The Discovery of Ledipasvir (GS-5885): The Potent Once-Daily Oral HCV NS5A Inhibitor in the Single-Tablet Regimen Harvoni

The advent of direct-acting antiviral agents (DAAs) has revolutionized the treatment and cure of chronic hepatitis C virus (HCV) infection. Herein is described the discovery of ledipasvir (LDV), an orally available HCV nonstructural protein 5A inhibitor with picomolar antiviral potency and a long pharmacokinetic half-life. The combination of LDV with the nonstructural protein 5B inhibitor sofosbuvir (SOF) is Harvoni® and represents the first approved single-tablet regimen for the treatment of HCV infection. This safe simple and efficacious regimen affords clinical trial cure rates over 95% and comparable effectiveness in real-world studies and has treatment durations as short as 8 weeks. The approval of Harvoni® heralded a new era for the treatment of HCV infection.