{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:26:15Z","timestamp":1790108775557,"version":"4.0.1"},"reference-count":34,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T00:00:00Z","timestamp":1645401600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background &amp; Aims<\/jats:title><jats:p>According to pivotal clinical trials, cure rates for sofosbuvir\u2010based antiviral therapy exceed 96%. Treatment failure is usually assumed to be because of virological resistance\u2010associated substitutions or clinical risk factors, yet the role of patient\u2010specific genetic factors has not been well explored. We determined if patient\u2010specific genetic factors help predict patients likely to fail sofosbuvir treatment in real\u2010world treatment situations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We recruited sofosbuvir\u2010treated patients with chronic hepatitis C from five Canadian treatment sites, and performed a case\u2010control pharmacogenomics study assessing both previously published and novel genetic polymorphisms. Specifically studied were variants predicted to impair CES1\u2010dependent production of sofosbuvir\u2019s active metabolite, interferon\u2010\u03bb signalling variants expected to impact a patient\u2019s immune response to the virus and an <jats:italic>HLA<\/jats:italic> variant associated with increased spontaneous and treatment\u2010induced viral clearance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Three hundred and fifty\u2010nine sofosbuvir\u2010treated patients were available for analyses after exclusions, with 34 (9.5%) failing treatment. We identified <jats:italic>CES1<\/jats:italic> variants as novel predictors for treatment failure in European patients (rs115629050 or rs4513095; odds ratio (OR): 5.43; 95% confidence interval (CI): 1.64\u201018.01; <jats:italic>P<\/jats:italic>\u00a0=\u00a0.0057), replicated associations with <jats:italic>IFNL4<\/jats:italic> variants predicted to increase interferon\u2010\u03bb signalling (eg rs12979860; OR: 2.25; 95% CI: 1.25\u20104.06; <jats:italic>P<\/jats:italic>\u00a0=\u00a0.0071) and discovered a novel association with a coding variant predicted to enhance the activity of IFNL4's receptor (rs2834167 in <jats:italic>IL10RB<\/jats:italic>; OR: 1.81; 95% CI: 1.01\u20103.24; <jats:italic>P<\/jats:italic>\u00a0=\u00a0.047).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Ultimately, this work demonstrates that patient\u2010specific genetic factors could be used as a tool to identify patients at higher risk of treatment failure and allow for these patients to receive effective therapy sooner.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15175","type":"journal-article","created":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T16:48:24Z","timestamp":1643820504000},"page":"796-808","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Patient\u2010specific genetic factors predict treatment failure in sofosbuvir\u2010treated patients with chronic hepatitis C"],"prefix":"10.1111","volume":"42","author":[{"given":"Catrina M.","family":"Loucks","sequence":"first","affiliation":[{"name":"BC Children\u2019s Hospital Research Institute  Vancouver Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver Canada"},{"name":"Department of Anesthesiology, Pharmacology &amp; Therapeutics Faculty of Medicine, University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9220-9631","authenticated-orcid":false,"given":"Jennifer J.","family":"Lin","sequence":"additional","affiliation":[{"name":"BC Children\u2019s Hospital Research Institute  Vancouver Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver Canada"},{"name":"Department of Medical Genetics, Faculty of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica N.","family":"Trueman","sequence":"additional","affiliation":[{"name":"BC Children\u2019s Hospital Research Institute  Vancouver Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britt I.","family":"Dr\u00f6gem\u00f6ller","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Genetics University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galen E. B.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Therapeutics University of Manitoba  Winnipeg Manitoba Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan\u2010Chun","family":"Chang","sequence":"additional","affiliation":[{"name":"BC Children\u2019s Hospital Research Institute  Vancouver Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy H.","family":"Li","sequence":"additional","affiliation":[{"name":"BC Children\u2019s Hospital Research Institute  Vancouver Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u2010Ann","family":"Ford","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel S.","family":"Lee","sequence":"additional","affiliation":[{"name":"Liver Unit University of Calgary Cumming School of Medicine  Calgary Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pam","family":"Crotty","sequence":"additional","affiliation":[{"name":"Liver Unit University of Calgary Cumming School of Medicine  Calgary Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard B.","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine Western University  London Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4733-4289","authenticated-orcid":false,"given":"Bandar","family":"Al\u2010Judaibi","sequence":"additional","affiliation":[{"name":"Division of Transplantation University of Rochester  Rochester New York USA"},{"name":"Department of