Sofosbuvir plus ledipasvir in combination for the treatment of hepatitis C infection

Sofsobuvir is the first-in-class NS5B nucleotide inhibitor to be launched as a treatment for the hepatitis C virus (HCV). Its viral potency, pan genotypic activity and high barrier to resistance make it the ideal candidate to become a backbone for several IFN-free regimens. Ledipasvir is a NS5A inhibitor with multi genotypic activity but modest barrier to resistance. The once-daily fixed-dose combination of sofosbuvir plus ledipasvir is the first-in-market single-tablet regimen for the treatment of hepatitis C infection. Recent data demonstrated that this FDC alone, or in combination with ribavirin, is able to achieve HCV cure of at least 90% or more among genotype 1,4, 5 and 6 patients. This combination appears to be suboptimal in genotype 3 patients and other direct acting antiviral combinations with sofosbuvir will help to fulfill this gap in the near future. The safety profile of the fixed dose combination is good. Resistance is not an issue with sofosbuvir but may be a significant issue with regards to ledipasvir for those rare individuals who harbor baseline HCV NS5A resistance-associated variants that conferred a high resistance level. The rational for using FDCs and the available clinical data are reviewed.