636-5222","authenticated-orcid":false,"given":"Carole","family":"Seguin-Devaux","sequence":"additional","affiliation":[{"name":"Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch sur Alzette, Luxembourg"},{"name":"The European Society for Translational Antiviral Research, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles","family":"Boucher","sequence":"additional","affiliation":[{"name":"Department of Viroscience, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands"},{"name":"The European Society for Translational Antiviral Research, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adolfo","family":"de Salazar","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology & Infectious Diseases, Instituto Bioanitario Ibs.Granada, Hospital Universitario San Cecilio, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Heger","sequence":"additional","affiliation":[{"name":"University Hospital Cologne, 50937 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3207-4226","authenticated-orcid":false,"given":"Orna","family":"Mor","sequence":"additional","affiliation":[{"name":"Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat-Gan 52621, Israel"},{"name":"Sackler Faculty s of Medicine, Tel Aviv 69978, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murat","family":"Sayan","sequence":"additional","affiliation":[{"name":"Clinical Laboratory, Faculty of Medicine, Kocaeli University, Kocaeli 41380, Turkey"},{"name":"Research Center of Experimental Health Sciences, Near East University, Nicosia 99138, North Cyprus, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Salmon-Ceron","sequence":"additional","affiliation":[{"name":"Assistance Publique Hopitaux de Paris, University of Paris, 75004 Paris, France"},{"name":"ESCMID Study Group for Viral Hepatitis (ESGVH), European Society of Clinical Microbiology and Infectious Diseases, 4100 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Weis","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 1165 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5294-2428","authenticated-orcid":false,"given":"Henrik","family":"Krarup","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics, Aalborg University Hospital, 9100 Aalborg, Denmark"},{"name":"Department of Clinical Medicine, Aalborg University, 9100 Aalborg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"de Knegt","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2586-4070","authenticated-orcid":false,"given":"Oana","family":"S\u0103ndulescu","sequence":"additional","affiliation":[{"name":"National Institute for Infectious Diseases \u201cProf. Dr. Matei Bals\u201d, 021105 Bucharest, Romania"},{"name":"Department of Infectious Diseases I, Carol Davila University of Medicine and Pharmacy, 021105 Bucharest, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6303-9293","authenticated-orcid":false,"given":"Vladimir","family":"Chulanov","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Phthisiopulmonology & Infectious Diseases, 620039 Moscow, Russia"},{"name":"Department of Infectious Diseases, Sechenov University, 119991 Moscow, Russia"},{"name":"Scientific Center for Genetics and Life Sciences, Division of Biotechnology, Sirius University of Science and Technology, 354340 Sochi, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"van de Vijver","sequence":"additional","affiliation":[{"name":"Department of Viroscience, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7611-781X","authenticated-orcid":false,"given":"Federico","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"The European Society for Translational Antiviral Research, 3584 CX Utrecht, The Netherlands"},{"name":"Department of Clinical Microbiology & Infectious Diseases, Instituto Bioanitario Ibs.Granada, Hospital Universitario San Cecilio, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Ceccherini-Silberstein","sequence":"additional","affiliation":[{"name":"The European Society for Translational Antiviral Research, 3584 CX Utrecht, The Netherlands"},{"name":"Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2018). 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