Resistance to hepatitis C virus protease inhibitors

•Baseline protease inhibitor resistance is rare, with the exception of Q80K.•Emergence of resistance is common in patients who do not achieve an SVR.•Resistance pathways are dependent on drug exposure and viral genotype.•Potency and genetic barrier of regimen play major roles in inhibiting resistance.•Resistant populations tend to be replaced by wild-type virus over time. Significant scientific advances have enabled the development of new classes of antivirals for the treatment of HCV. Protease inhibitors were the first approved, achieving substantially higher response rates, with shorter treatment durations, in the majority of genotype 1 infected patients. However, in patients who fail treatment, drug resistant variants frequently emerge. The pattern of resistant variants observed is a result of the specific inhibitor, viral subtype, and level of drug selective pressure. Data suggest the replacement of these variants over time; however, retreatment of these patients is an area of needed investigation. As multiple drug classes progress in development, combinations of agents improve treatment success, increase the genetic barrier to resistance, and provide shorter treatment durations for diverse patient populations.