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.
Bibliographical noteFunding Information:
No financial support was received for the writing of this article. 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.
J.M.P. has been an advisor and/or speaker for AbbVie, Assembly Biosciences, Arbutus, Merck, Gilead, Regulus, and Memo Therapeutics. J.D. receives research support from Gilead. A.Y.M.H. is a consultant for Boston Pharmaceuticals. Outside the submitted work, J.G. reports grants and personal fees from AbbVie, Gilead Sciences, Merck, and Cepheid and grants from Hologic and Indivior. M.W.D has been an advisor and/or speaker for Gilead, AbbVie, and Merck and has received grants from Gilead and AbbVie. F.G.G. has been an advisor and/or speaker for AbbVie, Merck, and Gilead. S.F. has been an advisor and/or speaker for Abbott diagnostics, AbbVie, Gilead, and AB Science. F.C.S. has been an advisor and/or speaker for AbbVie, Merck, and Gilead and received grants from Merck and Gilead.
© 2022 The Authors