{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:11:16Z","timestamp":1772118676442,"version":"3.50.1"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2018,7,16]],"date-time":"2018-07-16T00:00:00Z","timestamp":1531699200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2018,7,16]],"date-time":"2018-07-16T00:00:00Z","timestamp":1531699200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:p>\n                    Hepatitis C virus (HCV) infection induces interferon (IFN)\u2010stimulated genes (ISGs) and downstream innate immune responses. This study investigated whether baseline and on\u2010treatment differences in these responses predict response versus virological breakthrough during therapy with direct\u2010acting antivirals (DAAs). Thirteen HCV genotype 1b\u2013infected patients who had previously failed a course of pegylated IFN\/ribavirin were retreated with asunaprevir\/daclatasvir for 24 weeks. After pretreatment biopsy, patients were randomized to undergo a second biopsy at week 2 or 4 on therapy. Microarray and NanoString analyses were performed on paired liver biopsies and analyzed using linear mixed models. As biomarkers for peripheral IFN responses, peripheral blood natural killer cells were assessed for phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and tumor necrosis factor\u2013related apoptosis\u2010inducing ligand (TRAIL) expression and degranulation. Nine of 13 (69%) patients achieved sustained virological response at 12 weeks off therapy (SVR12), and 4 experienced virological breakthroughs between weeks 4 and 12. Patients who achieved SVR12 displayed higher ISG expression levels in baseline liver biopsies and a higher frequency of pSTAT1 and TRAIL\u2010expressing, degranulating natural killer cells in baseline blood samples than those who experienced virological breakthrough. Comparing gene expression levels from baseline and on\u2010therapy biopsies, 408 genes (\u00b11.2\u2010fold,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    &lt; 0.01) were differentially expressed. Genes down\u2010regulated on treatment were predominantly ISGs. Down\u2010regulation of ISGs was rapid and correlated with HCV RNA suppression.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    An enhanced IFN signature is observed at baseline in liver and blood of patients who achieve SVR12 compared to those who experience a virological breakthrough; the findings suggest that innate immunity may contribute to clearance of HCV during DAA therapy by preventing the emergence of resistance\u2010associated substitutions that lead to viral breakthrough during DAA therapy.\n                  <\/jats:p>","DOI":"10.1002\/hep.29921","type":"journal-article","created":{"date-parts":[[2018,4,27]],"date-time":"2018-04-27T21:00:21Z","timestamp":1524862821000},"page":"2078-2088","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":42,"title":["Baseline Intrahepatic and Peripheral Innate Immunity are Associated with Hepatitis C Virus Clearance During Direct\u2010Acting Antiviral Therapy"],"prefix":"10.1097","volume":"68","author":[{"given":"Hawwa","family":"Alao","sequence":"first","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maggie","family":"Cam","sequence":"additional","affiliation":[{"name":"Office of Science and Technology Resources,National Cancer Institute,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chithra","family":"Keembiyehetty","sequence":"additional","affiliation":[{"name":"Genomic Core facility,National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisavet","family":"Serti","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Suarez","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heiyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolaas H.","family":"Fourie","sequence":"additional","affiliation":[{"name":"Digestive Disorder Unit,National Institute of Nursing Research,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth C.","family":"Wright","sequence":"additional","affiliation":[{"name":"Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy A.","family":"Henderson","sequence":"additional","affiliation":[{"name":"Digestive Disorder Unit,National Institute of Nursing Research,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qisheng","family":"Li","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T. Jake","family":"Liang","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Rehermann","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney Diseases,Bethesda,MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2837-0188","authenticated-orcid":false,"given":"Marc G.","family":"Ghany","sequence":"additional","affiliation":[{"name":"Liver Diseases Branch,National Institute of Diabetes and Digestive and Kidney 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