TY - JOUR
T1 - Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies
AU - Di Maio, Velia C
AU - Cento, Valeria
AU - Lenci, Ilaria
AU - Aragri, Marianna
AU - Rossi, Piera
AU - Barbaliscia, Silvia
AU - Melis, Michela
AU - Verucchi, Gabriella
AU - Magni, Carlo F
AU - Teti, Elisabetta
AU - Bertoli, Ada
AU - Antonucci, FrancescoPaolo
AU - Bellocchi, Maria C
AU - Micheli, Valeria
AU - Masetti, Chiara
AU - Landonio, Simona
AU - Francioso, Simona
AU - Santopaolo, Francesco
AU - Pellicelli, Adriano M
AU - Calvaruso, Vincenza
AU - Gianserra, Laura
AU - Siciliano, Massimo
AU - Romagnoli, Dante
AU - Cozzolongo, Raffaele
AU - Grieco, Antonio
AU - Vecchiet, Jacopo
AU - Morisco, Filomena
AU - Merli, Manuela
AU - Brancaccio, Giuseppina
AU - Di Biagio, Antonio
AU - Loggi, Elisabetta
AU - Mastroianni, Claudio M
AU - Pace Palitti, Valeria
AU - Tarquini, Pierluigi
AU - Puoti, Massimo
AU - Taliani, Gloria
AU - Sarmati, Loredana
AU - Picciotto, Antonino
AU - Vullo, Vincenzo
AU - Caporaso, Nicola
AU - Paoloni, Maurizio
AU - Pasquazzi, Caterina
AU - Rizzardini, Giuliano
AU - Parruti, Giustino
AU - Craxì, Antonio
AU - Babudieri, Sergio
AU - Andreoni, Massimo
AU - Angelico, Mario
AU - Perno, Carlo F
AU - Ceccherini-Silberstein, Francesca
AU - HCV Italian Resistance Network Study Group
N1 - © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2017/4
Y1 - 2017/4
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1111/liv.13327
DO - 10.1111/liv.13327
M3 - Article
C2 - 28105744
VL - 37
SP - 514
EP - 528
JO - Liver International
JF - Liver International
SN - 1478-3223
IS - 4
ER -