text: The development of antiviral drugs capable of interfering with the proteins responsible for viral replication has been intimately linked with advancements in techniques for establishing the efficient cell culture systems needed to screen for them.
  In 1999 a breakthrough came when a full-length consensus genome cloned from HCV RNA was found to replicate at high levels when transfected into a human hepatoma cell line. This method has since been improved upon with the use of cell culture-adaptive mutations that enhance RNA replication.
  Screening has now produced a number of NS5A inhibitors, which have been incorporated into treatments for HCV. The first in this new class of drugs was daclatasvir (Daklinza), gaining first global approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) in July 2014 in combination with asunaprevir. Daclatasvir received FDA approval in July 2015. Other drugs have since been approved, among them notably the first FDA-approved NS5A inhibitor ledipasvir, approved October 2014 in combination with sofosbuvir to comprise the HCV drug Harvoni.
  Although NS5A inhibitors have proven effective antivirals, they must be used alongside complementary antiviral drugs due to how quickly they lead to the development of resistant mutations when given as a single agent. This has shaped the focus of NS5A inhibitor development, from which asymmetrical variants that metabolize into analogues with complementary resistance profiles have emerged, amongst other discoveries.