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

•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.