Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals
2022; Elsevier BV; Volume: 4; Issue: 5 Linguagem: Inglês
10.1016/j.jhepr.2022.100462
ISSN2589-5559
AutoresA Howe, Chaturaka Rodrigo, Evan B. Cunningham, Mark W. Douglas, Julia Dietz, Jason Grebely, Stephanie Popping, Javier Alejandro Sfalcin, Miłosz Parczewski, Christoph Sarrazin, Adolfo de Salazar, Ana Fuentes, Murat Sayan, Josep Quer, Midori Kjellin, Hege Kileng, Orna Mor, Johan Lennerstrand, Slim Fourati, V.C. Di Maio, Vladimir Chulanov, Jean‐Michel Pawlotsky, P. Richard Harrigan, Francesca Ceccherini‐Silberstein, Féderico García, Marianne Martinello, Gail Matthews, Fay Fabián Fernando, Juan Ignacio 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 R. Lloyd, Gregory J. Dore, Tanya Applegate, Juan Ignacio, Damir García‐Cehic, Josep Gregori, Francisco Rodríguez‐Frías, Ariadna Rando‐Segura, Yael Gozlan, M. Angélico, Massimo Andreoni, Sergio Babudieri, Ada Bertoli, Valeria Cento, Nicola Coppola, Antonio Craxı̀, Stefania Paolucci, Giustino Parruti, C. Pasquazzi, Carlo Federico Perno, Elisabetta Teti, C. Vironet, Anders Lannergård, Ann‐Sofi Duberg, Soo Aleman, Tore Jarl Gutteberg, Alexandre Soulier, Aurélie Gourgeon, Stéphane Chevaliez, Stanislas Pol, Fabrice Carrat, Dominique Salmon‐Céron, Rolf Kaiser, Elena Knopes, Perpétua Gómes, Rob de Kneght, Bart Rijnders, Mario Poljak, Maja M. 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 Martínez-Sapiña, María Magdalena Lara-Pérez, Silvia García‐Bujalance, Teresa Aldámiz‐Echevarría, Francisco Jesús Vera-Méndez, Juan A. Pineda, Marta Casado, J.M. Pascasio, Javier Salmerón, Juan Carlos Alados, Antonio Poyato, Francisco Téllez, António Rivero‐Juarez, Dolores Merino, María Jesús Vivancos, 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, J Primo, Mar Masiá, Núria Espinosa, Marcial Delgado, Miguel Ángel Von-Wichmann, Antonio Collado, Jesús Santos, Carlos Mínguez, Felícitas Díaz-Flores, Elisa Fernández, Enrique Bernal, José Pérez de los Cobos, José Joaquín Antón, Mónica Vélez, Antonio Aguilera, Daniel Navarro, Juan Ignacio Arenas, Clotilde Fernández, María Dolores Espinosa, María Rios, Roberto Alonso, Carmen Hidalgo, Rosario Hernández, María Jesús Téllez, Francisco J. Rodríguez‐Valadez, Pedro Antequera, Cristina Delgado, Patrícia Martin, Javier Crespo, B. Becerril, Óscar Pérez, Antonio García‐Herola, J.L. Montero, Carolina Freyre, Concepción Grau, Joaquín Cabezas, Miguel A. Jiménez, Manuel Alberto Macías Rodríguez, Cristina Quílez, Maria Rodriguez Pardo, Leopoldo Muñoz‐Medina, Blanca Figueruela,
Tópico(s)Liver Disease Diagnosis and Treatment
Resumo•An international cohort of 3,355 patients with hepatitis C from 22 countries was evaluated for drug resistance following DAA therapy.•Nearly all patients harbored drug-resistant variants after treatment failure, with over 2/3 having resistance against ≥2 drug classes.•Pathways to drug resistance included enrichment of highly resistant variants and selection of multiple resistant variants.•Previously unrecognized variants in patients who failed NS5A inhibitors were identified at high frequencies.•Resistance selection was frequent in older people with cirrhosis and those infected with genotypes 1b and 4 following DAA failure. Background & AimsDirect-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.MethodsSHARED 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.ResultsThe 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.ConclusionsDrug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized.Lay summaryAlthough direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses. 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. 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. 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. Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized.
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