{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:14:38Z","timestamp":1792206878459,"version":"4.4.0"},"reference-count":81,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T00:00:00Z","timestamp":1634515200000},"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>The approval of combination therapies with direct-acting antiviral (DAA) regimens has led to significant progress in the field of hepatitis C virus (HCV) treatment. Although most patients treated with these agents achieve a virological cure, resistance to DAAs is a major issue. The rapid emergence of resistance-associated substitutions (RASs), in particular in the context of incomplete drug pressure, has an impact on sustained virological response (SVR) rates. Several RASs in NS3, NS5A and NS5B have been linked with reduced susceptibility to DAAs. RAS vary based on HCV characteristics and the different drug classes. DAA-resistant HCV variant haplotypes (RVs) are dominant in cases of virological failure. Viruses with resistance to NS3-4A protease inhibitors are only detected in the peripheral blood in a time frame ranging from weeks to months following completion of treatment, whereas NS5A inhibitor-resistant viruses may persist for years. Novel agents have been developed that demonstrate promising results in DAA-experienced patients. The recent approval of broad-spectrum drug combinations with a high genetic barrier to resistance and antiviral potency may overcome the problem of resistance.<\/jats:p>","DOI":"10.3390\/v13102096","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T22:07:04Z","timestamp":1634767624000},"page":"2096","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["The Role of RASs \/RVs in the Current Management of HCV"],"prefix":"10.3390","volume":"13","author":[{"given":"Konstantinos","family":"Malandris","sequence":"first","affiliation":[{"name":"Second Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4962-790X","authenticated-orcid":false,"given":"Georgios","family":"Kalopitas","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki,\r\n54636 Thessaloniki, Greece"},{"name":"Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Theocharidou","sequence":"additional","affiliation":[{"name":"Second Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7985-3118","authenticated-orcid":false,"given":"Georgios","family":"Germanidis","sequence":"additional","affiliation":[{"name":"First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki,\r\n54636 Thessaloniki, Greece"},{"name":"Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1016\/j.jhep.2016.07.035","article-title":"The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control","volume":"65","author":"Bukh","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1128\/MMBR.05023-11","article-title":"Viral quasispecies evolution","volume":"76","author":"Domingo","year":"2012","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.virol.2015.03.022","article-title":"Viral quasispecies","volume":"479\u2013480","author":"Andino","year":"2015","journal-title":"Virology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.virol.2016.03.017","article-title":"Viral quasispecies complexity measures","volume":"493","author":"Gregori","year":"2016","journal-title":"Virology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14562","DOI":"10.1073\/pnas.1210592109","article-title":"Profibrogenic chemokines and viral evolution predict rapid progression of hepatitis C to cirrhosis","volume":"109","author":"Farci","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1002\/hep.21623","article-title":"Genetic and catalytic efficiency structure of an HCV protease quasispecies","volume":"45","author":"Franco","year":"2007","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"ofz076","DOI":"10.1093\/ofid\/ofz076","article-title":"Identification of 19 Novel Hepatitis C Virus Subtypes-Further Expanding HCV Classification","volume":"6","author":"Hedskog","year":"2019","journal-title":"Open Forum Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7593","DOI":"10.1128\/JVI.02824-12","article-title":"Response of hepatitis C virus to long-term passage in the presence of alpha interferon: Multiple mutations and a common phenotype","volume":"87","author":"Perales","year":"2013","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12098","DOI":"10.1128\/JVI.01860-14","article-title":"Increased replicative fitness can lead to decreased drug sensitivity of hepatitis C virus","volume":"88","author":"Sheldon","year":"2014","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"267483","DOI":"10.1155\/2012\/267483","article-title":"Hepatitis C variability, patterns of resistance, and impact on therapy","volume":"2012","author":"Strahotin","year":"2012","journal-title":"Adv. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"275","DOI":"10.2147\/IDR.S145362","article-title":"Pegylated-interferon plus ribavirin treatment does not alter the prevalence of resistance-associated substitutions to direct-acting antivirals in HCV genotype 1a patients","volume":"10","author":"Chen","year":"2017","journal-title":"Infect. Drug Resist."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.jhep.2020.08.018","article-title":"EASL recommendations on treatment of hepatitis C: Final update of the series\u2606","volume":"73","author":"Pawlotsky","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1055\/s-0039-1687823","article-title":"Retreatment of Hepatitis C Virus-Infected Patients with Direct-Acting Antiviral Failures","volume":"39","author":"Pawlotsky","year":"2019","journal-title":"Semin. Liver Dis."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kalaghatgi, P., Sikorski, A.M., Knops, E., Rupp, D., Sierra, S., Heger, E., Neumann-Fraune, M., Beggel, B., Walker, A., and Timm, J. (2016). Geno2pheno[HCV]\u2014A Web-based Interpretation System to Support Hepatitis C Treatment Decisions in the Era of Direct-Acting Antiviral Agents. