{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:49:32Z","timestamp":1780584572866,"version":"3.54.1"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2019,6,5]],"date-time":"2019-06-05T00:00:00Z","timestamp":1559692800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:p>Protease inhibitors (PIs) are important components of treatment regimens for patients with chronic hepatitis C virus (HCV) infection. However, emergence and persistence of antiviral resistance could reduce their efficacy. Thus, defining resistance determinants is highly relevant for efforts to control HCV. Here, we investigated patterns of PI resistance\u2013associated substitutions (RASs) for the major HCV genotypes and viral determinants for persistence of key RASs. We identified protease position 156 as a RAS hotspot for genotype 1\u20104, but not 5 and 6, escape variants by resistance profiling using PIs grazoprevir and paritaprevir in infectious cell culture systems. However, except for genotype 3, engineered 156\u2010RASs were not maintained. For genotypes 1 and 2, persistence of 156\u2010RASs depended on genome\u2010wide substitution networks, co\u2010selected under continued PI treatment and identified by next\u2010generation sequencing with substitution linkage and haplotype reconstruction. Persistence of A156T for genotype 1 relied on compensatory substitutions increasing replication and assembly. For genotype 2, initial selection of A156V facilitated transition to 156L, persisting without compensatory substitutions. The developed genotype 1, 2, and 3 variants with persistent 156\u2010RASs had exceptionally high fitness and resistance to grazoprevir, paritaprevir, glecaprevir, and voxilaprevir. A156T dominated in genotype 1 glecaprevir and voxilaprevir escape variants, and pre\u2010existing A156T facilitated genotype 1 escape from clinically relevant combination treatments with grazoprevir\/elbasvir and glecaprevir\/pibrentasvir. In genotype 1 infected patients with treatment failure and 156\u2010RASs, we observed genome\u2010wide selection of substitutions under treatment. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Comprehensive PI resistance profiling for HCV genotypes 1\u20106 revealed 156\u2010RASs as key determinants of high\u2010level resistance across clinically relevant PIs. We obtained <jats:italic toggle=\"yes\">in vitro<\/jats:italic> proof of concept for persistence of highly fit genotype 1\u20103 156\u2010variants, which might pose a threat to clinically relevant combination treatments.<\/jats:p>","DOI":"10.1002\/hep.30647","type":"journal-article","created":{"date-parts":[[2019,4,9]],"date-time":"2019-04-09T17:40:56Z","timestamp":1554831656000},"page":"771-787","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":57,"title":["Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants"],"prefix":"10.1097","volume":"70","author":[{"given":"Sanne Brun","family":"Jensen","sequence":"first","affiliation":[{"name":"Copenhagen Hepatitis C Program (CO\u2010HEP), Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences,University of 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