Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

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 MaioVladimir 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, SHARED Collaborators, Carole Seguin-Devaux

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)


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.

Original languageEnglish
Article number100462
JournalJHEP Reports
Issue number5
Publication statusPublished - May 2022


  • DAA
  • HCV
  • NS5A
  • RAS
  • virologic failure


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