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.

Di Maio, V., Cento, V., Lenci, I., Aragri, M., Rossi, P., Barbaliscia, S., et al. (2017). Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies. LIVER INTERNATIONAL, 37(4), 514-528 [10.1111/liv.13327].

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

Rossi, P;Teti, E;Bertoli, A;Masetti, C;Francioso, S;Sarmati, L;Andreoni, M;Angelico, M;Ceccherini Silberstein, F;Pisani, V;Baiocchi, L;De Leonardis, F;Di Paolo, D;Milana, M;Sarrecchia, C;Svicher, V;Tisone, G;
2017-01-20

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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07 - Microbiologia e Microbiologia Clinica
English
antiviral therapy; direct-acting antivirals; hepatitis C virus; resistance test; resistance-associated substitutions
Di Maio, V., Cento, V., Lenci, I., Aragri, M., Rossi, P., Barbaliscia, S., et al. (2017). Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies. LIVER INTERNATIONAL, 37(4), 514-528 [10.1111/liv.13327].
Di Maio, V; Cento, V; Lenci, I; Aragri, M; Rossi, P; Barbaliscia, S; Melis, M; Verucchi, G; Magni, C; Teti, E; Bertoli, A; Antonucci, F; Bellocchi, M; Micheli, V; Masetti, C; Landonio, S; Francioso, S; Santopaolo, F; Pellicelli, A; Calvaruso, V; Gianserra, L; Siciliano, M; Romagnoli, D; Cozzolongo, R; Grieco, A; Vecchiet, J; Morisco, F; Merli, M; Brancaccio, G; Di Biagio, A; Loggi, E; Mastroianni, C; Pace Palitti, V; Tarquini, P; Puoti, M; Taliani, G; Sarmati, L; Picciotto, A; Vullo, V; Caporaso, N; Paoloni, M; Pasquazzi, C; Rizzardini, G; Parruti, G; Craxi, A; Babudieri, S; Andreoni, M; Angelico, M; Perno, C; Ceccherini Silberstein, F; Mariani, R; Iapadre, N; Grimaldi, A; Cozzolongo, R; Andreone, P; Verucchi, G; Menzaghi, B; Quirino, T; Pisani, V; Torti, C; Vecchiet, J; Bruzzone, B; De Maria, A; Marenco, S; Nicolini, L; Viscoli, C; Casinelli, K; Delle Monache, M; Lichtner, M; Aghemo, A; Boccaccio, V; Bruno, S; Cerrone, M; Colombo, M; D'Arminio Monforte, A; Danieli, E; Donato, F; Gubertini, G; Lleo, A; Magni, C; Mancon, A; Monico, S; Niero, F; Russo, M; Gnocchi, M; Orro, A; Milanesi, L; Baldelli, E; Bertolotti, M; Borghi, V; Mussini, C; Brancaccio, G; Gaeta, G; Lembo, V; Sangiovanni, V; Di Marco, V; Mazzola, A; Petta, S; D'Amico, E; Cacciatore, P; Consorte, A; Pieri, A; Polilli, E; Sozio, F; Antenucci, F; Aragri, M; Baiocchi, L; Barbaliscia, S; Biliotti, E; Biolato, M; Carioti, L; Cerasari, G; Cerva, C; Ciotti, M; D'Ambrosio, C; D'Ettorre, G; De Leonardis, F; De Sanctis, A; Di Maio, V; Di Paolo, D; Furlan, C; Gallo, P; Gasbarrini, A; Giannelli, V; Grieco, S; Lambiase, L; Lattanzi, B; Lenci, I; Lula, R; Malagnino, V; Manuelli, M; Miglioresi, L; Milana, M; Moretti, A; Nosotti, L; Palazzo, D; Pellicelli, A; Romano, M; Sarrecchia, C; Sforza, D; Sorbo, M; Spaziante, M; Svicher, V; Tisone, G; Vespasiani-Gentilucci, U; D'Adamo, G; Mangia, A; Maida, I; Mura, M; Falconi, L; Di Giammartino, D
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