Velia C Di Maio1, Valeria Cento1, Ilaria Lenci2, Marianna Aragri1, Piera Rossi2, Silvia Barbaliscia1, Michela Melis3, Gabriella Verucchi4, Carlo F Magni5, Elisabetta Teti6, Ada Bertoli1, FrancescoPaolo Antonucci1, Maria C Bellocchi1, Valeria Micheli7, Chiara Masetti2, Simona Landonio5, Simona Francioso2, Francesco Santopaolo2, Adriano M Pellicelli8, Vincenza Calvaruso9, Laura Gianserra10, Massimo Siciliano11, Dante Romagnoli12, Raffaele Cozzolongo13, Antonio Grieco11, Jacopo Vecchiet14, Filomena Morisco15, Manuela Merli16, Giuseppina Brancaccio17, Antonio Di Biagio18, Elisabetta Loggi19, Claudio M Mastroianni20, Valeria Pace Palitti21, Pierluigi Tarquini22, Massimo Puoti23, Gloria Taliani24, Loredana Sarmati6, Antonino Picciotto25, Vincenzo Vullo26, Nicola Caporaso15, Maurizio Paoloni27, Caterina Pasquazzi10, Giuliano Rizzardini5,28, Giustino Parruti29, Antonio Craxì9, Sergio Babudieri3, Massimo Andreoni6, Mario Angelico2, Carlo F Perno1, Francesca Ceccherini-Silberstein1. 1. Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy. 2. Hepatology Unit, University Hospital of Rome Tor Vergata, Rome, Italy. 3. Infectious Diseases Unit, University of Sassari, Sassari, Italy. 4. Infection Disease Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy. 5. Division of Infectious Disease, Hospital Sacco of Milan, Milan, Italy. 6. Infectious Diseases, University Hospital of Rome Tor Vergata, Rome, Italy. 7. Unit of Microbiology, Hospital Sacco of Milan, Milan, Italy. 8. Liver Disease Unit, Department of Liver Transplantation, San Camillo Forlanini Hospital, Rome, Italy. 9. Gastroenterology, "P. Giaccone" University Hospital, Palermo, Italy. 10. Infectious Diseases, Sant'Andrea Hospital - Sapienza University of Rome, Rome, Italy. 11. Gastroenterology, Catholic University of Rome, Rome, Italy. 12. Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. 13. Department of Gastroenterology, Scientific Institute for Digestive Disease "Saverio de Bellis" Hospital, Castellana Grotte, Bari, Italy. 14. Infectious Disease Clinic, Hospital of Chieti, Chieti, Italy. 15. Gastroenterology, Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. 16. Gastroenterology, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy. 17. Infectious Diseases and Viral Hepatitis Unit, Second University, Naples, Italy. 18. Infectious Diseases Unit, Department of Social Health (DISSAL) of the University of Genoa, IRCCS S. Martino-IST, Genoa, Italy. 19. Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. 20. Department of Public Health and Infectious Diseases, Sapienza University, Polo Pontino, Latina, Italy. 21. Hepatology Unit, Pescara General Hospital, Pescara, Italy. 22. Infectious Disease, Hospital "G. Mazzini", Teramo, Italy. 23. Department of Infectious Diseases, Hospital Niguarda Ca'Granda, Milan, Italy. 24. Infectious and Tropical Diseases Unit, Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy. 25. Department of Internal Medicine, Gastroenterology Unit, University of Genova, Genoa, Italy. 26. Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy. 27. Infectious Disease Unit, Avezzano General Hospital, Avezzano, Italy. 28. School of Clinical Medicine, Faculty of Health Science University of the Witwatersrand, Johannesburg, South Africa. 29. Infectious Disease Unit, Pescara General Hospital, Pescara, Italy.
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.
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.
Authors: Brenda Martínez-González; María Eugenia Soria; Lucía Vázquez-Sirvent; Cristina Ferrer-Orta; Rebeca Lobo-Vega; Pablo Mínguez; Lorena de la Fuente; Carlos Llorens; Beatriz Soriano; Ricardo Ramos-Ruíz; Marta Cortón; Rosario López-Rodríguez; Carlos García-Crespo; Pilar Somovilla; Antoni Durán-Pastor; Isabel Gallego; Ana Isabel de Ávila; Soledad Delgado; Federico Morán; Cecilio López-Galíndez; Jordi Gómez; Luis Enjuanes; Llanos Salar-Vidal; Mario Esteban-Muñoz; Jaime Esteban; Ricardo Fernández-Roblas; Ignacio Gadea; Carmen Ayuso; Javier Ruíz-Hornillos; Nuria Verdaguer; Esteban Domingo; Celia Perales Journal: Pathogens Date: 2022-06-08
Authors: Karin Neukam; Alfredo P Martínez; Andrés C A Culasso; Ezequiel Ridruejo; Gabriel García; Federico A Di Lello Journal: PLoS One Date: 2017-07-28 Impact factor: 3.240