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

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 Santopaolo; Adriano M Pellicelli; Vincenza Calvaruso; Laura Gianserra; Massimo Siciliano; Dante Romagnoli; Raffaele Cozzolongo; Antonio Grieco; Jacopo Vecchiet; 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; HCV Italian Resistance Network Study Group

doi:10.1111/liv.13327

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

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 Santopaolo, Adriano M Pellicelli, Vincenza CalvarusoLaura Gianserra, Massimo Siciliano, Dante Romagnoli, Raffaele Cozzolongo, Antonio Grieco, Jacopo Vecchiet, 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, HCV Italian Resistance Network Study Group

Ente Ospedaliero Specializzato in Gastroenterologia "Saverio de Bellis"

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	514-528
Number of pages	15
Journal	Liver International
Volume	37
Issue number	4
DOIs	https://doi.org/10.1111/liv.13327
Publication status	Published - Apr 2017

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Di Maio, V. C., Cento, V., Lenci, I., Aragri, M., Rossi, P., Barbaliscia, S., Melis, M., Verucchi, G., Magni, C. F., Teti, E., Bertoli, A., Antonucci, F., Bellocchi, M. C., Micheli, V., Masetti, C., Landonio, S., Francioso, S., Santopaolo, F., Pellicelli, A. M., ... HCV Italian Resistance Network Study Group (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. https://doi.org/10.1111/liv.13327

Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies. / Di Maio, Velia C; Cento, Valeria; Lenci, Ilaria; Aragri, Marianna; Rossi, Piera; Barbaliscia, Silvia; Melis, Michela; Verucchi, Gabriella; Magni, Carlo F; Teti, Elisabetta; Bertoli, Ada; Antonucci, FrancescoPaolo; Bellocchi, Maria C; Micheli, Valeria; Masetti, Chiara; Landonio, Simona; Francioso, Simona; Santopaolo, Francesco; Pellicelli, Adriano M; Calvaruso, Vincenza; Gianserra, Laura; Siciliano, Massimo; Romagnoli, Dante; Cozzolongo, Raffaele; Grieco, Antonio; Vecchiet, Jacopo; Morisco, Filomena; Merli, Manuela; Brancaccio, Giuseppina; Di Biagio, Antonio; Loggi, Elisabetta; Mastroianni, Claudio M; Pace Palitti, Valeria; Tarquini, Pierluigi; Puoti, Massimo; Taliani, Gloria; Sarmati, Loredana; Picciotto, Antonino; Vullo, Vincenzo; Caporaso, Nicola; Paoloni, Maurizio; Pasquazzi, Caterina; Rizzardini, Giuliano; Parruti, Giustino; Craxì, Antonio; Babudieri, Sergio; Andreoni, Massimo; Angelico, Mario; Perno, Carlo F; Ceccherini-Silberstein, Francesca; HCV Italian Resistance Network Study Group.

In: Liver International, Vol. 37, No. 4, 04.2017, p. 514-528.

Research output: Contribution to journal › Article › peer-review

Di Maio, VC, Cento, V, Lenci, I, Aragri, M, Rossi, P, Barbaliscia, S, Melis, M, Verucchi, G, Magni, CF, Teti, E, Bertoli, A, Antonucci, F, Bellocchi, MC, Micheli, V, Masetti, C, Landonio, S, Francioso, S, Santopaolo, F, Pellicelli, AM, 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, CM, 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, Craxì, A, Babudieri, S, Andreoni, M, Angelico, M, Perno, CF, Ceccherini-Silberstein, F & HCV Italian Resistance Network Study Group 2017, 'Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies', Liver International, vol. 37, no. 4, pp. 514-528. https://doi.org/10.1111/liv.13327

Di Maio, Velia C ; Cento, Valeria ; Lenci, Ilaria ; Aragri, Marianna ; Rossi, Piera ; Barbaliscia, Silvia ; Melis, Michela ; Verucchi, Gabriella ; Magni, Carlo F ; Teti, Elisabetta ; Bertoli, Ada ; Antonucci, FrancescoPaolo ; Bellocchi, Maria C ; Micheli, Valeria ; Masetti, Chiara ; Landonio, Simona ; Francioso, Simona ; Santopaolo, Francesco ; Pellicelli, Adriano M ; Calvaruso, Vincenza ; Gianserra, Laura ; Siciliano, Massimo ; Romagnoli, Dante ; Cozzolongo, Raffaele ; Grieco, Antonio ; Vecchiet, Jacopo ; Morisco, Filomena ; Merli, Manuela ; Brancaccio, Giuseppina ; Di Biagio, Antonio ; Loggi, Elisabetta ; Mastroianni, Claudio M ; Pace Palitti, Valeria ; Tarquini, Pierluigi ; Puoti, Massimo ; Taliani, Gloria ; Sarmati, Loredana ; Picciotto, Antonino ; Vullo, Vincenzo ; Caporaso, Nicola ; Paoloni, Maurizio ; Pasquazzi, Caterina ; Rizzardini, Giuliano ; Parruti, Giustino ; Craxì, Antonio ; Babudieri, Sergio ; Andreoni, Massimo ; Angelico, Mario ; Perno, Carlo F ; Ceccherini-Silberstein, Francesca ; HCV Italian Resistance Network Study Group. / Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies. In: Liver International. 2017 ; Vol. 37, No. 4. pp. 514-528.

@article{09e007d835344bcc9365b6099174d5ae,

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

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.",

keywords = "Journal Article",

author = "{Di Maio}, {Velia C} and Valeria Cento and Ilaria Lenci and Marianna Aragri and Piera Rossi and Silvia Barbaliscia and Michela Melis and Gabriella Verucchi and Magni, {Carlo F} and Elisabetta Teti and Ada Bertoli and FrancescoPaolo Antonucci and Bellocchi, {Maria C} and Valeria Micheli and Chiara Masetti and Simona Landonio and Simona Francioso and Francesco Santopaolo and Pellicelli, {Adriano M} and Vincenza Calvaruso and Laura Gianserra and Massimo Siciliano and Dante Romagnoli and Raffaele Cozzolongo and Antonio Grieco and Jacopo Vecchiet and Filomena Morisco and Manuela Merli and Giuseppina Brancaccio and {Di Biagio}, Antonio and Elisabetta Loggi and Mastroianni, {Claudio M} and {Pace Palitti}, Valeria and Pierluigi Tarquini and Massimo Puoti and Gloria Taliani and Loredana Sarmati and Antonino Picciotto and Vincenzo Vullo and Nicola Caporaso and Maurizio Paoloni and Caterina Pasquazzi and Giuliano Rizzardini and Giustino Parruti and Antonio Crax{\`i} and Sergio Babudieri and Massimo Andreoni and Mario Angelico and Perno, {Carlo F} and Francesca Ceccherini-Silberstein and {HCV Italian Resistance Network Study Group}",

note = "{\textcopyright} 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.",

year = "2017",

month = apr,

doi = "10.1111/liv.13327",

language = "English",

volume = "37",

pages = "514--528",

journal = "Liver International",

issn = "1478-3223",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "4",

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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

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 -