1. Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals
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Anita Y.M. Howe, Chaturaka Rodrigo, Evan B. Cunningham, Mark W. Douglas, Julia Dietz, Jason Grebely, Stephanie Popping, Javier Alejandro Sfalcin, Milosz Parczewski, Christoph Sarrazin, Adolfo de Salazar, Ana Fuentes, Murat Sayan, Josep Quer, Midori Kjellin, Hege Kileng, Orna Mor, Johan Lennerstrand, Slim Fourati, Velia Chiara Di Maio, Vladimir Chulanov, Jean-Michel Pawlotsky, P. Richard Harrigan, Francesca Ceccherini-Silberstein, Federico Garcia, Marianne Martinello, Gail Matthews, Fay Fabián Fernando, Juan I. Esteban, Beat Müllhaupt, Julian Schulze zur Wiesch, Peter Buggisch, Christoph Neumann-Haefelin, Thomas Berg, Christoph P. Berg, Jörn M. Schattenberg, Christophe Moreno, Rudolf Stauber, Andrew Lloyd, Gregory Dore, Tanya Applegate, Juan Ignacio, Damir Garcia-Cehic, Josep Gregori, Francisco Rodriguez-Frias, Ariadna Rando, Yael Gozlan, Mario Angelico, Massimo Andreoni, Sergio Babudieri, Ada Bertoli, Valeria Cento, Nicola Coppola, Antonio Craxì, Stefania Paolucci, Giustino Parruti, Caterina Pasquazzi, Carlo Federico Perno, Elisabetta Teti, C. Vironet, Anders Lannergård, Ann-Sofi Duberg, Soo Aleman, Tore Gutteberg, Alexandre Soulier, Aurélie Gourgeon, Stephane Chevaliez, Stanislas Pol, Fabrice Carrat, Dominique Salmon, Rolf Kaiser, Elena Knopes, Perpetua Gomes, Rob de Kneght, Bart Rijnders, Mario Poljak, Maja Lunar, Rafael Usubillaga, Carole Seguin_Devaux, Enoch Tay, Caroline Wilson, Dao Sen Wang, Jacob George, Jen Kok, Ana Belén Pérez, Natalia Chueca, Miguel García-Deltoro, Ana María Martínez-Sapiña, María Magdalena Lara-Pérez, Silvia García-Bujalance, Teresa Aldámiz-Echevarría, Francisco Jesús Vera-Méndez, Juan Antonio Pineda, Marta Casado, Juan Manuel Pascasio, Javier Salmerón, Juan Carlos Alados-Arboledas, Antonio Poyato, Francisco Téllez, Antonio Rivero-Juárez, Dolores Merino, María Jesús Vivancos-Gallego, José Miguel Rosales-Zábal, María Dolores Ocete, Miguel Ángel Simón, Pilar Rincón, Sergi Reus, Alberto De la Iglesia, Isabel García-Arata, Miguel Jiménez, Fernando Jiménez, José Hernández-Quero, Carlos Galera, Mohamed Omar Balghata, Joaquín Primo, Mar Masiá, Nuria Espinosa, Marcial Delgado, Miguel Ángel von-Wichmann, Antonio Collado, Jesús Santos, Carlos Mínguez, Felícitas Díaz-Flores, Elisa Fernández, Enrique Bernal, José De Juan, José Joaquín Antón, Mónica Vélez, Antonio Aguilera, Daniel Navarro, Juan Ignacio Arenas, Clotilde Fernández, María Dolores Espinosa, María José Ríos, Roberto Alonso, Carmen Hidalgo, Rosario Hernández, María Jesús Téllez, Francisco Javier Rodríguez, Pedro Antequera, Cristina Delgado, Patricia Martín, Javier Crespo, Berta Becerril, Oscar Pérez, Antonio García-Herola, José Montero, Carolina Freyre, Concepción Grau, Joaquin Cabezas, Miguel Jimenez, Manuel Alberto Macias Rodriguez, Cristina Quilez, Maria Rodriguez Pardo, Leopoldo Muñoz-Medina, Blanca Figueruela, Virology, Internal Medicine, Medical Microbiology & Infectious Diseases, Institut Català de la Salut, [Howe AYM] British Columbia Centre for Disease