Resistance mechanisms in HCV: from evolution to intervention

Recent advances in our understanding of the HCV life cycle and the functions of virally encoded proteins enabled the development of specifically targeted antiviral therapies for HCV, which directly inhibit HCV replication. Early clinical trials show great efficacy; however, from the first trials it became evident that, similar to HIV and HBV, selection of resistant variants will be problematic. Error-prone replication of HCV, resulting in a complex quasispecies population within each infected individual, enables rapid adaptation to changing environments. In this review, the evolutionary mechanisms involved in the selection process resulting in drug resistance are discussed. We give an overview of the resistance profiles to recently developed HCV protease and polymerase inhibitors and discuss potential implications for future treatment developments.