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155869"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1053\/j.gastro.2016.04.003","article-title":"Hepatitis C Virus Resistance to Direct-Acting Antiviral Drugs in Interferon-Free Regimens","volume":"151","author":"Pawlotsky","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"AASLD-IDSA HCV Guidance Panel (2018). Hepatitis C Guidance 2018 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clin. Infect. Dis., 67, 1477\u20131492.","DOI":"10.1093\/cid\/ciy585"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2018). EASL Recommendations on Treatment of Hepatitis C 2018. J. Hepatol., 69, 461\u2013511.","DOI":"10.1016\/j.jhep.2018.03.026"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1053\/j.gastro.2017.11.007","article-title":"Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals","volume":"154","author":"Dietz","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1053\/j.gastro.2018.10.024","article-title":"Status of Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection and Remaining Challenges","volume":"156","author":"Baumert","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.jhep.2017.01.007","article-title":"NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome","volume":"66","author":"Zeuzem","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1002\/hep4.1060","article-title":"The emergence of NS5B resistance associated substitution S282T after sofosbuvir-based treatment","volume":"1","author":"Gane","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Soria, M.E., Garc\u00eda-Crespo, C., Mart\u00ednez-Gonz\u00e1lez, B., V\u00e1zquez-Sirvent, L., Lobo-Vega, R., de \u00c1vila, A.I., Gallego, I., Chen, Q., Garc\u00eda-Cehic, D., and Llorens-Revull, M. (2020). Amino Acid Substitutions Associated with Treatment Failure for Hepatitis C Virus Infection. J. Clin. Microbiol., 58.","DOI":"10.1128\/JCM.01985-20"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.2147\/IDR.S172226","article-title":"Baseline hepatitis C virus resistance-associated substitutions present at frequencies lower than 15% may be clinically significant","volume":"11","author":"Perales","year":"2018","journal-title":"Infect. Drug Resist."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/hep4.1050","article-title":"Sequencing of hepatitis C virus for detection of resistance to direct-acting antiviral therapy: A systematic review","volume":"1","author":"Bartlett","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nrmicro3046","article-title":"The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection","volume":"11","author":"Bartenschlager","year":"2013","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cento, V., Mirabelli, C., Salpini, R., Dimonte, S., Artese, A., Costa, G., Mercurio, F., Svicher, V., Parrotta, L., and Bertoli, A. (2012). HCV genotypes are differently prone to the development of resistance to linear and macrocyclic protease inhibitors. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039652"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1111\/liv.14797","article-title":"Resistance analysis and treatment outcomes in hepatitis C virus genotype 3-infected patients within the Italian network VIRONET-C","volume":"41","author":"Barbaliscia","year":"2021","journal-title":"Liver Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.drup.2018.01.004","article-title":"Hepatitis C virus drug resistance associated substitutions and their clinical relevance: Update 2018","volume":"37","author":"Sorbo","year":"2018","journal-title":"Drug Resist. Updates"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11850","DOI":"10.1021\/jacs.6b06454","article-title":"Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3\/4A Protease","volume":"138","author":"Soumana","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.antiviral.2017.02.014","article-title":"Current therapy for chronic hepatitis C: The role of direct-acting antivirals","volume":"142","author":"Li","year":"2017","journal-title":"Antiviral. Res."},{"key":"ref_31","first-page":"P849","article-title":"Analysis of HCV variants in the MAGELLAN-I study (Part 1): ABT-493 and ABT-530 combination therapy of genotype 1-infected patients who had failed prior direct acting antiviral-containing regimens","volume":"64","author":"Ng","year":"2016","journal-title":"Hepatology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.jhep.2015.09.011","article-title":"The importance of resistance to direct antiviral drugs in HCV infection in clinical practice","volume":"64","author":"Sarrazin","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.jhep.2014.11.032","article-title":"Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon\/ribavirin in Phase IIb\/III studies","volume":"62","author":"Lenz","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1111\/liv.13327","article-title":"Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies","volume":"37","author":"Cento","year":"2017","journal-title":"Liver Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1002\/hep.27934","article-title":"Hepatitis C virus drug resistance-associated substitutions: State of the art summary","volume":"62","author":"Lontok","year":"2015","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1002\/hep.26388","article-title":"Resistance analysis of hepatitis C virus genotype 1 prior treatment null responders receiving daclatasvir and asunaprevir","volume":"58","author":"McPhee","year":"2013","journal-title":"Hepatology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1016\/S0140-6736(14)61059-X","article-title":"All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: A multinational, phase 3, multicohort study","volume":"384","author":"Manns","year":"2014","journal-title":"Lancet"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1021\/ml300017p","article-title":"Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3\/4a Protease Inhibitor","volume":"3","author":"Harper","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4161","DOI":"10.1128\/AAC.00324-12","article-title":"MK-5172, a selective inhibitor of hepatitis C virus NS3\/4a protease with broad activity across genotypes and resistant variants","volume":"56","author":"Summa","year":"2012","journal-title":"Antimicrob. Agents. Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1053\/j.gastro.2016.10.017","article-title":"Regulatory Analysis of Effects of Hepatitis C Virus NS5A Polymorphisms on Efficacy of Elbasvir and Grazoprevir","volume":"152","author":"Komatsu","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7326\/M15-0785","article-title":"Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial","volume":"163","author":"Zeuzem","year":"2015","journal-title":"Ann. Intern. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1056\/NEJMoa1315722","article-title":"Treatment of HCV with ABT-450\/r-ombitasvir and dasabuvir with ribavirin","volume":"370","author":"Feld","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1056\/NEJMoa1402338","article-title":"ABT-450\/r-ombitasvir and dasabuvir with or without ribavirin for HCV","volume":"370","author":"Ferenci","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6807","DOI":"10.1128\/AAC.01229-15","article-title":"Hepatitis C virus genotype 4 resistance and subtype demographic characterization of patients treated with ombitasvir plus paritaprevir\/ritonavir","volume":"59","author":"Schnell","year":"2015","journal-title":"Antimicrob. Agents. Chemother."},{"key":"ref_45","unstructured":"Ng, T., Reisch, T., and Middleton, T. (2014, January 3\u20136). ABT-493, a potent HCV NS3\/4A protease inhibitor with broad genotype coverage (Abstract 636). Proceedings of the Conference on Retroviruses and Opportunistic Infections (CROI), Boston, MA, USA."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"S500","DOI":"10.1016\/S0168-8278(17)31399-5","article-title":"Pooled resistance analysis in HCV genotype 1\u20136-infected patients treated with glecaprevir\/pibrentasvir in phase 2 and 3 clinical trials","volume":"66","author":"Krishnan","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10031","DOI":"10.1021\/jm501291c","article-title":"Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition","volume":"57","author":"Nettles","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1053\/j.gastro.2014.04.021","article-title":"Kinetic analyses reveal potent and early blockade of hepatitis C virus assembly by NS5A inhibitors","volume":"147","author":"McGivern","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.jinf.2019.10.007","article-title":"Consensus recommendations for resistance testing in the management of chronic hepatitis C virus infection: Public Health England HCV Resistance Group","volume":"79","author":"Bradshaw","year":"2019","journal-title":"J. Infect."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1111\/jvh.12932","article-title":"Evolution and persistence of resistance-associated substitutions of hepatitis C virus after direct-acting antiviral treatment failures","volume":"25","author":"Jeong","year":"2018","journal-title":"J. Viral. Hepat."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.jhep.2017.09.008","article-title":"Frequent NS5A and multiclass resistance in almost all HCV genotypes at DAA failures: What are the chances for second-line regimens?","volume":"68","author":"Cento","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1002\/hep.28473","article-title":"Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+)","volume":"63","author":"Leroy","year":"2016","journal-title":"Hepatology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5155","DOI":"10.1128\/AAC.02788-14","article-title":"Comparison of Daclatasvir Resistance Barriers on NS5A from Hepatitis C Virus Genotypes 1 to 6: Implications for Cross-Genotype Activity","volume":"58","author":"Wang","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1002\/hep.29693","article-title":"Impact of hepatitis C virus polymorphisms on direct-acting antiviral treatment efficacy: Regulatory analyses and perspectives","volume":"67","author":"Harrington","year":"2018","journal-title":"Hepatology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.jhep.2015.04.009","article-title":"Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent","volume":"63","author":"Forns","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1053\/j.gastro.2017.01.050","article-title":"Safety and Efficacy of Elbasvir\/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis","volume":"152","author":"Jacobson","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1002\/hep.28706","article-title":"Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection","volume":"64","author":"Abergel","year":"2016","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/jvh.12783","article-title":"Nonstructural protein 5A resistance profile in patients with chronic hepatitis C treated with ledipasvir-containing regimens without sofosbuvir","volume":"25","author":"Kitrinos","year":"2018","journal-title":"J. Viral. Hepat."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.jhep.2016.11.022","article-title":"Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir\/sofosbuvir","volume":"66","author":"Wyles","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5445","DOI":"10.1128\/AAC.00998-15","article-title":"Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir","volume":"59","author":"Krishnan","year":"2015","journal-title":"Antimicrob. Agents. Chemother."