Control, British Columbia, Canada. [Rodrigo C] School of Medical Sciences, UNSW Sydney, Sydney, Australia. [Cunningham EB, Grebely J] The Kirby Institute, UNSW Sydney, Sydney, Australia. [Douglas MW] Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney at Westmead Hospital, Westmead, Australia. [Dietz J] Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany. [Quer J] Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. CIBEREHD, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Howe, Anita Y. M., Rodrigo, Chaturaka, Cunningham, Evan, Douglas, Mark W., Dietz, Julia, Grebely, Jason, Popping, Stephanie, Alejandro Sfalcin, Javier, Parczewski, Milosz, Sarrazin, Christoph, de Salazar, Adolfo, Fuentes, Ana, Sayan, Murat, Quer, Josep, Kjellin, Midori, Kileng, Hege, Mor, Orna, Lennerstrand, Johan, Fourati, Slim, Chiara di Maio, Velia, Chulanov, Vladimir, Pawlotsky, Jean-Michel, Richard Harrigan, P., Ceccherini-Silberstein, Francesca, Garcia, Federico, Martinello, Marianne, Matthews, Gail, Fabi??n Fernando, Fay, Esteban, Juan I., M??llhaupt, Beat, Schulze zur Wiesch, Julian, Buggisch, Peter, Neumann-Haefelin, Christoph, Berg, Thoma, Berg, Christoph P., Schattenberg, J??rn M., Moreno, Christophe, Stauber, Rudolf, Lloyd, Andrew, Dore, Gregory, Applegate, Tanya, Ignacio, Juan, Garcia-Cehic, Damir, Gregori, Josep, Rodriguez-Frias, Francisco, Rando, Ariadna, Angelico, Mario, Andreoni, Massimo, Babudieri, Sergio, Bertoli, Ada, Cento, Valeria, Coppola, Nicola, Crax??, Antonio, Paolucci, Stefania, Parruti, Giustino, Pasquazzi, Caterina, Federico Perno, Carlo, Teti, Elisabetta, Vironet, C., Lannerg??rd, Ander, Duberg, Ann-Sofi, Aleman, Soo, Gutteberg, Tore, Soulier, Alexandre, Gourgeon, Aur??lie, Chevaliez, Stephane, Pol, Stanisla, Carrat, Fabrice, Salmon, Dominique, Kaiser, Rolf, Knopes, Elena, Gomes, Perpetua, de Kneght, Rob, Rijnders, Bart, Poljak, Mario, Lunar, Maja, Usubillaga, Rafael, Seguin, Carole, Tay, Enoch, Wilson, Caroline, Sen Wang, Dao, George, Jacob, Kok, Jen, Bel??n P??rez, Ana, Chueca, Natalia, Garc??a-Deltoro, Miguel, Mar??a Mart??nez-Sapi??a, Ana, Magdalena Lara-P??rez, Mar??a, Garc??a-Bujalance, Silvia, Ald??miz-Echevarr??a, Teresa, Jes??s Vera-M??ndez, Francisco, Antonio Pineda, Juan, Casado, Marta, Manuel Pascasio, Juan, Salmer??n, Javier, Carlos Alados-Arboledas, Juan, Poyato, Antonio, T??llez, Francisco, Rivero-Ju??rez, Antonio, Merino, Dolore, Jes??s Vivancos-Gallego, Mar??a, Miguel Rosales-Z??bal, Jos??, Dolores Ocete, Mar??a, ngel Sim??n, Miguel, Rinc??n, Pilar, Reus, Sergi, De la Iglesia, Alberto, Garc??a-Arata, Isabel, Jim??nez, Miguel, Jim??nez, Fernando, Hern??ndez-Quero, Jos??, Galera, Carlo, Omar Balghata, Mohamed, Primo, Joaqu??n, Masi??, Mar, Espinosa, Nuria, Delgado, Marcial, ngel von-Wichmann, Miguel, Collado, Antonio, Santos, Jes??, M??nguez, Carlo, D??az-Flores, Fel??cita, Fern??ndez, Elisa, Bernal, Enrique, De Juan, Jos??, Joaqu??n Ant??n, Jos??, V??lez, M??nica, Aguilera, Antonio, Navarro, Daniel, Ignacio Arenas, Juan, Fern??ndez, Clotilde, Dolores Espinosa, Mar??a, Jos?? R??os, Mar??a, Alonso, Roberto, Hidalgo, Carmen, Hern??ndez, Rosario, Jes??s T??llez, Mar??a, Javier Rodr??guez, Francisco, Antequera, Pedro, Delgado, Cristina, Mart??n, Patricia, Crespo, Javier, Becerril, Berta, P??rez, Oscar, Garc??a-Herola, Antonio, Montero, Jos??, Freyre, Carolina, Grau, Concepci??n, Cabezas, Joaquin, Jimenez, Miguel, Alberto Macias Rodriguez, Manuel, Quilez, Cristina, Rodriguez Pardo, Maria, Mu??oz-Medina, Leopoldo, and Figueruela, Blanca
