6533b872fe1ef96bd12d2efe

RESEARCH PRODUCT

Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies

Velia C. Di MaioValeria CentoIlaria LenciMarianna AragriPiera RossiSilvia BarbalisciaMichela MelisGabriella VerucchiCarlo F. MagniElisabetta TetiAda BertoliFrancescopaolo AntonucciMaria C. BellocchiValeria MicheliChiara MasettiSimona LandonioSimona FranciosoFrancesco SantopaoloAdriano M. PellicelliVincenza CalvarusoLaura GianserraMassimo SicilianoDante RomagnoliRaffaele CozzolongoAntonio GriecoJacopo VecchietFilomena MoriscoManuela MerliGiuseppina BrancaccioAntonio Di BiagioElisabetta LoggiClaudio Maria MastroianniValeria Pace PalittiPierluigi TarquiniMassimo PuotiGloria TalianiLoredana SarmatiAntonino PicciottoVincenzo VulloNicola CaporasoMaurizio PaoloniCaterina PasquazziGiuliano RizzardiniGiustino ParrutiAntonio CraxìSergio BabudieriMassimo AndreoniMario AngelicoCarlo F. PernoFrancesca Ceccherini-silbersteinR. MarianiN. IapadreA. GrimaldiR. CozzolongoP. AndreoneG. VerucchiB. MenzaghiT. QuirinoV. PisaniMaria Chiara TortiJ. VecchietB. BruzzoneA. De MariaS. MarencoL. A. NicoliniC. ViscoliK. CasinelliM. Delle MonacheMiriam LichtnerA. AghemoV. BoccaccioS. BrunoM. CerroneM. ColomboA. D'arminio MonforteE. DanieliF. DonatoG. GubertiniA. LleoC. F. MagniA. ManconS. MonicoF. NieroM. L. RussoM. GnocchiA. OrroL. MilanesiE. BaldelliM. BertolottiV. BorghiC. MussiniG. BrancaccioG. B. GaetaV. LemboV. SangiovanniV. Di MarcoA. MazzolaS. PettaE. D'amicoP. CacciatoreA. ConsorteA. PieriE. PolilliF. SozioF. AntenucciM. AragriL. BaiocchiS. BarbalisciaElisa BiliottiM. BiolatoL. CariotiF. Ceccherini SilbersteinG. CerasariC. CervaM. CiottiC. D'ambrosioG. D'ettorreF. De LeonardisA. De SanctisV. C. Di MaioD. Di PaoloCaterina FurlanP. GalloA. GasbarriniV. GiannelliS. GriecoL. LambiaseB. LattanziI. LenciR. LulaV. MalagninoM. ManuelliL. MiglioresiM. MilanaA. MorettiL. NosottiDonatella PalazzoA. PellicelliM. RomanoC. SarrecchiaD. SforzaM. C. SorboM. SpazianteV. SvicherG. TisoneU. Vespasiani GentilucciG. D'adamoA. MangiaI. MaidaM. S. MuraL. FalconiD. Di Giammartino

subject

Male0301 basic medicinehepatitis C virusSustained Virologic ResponseSofosbuvirHepacivirusDrug ResistanceHepacivirusresistance-associated substitutionsViral Nonstructural ProteinsVARIANTSNS5Amedicine.disease_causeGastroenterologychemistry.chemical_compound0302 clinical medicineRecurrenceINFECTIONantiviral therapyMedicinehepatitis C viruViralTreatment FailureChronicantiviral therapy; direct-acting antivirals; hepatitis C virus; resistance test; resistance-associated substitutions; hepatologybiologyGENOTYPE 1virus diseasesMiddle Agedantiviral therapy; direct-acting antivirals; hepatitis C virus; resistance test; resistance-associated substitutionsSettore MED/07 - Microbiologia e Microbiologia ClinicaHepatitis CItalyCombinationInterferonDrug Therapy CombinationFemale030211 gastroenterology & hepatologyAuthor Keywords:antiviral therapyRIBAVIRINSequence AnalysisHumanmedicine.drugmedicine.medical_specialtyDaclatasvirGenotypeHepatitis C virusAntiviral AgentsLONG-TERM PERSISTENCEDACLATASVIR03 medical and health sciencesDrug Therapyantiviral therapy; direct-acting antivirals; hepatitis C virus; resistance test; resistance-associated substitutions; Aged; Antiviral Agents; Drug Resistance Viral; Drug Therapy Combination; Female; Genotype; Hepacivirus; Hepatitis C Chronic; Humans; Interferons; Italy; Male; Middle Aged; Mutation; Recurrence; Ribavirin; Sequence Analysis DNA; Sofosbuvir; Sustained Virologic Response; Treatment Failure; Viral Nonstructural Proteins; HepatologyTREATMENT-NAIVEInternal medicineDrug Resistance ViralRibavirinHumansNS5Aresistance testdirect-acting antiviralsAgedAntiviral Agentresistance-associated substitutiondirect-acting antiviralHepaciviruHepatologyresistance test KeyWords Plus:HEPATITIS-C VIRUSbusiness.industryRibavirinViral Nonstructural ProteinSequence Analysis DNADNAHepatitis C ChronicHepatologybiology.organism_classificationClinical trial030104 developmental biologySOFOSBUVIRchemistrySequence AnalysihepatologyMutationImmunologyInterferonsSofosbuvirbusiness

description

Background & Aims: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures. Methods: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N= 200) and whenever possible at baseline (N= 70). Results: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P= 2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure. Conclusions: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring.

yearjournalcountryeditionlanguage
2017-01-20
10.1111/liv.13327http://hdl.handle.net/11573/949397