Liver Transplantation and Hepatobiliary Surgery King Faisal Specialist Hospital and Research Center  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute I.","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Department of Medicine Western University  London Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alnoor","family":"Ramji","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanette F.","family":"Farivar","sequence":"additional","affiliation":[{"name":"Pacific Gastroenterology Associates  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Tam","sequence":"additional","affiliation":[{"name":"LAIR Centre  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori Lee","family":"Walston","sequence":"additional","affiliation":[{"name":"LAIR Centre  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin J. D.","family":"Ross","sequence":"additional","affiliation":[{"name":"BC Children\u2019s Hospital Research Institute  Vancouver Canada"},{"name":"Department of Medical Genetics, Faculty of Medicine University of British Columbia  Vancouver Canada"},{"name":"Faculty of Pharmaceutical Sciences The University of British Columbia  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4485-4054","authenticated-orcid":false,"given":"Bruce C.","family":"Carleton","sequence":"additional","affiliation":[{"name":"BC Children\u2019s Hospital Research Institute  Vancouver Canada"},{"name":"Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine University of British Columbia  Vancouver Canada"},{"name":"Department of Medical Genetics, Faculty of Medicine University of British Columbia  Vancouver Canada"},{"name":"Pharmaceutical Outcomes Program (POPi), British Columbia Children\u2019s Hospital  Vancouver Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,21]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.7326\/M16-2575"},{"key":"e_1_2_16_3_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.05.007"},{"key":"e_1_2_16_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27375"},{"key":"e_1_2_16_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.161802"},{"key":"e_1_2_16_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.641"},{"key":"e_1_2_16_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.001233"},{"key":"e_1_2_16_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2016.05.025"},{"key":"e_1_2_16_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.101"},{"key":"e_1_2_16_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.12916"},{"key":"e_1_2_16_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2016.09.003"},{"key":"e_1_2_16_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.12715"},{"key":"e_1_2_16_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.06.069"},{"key":"e_1_2_16_14_1","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2019.0013"},{"key":"e_1_2_16_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.13401"},{"key":"e_1_2_16_16_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-158-4-201302190-00003"},{"key":"e_1_2_16_17_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.12.014"},{"key":"e_1_2_16_18_1","doi-asserted-by":"publisher","DOI":"10.1503\/cmaj.170453"},{"key":"e_1_2_16_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.1772"},{"key":"e_1_2_16_20_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2005-864781"},{"key":"e_1_2_16_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24105"},{"key":"e_1_2_16_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21669"},{"key":"e_1_2_16_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.07.033"},{"key":"e_1_2_16_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00453.2016"},{"key":"e_1_2_16_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12423"},{"key":"e_1_2_16_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2019.144289"},{"key":"e_1_2_16_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602800103"},{"key":"e_1_2_16_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27366"},{"key":"e_1_2_16_29_1","volume-title":"Drugs for chronic hepatitis C infection: cost\u2010effectiveness analysis","author":"Wong W","year":"2016"},{"key":"e_1_2_16_30_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402355"},{"key":"e_1_2_16_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2521"},{"key":"e_1_2_16_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3835"},{"key":"e_1_2_16_33_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1613512"},{"key":"e_1_2_16_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jve.2020.06.001"},{"key":"e_1_2_16_35_1","volume-title":"Pharmacoeconomic Review Report: Sofosbuvir\/Velpatasvir\/Voxilaprevir (Vosevi): (Gilead Sciences Canada, Inc.): Indication: Hepatitis C Infection Genotype 1 to 6","year":"2018"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.15175","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/liv.15175","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.15175","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,27]],"date-time":"2023-08-27T12:56:06Z","timestamp":1693140966000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.15175"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,21]]},"references-count":34,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1111\/liv.15175"],"URL":"https:\/\/doi.org\/10.1111\/liv.15175","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,21]]},"assertion":[{"value":"2021-09-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-02-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}