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fenómenos microbiológicos::farmacorresistencia microbiana::farmacorresistencia viral [FENÓMENOS Y PROCESOS] ,Infectious Medicine ,NNI, non-nucleoside ,aOR, adjusted odds ratio ,viruses ,GT, genotype ,Infektionsmedicin ,Gastroenterology and Hepatology ,NS5A ,NS5AI, NS5A replication complex inhibitor ,LDV, ledipasvir ,Settore MED/07 ,PIB, pibrentasvir ,RASs, resistance-associated substitutions ,SDG 3 - Good Health and Well-being ,SHARED, The Surveillance of Hepatitis C Antiviral Resistance, Epidemiology and methoDologies ,Microbiological Phenomena::Drug Resistance, Microbial::Drug Resistance, Viral [PHENOMENA AND PROCESSES] ,Internal Medicine ,Gastroenterologi ,virologic failure ,Immunology and Allergy ,Medicaments antivírics ,Resistència als medicaments ,DAA ,Hepatology ,virosis::hepatitis viral humana::hepatitis C [ENFERMEDADES] ,Gastroenterology ,Virus Diseases::Hepatitis, Viral, Human::Hepatitis C [DISEASES] ,virus diseases ,DAA, direct-acting antiviral ,DCV, daclatasvir ,Hepatitis C ,Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents [CHEMICALS AND DRUGS] ,PI, NS3 protease inhibitor ,OR, odds ratio ,SVR, sustained virologic response ,VEL, velpatasvir ,DSV, dasabuvir ,acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antiinfecciosos::antivíricos [COMPUESTOS QUÍMICOS Y DROGAS] ,SOF, sofosbuvir ,HCV ,sFC, substitution frequency change ,NI, nucleoside ,RAS - Abstract
Virologic failure; Hepatitis C Fracaso virológico; Hepatitis C Fracàs virològic; Hepatitis C Background & Aims Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. The initial SHARED development was funded in part by Merck and a User Partnership Program grant from Genome British Columbia to P.R.H and A.Y.M.H (UPP029). The Kirby Institute is funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian (or any other) Government. C.R. and J.G. are supported by an NHMRC Investigator Grant (nos. 1173666, 1176131). An NHMRC Program Grant supported RAS testing and data collection by M.W.D. (1053206) and small grants from the Australian Centre for HIV and Hepatitis Virology Research, The University of Sydney, Western Sydney Local Health District Research Education Network, and the Robert W. Storr bequest to the Sydney Medical Foundation (University of Sydney). S.P. received personal fees from Gilead Sciences. Regarding the Italian data, the work was supported in part by the Italian Ministry of Instruction, University and Research (MIUR) (Bandiera InterOmics Protocollo PB05 1°), by the Italian Ministry of Health (RF-2016-02362422), and by Aviralia and Vironet C Foundations.
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- 2022