Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals
A 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, Velia Chiara 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‐Frias, Ariadna Rando, 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, Antonio Rivero‐Juárez
Abstract
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. Lay summary: Although 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.