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"S83","DOI":"10.1016\/S0168-8278(17)30432-4","article-title":"MAGELLAN-1, Part 2: Glecaprevir and pibrentasvir for 12 or 16 weeks in patients with chronic hepatitis C virus genotype 1 or 4 and prior direct-acting antiviral treatment failure","volume":"66","author":"Poordad","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"S708","DOI":"10.1016\/S0168-8278(17)31898-6","article-title":"Resistance analysis in the MAGELLAN-1 study (Part 2): Glecaprevir\/ pibrentasvir therapy in HCV-infected patients who had failed prior DAA regimens containing NS3\/4A protease and\/or NS5A inhibitors","volume":"66","author":"Schnell","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.1093\/jac\/dkaa304","article-title":"Prevalence of resistance-associated substitutions and retreatment of patients failing a glecaprevir\/pibrentasvir regimen","volume":"75","author":"Dietz","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1056\/NEJMoa1512610","article-title":"Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection","volume":"373","author":"Feld","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2608","DOI":"10.1056\/NEJMoa1512612","article-title":"Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection","volume":"373","author":"Foster","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.jhep.2017.11.032","article-title":"Resistance analysis in patients with genotype 1-6 HCV infection treated with sofosbuvir\/velpatasvir in the phase III studies","volume":"68","author":"Hezode","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.1128\/AAC.00054-12","article-title":"Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus","volume":"56","author":"Lam","year":"2012","journal-title":"Antimicrob. Agents. Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1016\/j.jhep.2018.07.002","article-title":"Challenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection","volume":"69","author":"Vermehren","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/hep.27375","article-title":"Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir","volume":"61","author":"Donaldson","year":"2015","journal-title":"Hepatology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1093\/cid\/ciu697","article-title":"Infrequent development of resistance in genotype 1-6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials","volume":"59","author":"Svarovskaia","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1093\/infdis\/jiv564","article-title":"L159F and V321A Sofosbuvir-Associated Hepatitis C Virus NS5B Substitutions","volume":"213","author":"Svarovskaia","year":"2016","journal-title":"J. Infect. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"104694","DOI":"10.1016\/j.antiviral.2019.104694","article-title":"Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure","volume":"174","author":"Chen","year":"2020","journal-title":"Antiviral. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1056\/NEJMoa1613512","article-title":"Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection","volume":"376","author":"Gordon","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"S299","DOI":"10.1016\/S0168-8278(17)30915-7","article-title":"No impact of RASs on the high efficacy of SOF\/VEL\/VOX for 12 weeks in DAA-experienced patients: An integrated resistance analysis of the POLARIS-1 and POLARIS-4 studies","volume":"66","author":"Sarrazin","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1093\/cid\/cix916","article-title":"Retreatment With Sofosbuvir Plus Grazoprevir\/Elbasvir Plus Ribavirin of Patients With Hepatitis C Virus Genotype 1 or 4 Who Previously Failed an NS5A- or NS3-Containing Regimen: The ANRS HC34 REVENGE Study","volume":"66","author":"Laforest","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1016\/S0168-8278(17)30433-6","article-title":"Effect of resistance-associated substitutions on retreatment of direct acting antiviral-exposed patients in the real-world setting (ANRS CO22 HEPATHER)","volume":"66","author":"Chevaliez","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1016\/j.jhep.2021.03.004","article-title":"Treatment failure with DAA therapy: Importance of resistance","volume":"74","author":"Sarrazin","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.jhep.2020.11.017","article-title":"Failure on voxilaprevir, velpatasvir, sofosbuvir and efficacy of rescue therapy","volume":"74","author":"Dietz","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1002\/hep.30647","article-title":"Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants","volume":"70","author":"Jensen","year":"2019","journal-title":"Hepatology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1111\/jvh.13549","article-title":"Real world SOF\/VEL\/VOX retreatment outcomes and viral resistance analysis for HCV patients with prior failure to DAA therapy","volume":"28","author":"Smith","year":"2021","journal-title":"J. Viral. Hepat."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.jhep.2021.04.057","article-title":"Linkage of resistance-associated substitutions in GT1 sofosbuvir+NS5A inhibitor failures treated with glecaprevir\/pibrentasvir","volume":"75","author":"Wang","year":"2021","journal-title":"J. Hepatol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/10\/2096\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:17:04Z","timestamp":1760167024000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/10\/2096"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,18]]},"references-count":81,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["v13102096"],"URL":"https:\/\/doi.org\/10.3390\/v13102096","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,18]]}}}