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

Antonio Grieco, Massimo Siciliano, Velia C. Di Maio, Valeria Cento, Ilaria Lenci, Marianna Aragri, Piera Rossi, Silvia Barbaliscia, Michela Melis, Gabriella Verucchi, Carlo F. Magni, Elisabetta Teti, Ada Bertoli, Francescopaolo Antonucci, Maria C. Bellocchi, Valeria Micheli, Chiara Masetti, Simona Landonio, Simona Francioso, Francesco SantopaoloAdriano M. Pellicelli, Vincenza Calvaruso, Laura Gianserra, Dante Romagnoli, Raffaele Cozzolongo, Filomena Morisco, Manuela Merli, Giuseppina Brancaccio, Antonio Di Biagio, Elisabetta Loggi, Claudio M. Mastroianni, Valeria Pace Palitti, Pierluigi Tarquini, Massimo Puoti, Gloria Taliani, Loredana Sarmati, Antonino Picciotto, Vincenzo Vullo, Nicola Caporaso, Maurizio Paoloni, Caterina Pasquazzi, Giuliano Rizzardini, Giustino Parruti, Antonio Craxì, Sergio Babudieri, Massimo Andreoni, Mario Angelico, Carlo F. Perno, Francesca Ceccherini-Silberstein

Risultato della ricerca: Contributo in rivistaArticolo in rivista

55 Citazioni (Scopus)

Abstract

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<.001). Interestingly, 57.1% of DAA IFN-free non-responders had a misclassified genotype, and 3/4 sofosbuvir breakthroughs showed the major-RAS-S282T, while RAS-L159F was frequently found in sofosbuvir relapsers (18.2%). Notably, 9.0% of patients showed also extra target RASs, and 47.4% of patients treated with ≥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.
Lingua originaleEnglish
pagine (da-a)514-528
Numero di pagine15
RivistaOPEN ACCESS SCIENTIFIC REPORTS
Volume37
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • 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
  • antiviral therapy
  • direct-acting antivirals
  • hepatitis C virus
  • resistance test
  • resistance-associated substitutions

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