At week 4 of treatment, the patient reported feeling well and HCV RNA viral load was found to be undetectable; liver enzymes also began to decrease. At 12 and 24 weeks, viral load remained undetectable and three months after completing therapy, the patient had undetectable viral load and AFP was 5.1ng/mL.  Six months after completing therapy, tests confirmed undetectable viral load and cure of HCV.  In addition to being cured, her AFP had dropped to a normal range, indicating a decreased lifetime risk of hepatocellular carcinoma.

Several factors (eg, genotype 1a virus, older age, cirrhosis, high viral load) play into why this patient had a poor response to all her previous treatments. Resistance testing showed the patient had resistance-associated variants to telaprevir. For patients with genotype 1a virus, treatment failure with simeprevir + sofosbuvir can be more common, in addition, treatment failure could lead to simeprevir resistance and cross-resistance with other NS3 protease inhibitors. Retreatment with other DAA combinations that include an NS3 protease inhibitor could therefore lead to potential treatment failure.  

Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is a nucleotide analogue inhibitor of HCV NS5B polymerase. Unlike sofosbuvir, which requires only one single nucleotide substitution to confer resistance, it is believed that NS5A inhibitors require multiple mutations to achieve significant resistance. This makes the combination of ledipasvir/sofosbuvir a viable one for patients who have previously failed multiple regimens as the risk of resistance is reduced.

While more research is needed to justify routine use, in this patient, a 20-year-long HCV infection was cured using the combination of ledipasvir/sofosbuvir after multiple treatment failures including a regimen containing sofosbuvir + simeprevir. The authors add that “resistance testing should be performed prior to starting a heavily treatment-experienced individual on retreatment.”


Johnson, S. W., Davis, M. M., Stever, L. M. and Priest, D. H. (2016), Curing the historically incurable: treatment success with ledipasvir/sofosbuvir for chronic hepatitis C virus in a heavily treatment-experienced individual. J Clin Pharm Ther. doi:10.1111/jcpt.12455