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Prevalence of resistance-associated substitutions and retreatment of patients failing a glecaprevir/pibrentasvir regimen

2020; Oxford University Press; Volume: 75; Issue: 11 Linguagem: Inglês

10.1093/jac/dkaa304

1460-2091

Adolfo de Salazar, Julia Dietz, V.C. Di Maio, Johannes Vermehren, Stefania Paolucci, Beat Müllhaupt, Nicola Coppola, Joaquín Cabezas, Rudolf Stauber, Massimo Puoti, Juan Ignacio Arenas Ruiz Tapiador, Christiana Graf, M. Aragri, Miguel A. Jiménez, Annapaola Callegaro, Juan Manuel Pascasio Acevedo, Manuel Alberto Macías Rodríguez, José Miguel Rosales Zábal, Valeria Micheli, Miguel García Deltoro, Francisco Téllez, Féderico García, Christoph Sarrazin, Francesca Ceccherini‐Silberstein, Tobias Götze, Ali Canbay, Kerstin Port, Markus Cornberg, Michael Manns, Lars Reinhardt, Volker Ellenrieder, Eugen Zizer, Nektarios Dikopoulos, Johanna Backhus, Thomas Seufferlein, Susanne Beckebaum, S Hametner, R Schöfl, Claus Niederau, P. Schlee, M. Dreck, B. Görlitz, Holger Hinrichsen, Barbara Seegers, M. Jung, R. Link, Stefan Mauss, V. Meister, Eiko Schnaitmann, C. Sick, Karl‐Georg Simon, K. J. Schmidt, Massimo Andreoni, Antonio Craxı̀, P. Giaccone, Carlo Federico Perno, Maurizio Zazzi, Ada Bertoli, M. Angélico, Chiara Masetti, V. Giannelli, San Camillo, Paola Begini, A. De Santis, Gloria Taliani, Miriam Lichtner, Barbara Rossetti, C. Caudai, Raffaele Cozzolongo, S De Bellis, Mario Starace, Carmine Minichini, Gianfranco Gaeta, Mariantonietta Pisaturo, Vincenzo Messina, Chiara Dentone, Bianca Bruzzone, Simona Landonio, C. Magni, Marco Merli, Elisabetta De Gasperi, Granda Ospedale Maggiore Policlinico, Hamid Hasson, Enzo Boeri, Ilaria Beretta, Chiara Molteni, A Manzoni Elena Maffezzini, Nicoletta Dorigoni, Lorenza Guella, Tobias Götze, Ali Canbay, Kerstin Port, Markus Cornberg, Michael Manns, Lars Reinhardt, Volker Ellenrieder, Eugen Zizer, Nektarios Dikopoulos, Johanna Backhus, Thomas Seufferlein, Susanne Beckebaum, S Hametner, R Schöfl, Claus Niederau, P. Schlee, M. Dreck, B. Görlitz, Holger Hinrichsen, Barbara Seegers, M. Jung, R. Link, Stefan Mauss, V. Meister, Eiko Schnaitmann, C. Sick, Karl‐Georg Simon, K. J. Schmidt, Massimo Andreoni, Antonio Craxı̀, P. Giaccone, Carlo Federico Perno, Maurizio Zazzi, Ada Bertoli, M. Angélico, Chiara Masetti, V. Giannelli, San Camillo, Paola Begini, A. De Santis, Gloria Taliani, Miriam Lichtner, Barbara Rossetti, C. Caudai, Raffaele Cozzolongo, S De Bellis, Mario Starace, Carmine Minichini, Gianfranco Gaeta, Mariantonietta Pisaturo, Vincenzo Messina, Chiara Dentone, Bianca Bruzzone, Simona Landonio, C. Magni, Marco Merli, Elisabetta De Gasperi, Granda Ospedale Maggiore Policlinico, Hamid Hasson, Enzo Boeri, Ilaria Beretta, Chiara Molteni, A Manzoni Elena Maffezzini, Nicoletta Dorigoni, Lorenza Guella,

HIV Research and Treatment

Abstract Objectives To investigate resistance-associated substitutions (RASs) as well as retreatment efficacies in a large cohort of European patients with failure of glecaprevir/pibrentasvir. Methods Patients were identified from three European Resistance Reference centres in Spain, Italy and Germany. Sequencing of NS3, NS5A and NS5B was conducted and substitutions associated with resistance to direct antiviral agents were analysed. Clinical and virological parameters were documented retrospectively and retreatment efficacies were evaluated. Results We evaluated 90 glecaprevir/pibrentasvir failures [3a (n = 36), 1a (n = 23), 2a/2c (n = 20), 1b (n = 10) and 4d (n = 1)]. Ten patients were cirrhotic, two had previous exposure to PEG-interferon and seven were coinfected with HIV; 80 had been treated for 8 weeks. Overall, 31 patients (34.4%) failed glecaprevir/pibrentasvir without any NS3 or NS5A RASs, 62.4% (53/85) showed RASs in NS5A, 15.6% (13/83) in NS3 and 10% (9/90) in both NS5A and NS3. Infection with HCV genotypes 1a and 3a was associated with a higher prevalence of NS5A RASs. Patients harbouring two (n = 34) or more (n = 8) RASs in NS5A were frequent. Retreatment was initiated in 56 patients, almost all (n = 52) with sofosbuvir/velpatasvir/voxilaprevir. The overall sustained virological response rate was 97.8% in patients with end-of-follow-up data available. Conclusions One-third of patients failed glecaprevir/pibrentasvir without resistance. RASs in NS5A were more prevalent than in NS3 and were frequently observed as dual and triple combination patterns, with a high impact on NS5A inhibitor activity, particularly in genotypes 1a and 3a. Retreatment of glecaprevir/pibrentasvir failures with sofosbuvir/velpatasvir/voxilaprevir achieved viral suppression across all genotypes.