{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T08:56:03Z","timestamp":1777452963971,"version":"3.51.4"},"reference-count":25,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2018,4,1]],"date-time":"2018-04-01T00:00:00Z","timestamp":1522540800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antiviral Therapy"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Direct-acting antiviral (DAA) therapy has dramatically increased sustained virological response rates in HCV-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5A-targeted therapy, still emerge. This real-life study analysed the type and frequency of RAS in rare cases of patients failing DAA regimens in 12 clinical centres in Israel.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Blood samples and clinical data from 49 patients who failed various DAAs were collected. RAS identified in the NS3 and NS5A regions by population (Sanger) and next-generation sequencing (NGS) were compared by treatment regimen and HCV subtypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The majority (71.4%, 35\/49) of patients were infected with the genotype (GT)1b strain, while 12.2% (6\/49) carried GT1a and 14.3% GT3a\/b (7), GT4a (1) and GT1b\/GT3a. RAS were identified in 85.7% (42\/49) of failures, of which 90.5% (38\/42) were clinically relevant RAS (known to be associated with a specific GT and DAA in patients failing therapy or those with more than twofold change in in vitro replicon assays). The most abundant RAS were 168A\/E\/Q\/G\/N\/V (32.6%, 16\/49) identified in NS3, and 93H\/N (61.2%, 30\/49), 31I\/M\/V (34.7%, 17\/49) and 30R\/H\/K (12.2%, 6\/49), identified in NS5A. Significantly more clinically relevant RAS were identified in NS5A (82.2%, 37\/45) than in NS3 (35.7%, 10\/28; P&lt;0.01). While RAS were identified in all GT1a, GT3b and GT4a failures (100%, 10\/10), only 71.8% (28\/39) of GT1b or GT3a failures had RAS ( P=0.09). In four cases, NGS identified additional clinically relevant RAS and in one patient, NGS deciphered coexistence of GT3a and GT1b infections.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings, together with additional real-life data, will contribute to the optimization of retreatment in DAA failure, when cost-related and suboptimal regimens must be employed.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3851\/imp3301","type":"journal-article","created":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T08:06:37Z","timestamp":1552896397000},"page":"221-228","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["High Frequency of Multiclass HCV Resistance-Associated Mutations in Patients Failing Direct-Acting Antivirals: Real-Life Data"],"prefix":"10.1177","volume":"24","author":[{"given":"Yael","family":"Gozlan","sequence":"first","affiliation":[{"name":"Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat Gan, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Efrat","family":"Bucris","sequence":"additional","affiliation":[{"name":"Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat Gan, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Shirazi","sequence":"additional","affiliation":[{"name":"Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat Gan, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avia","family":"Rakovsky","sequence":"additional","affiliation":[{"name":"Central Virology Laboratory, Ministry of Health, Sheba Medical Center, Ramat Gan, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziv","family":"Ben-Ari","sequence":"additional","affiliation":[{"name":"Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel"},{"name":"The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israe"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yana","family":"Davidov","sequence":"additional","affiliation":[{"name":"Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ella","family":"Veizman","sequence":"additional","affiliation":[{"name":"Liver Unit, Rambam Medical Center, Haifa, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tarek","family":"Saadi","sequence":"additional","affiliation":[{"name":"Liver Unit, Rambam Medical Center, Haifa, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marius","family":"Braun","sequence":"additional","affiliation":[{"name":"The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israe"},{"name":"Liver Institute, Rabin Medical Center, Petah Tikva, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Cohen-Naftaly","sequence":"additional","affiliation":[{"name":"The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israe"},{"name":"Liver Institute, Rabin Medical Center, Petah Tikva, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amir","family":"Shlomai","sequence":"additional","affiliation":[{"name":"The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israe"},{"name":"Liver Institute, Rabin Medical Center, Petah Tikva, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oren","family":"Shibolet","sequence":"additional","affiliation":[{"name":"The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israe"},{"name":"Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ehud","family":"Zigmond","sequence":"additional","affiliation":[{"name":"The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israe"},{"name":"Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Katchman","sequence":"additional","affiliation":[{"name":"The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israe"},{"name":"Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoram","family":"Menachem","sequence":"additional","affiliation":[{"name":"The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israe"},{"name":"Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rifaat","family":"Safadi","sequence":"additional","affiliation":[{"name":"Liver Unit, Carmel Medical Center, Haifa, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eitan","family":"Galun","sequence":"additional","affiliation":[{"name":"Liver Unit, Hadassah Medical Center, Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eli","family":"Zuckerman","sequence":"additional","affiliation":[{"name":"Liver Unit, Carmel Medical Center, Haifa, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Assy","family":"Nimer","sequence":"additional","affiliation":[{"name":"Faculty of Medicine in the Galilee, Bar-Ilan University, Ramat Gan, Israel"},{"name":"Internal Medicine Department, Galilee Medical Center, Nahariya, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rawi","family":"Hazzan","sequence":"additional","affiliation":[{"name":"Liver Unit, Haemek Medical Center, Afula, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaakov","family":"Maor","sequence":"additional","affiliation":[{"name":"The Institute of Gastroenterology and Hepatology, Kaplan Medical Center, Rehovot, Israe"},{"name":"The Hebrew University Faculty of Medicine, Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abu Moch","family":"Saif","sequence":"additional","affiliation":[{"name":"Liver Unit, Hillel Yaffe Medical Center, Hadera, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ohad","family":"Etzion","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology & Liver Diseases, Soroka University Medical Center, Beer Sheva, 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