Background: Chronic infection with the hepatitis C virus (HCV) is a leading cause of liver-related mortality. Direct-acting antivirals (DAAs) have revolutionized treatment by offering profound improvements in sustained viral clearance (SVR) and tolerability resulting in a rapid expansion of treatment for individuals for whom HCV treatment had previously been less feasible, such as those with advanced liver disease or with drug and/or alcohol-related substance use. Given these clinical policy shifts, the primary objective of this study was to assess the impact of SVR on liver-related death among important clinical groups and the secondary objective was to explore changes in predictors of liver-related death by treatment era using real-world data from a large population-based cohort. Methods: We conducted a population-based, linked cohort study of all Ontario residents with HCV viremia between January 1st, 1999, and December 31st, 2018, with follow-up to 31st May 2021 (N=73,411). Population-level health administrative, clinical, and demographic data were accessed at ICES. Cause-specific hazard models were used to explore the impact of SVR on liver-related death and to identify factors associated with the rate of liver-related death in the DAA and pre-DAA treatment eras. The moderating effects of liver disease severity and substance-use disorder on the relationship between SVR and liver-related-mortality was explored by stratification. Results: Among Ontario residents diagnosed with living with HCV, the achievement of SVR was associated with a significant reduction in liver-related mortality (adjusted hazard ratio [aHR] 0.22, 95%CI: 0.20-0.24 vs. no SVR). This was also observed across progressive liver disease severity levels (aHR 0.13, 95%CI: 0.10-0.17 for individuals without cirrhosis; aHR 0.11, 95%CI: 0.06-0.17 for those with compensated cirrhosis, and aHR 0.24, 95%CI: 0.22-0.27 for those with advanced liver disease vs. no SVR) and by substance use status (aHR 0.24, 95%CI: 0.21-0.27 for those with a history of substance use disorder; and aHR 0.21, 95%CI: 0.18-0.24 for those without vs. no SVR). Additionally, factors such as age at diagnosis, sex, liver disease severity, immigration status, birth year, substance use, HBV-coinfection, viral genotype, and markers of social marginalization were independent predictors of liver-related mortality. However, sex and viral genotype no longer displayed significant associations with liver-related death in the DAA era as was observed in the earlier treatment era. Conclusions: This study provides real-world evidence showing the profound impact of SVR on liver-related mortality in a population-based sample of individuals with CHC and highlights the importance of early diagnosis and treatment. This study further demonstrates significant mortality benefits of SVR regardless of substance use status highlighting the importance of supporting marginalized individuals in treatment access.

Dr. W. Wong reports a grant from the Canadian Liver Foundation, outside the submitted work.

This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). A. Erman is supported by a postdoctoral fellowship from the Canadian Institute of Health Research (CIHR) [FRN:201910MFE-430962-169632]. This research was supported, in part, by a Canada Research Chair in Economics of Infectious Diseases held by Beate Sander [CRC-950-232429]. This study also received funding from CIHR grant [PJT-156066]. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred.

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This study was approved by the University Health Network Research Ethics Board. ICES is an independent non-profit research institute with legal status under Ontario health information privacy law to collect and analyze healthcare data for the purposes of healthcare evaluation and improvement without consent. The use of data in this project was authorized under section 45 of the Ontario Personal Health Information Protection Act, which does not require review by a Research Ethics Board.

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