Hepatology (Baltimore, Md.) 2016 8 17() doi 10.1002/hep.28767
Hepatitis C virus (HCV)-induced end-stage liver disease is the major indication for liver transplantation (LT). However, re-infection of the liver graft is still common, especially in patients with detectable viral load at the time of transplantation. Limited data is available with direct-acting antivirals (DAAs) in the transplant setting for prevention of graft infection. The human hepatitis C immune globulin (HCIG) Civacir® is an investigational drug that is currently developed in an ongoing phase III clinical trial assessing safety and efficacy to prevent the HCV recurrence after liver transplant in the US.(1) Using well characterized patient-derived HCV variants selected during LT we aimed to study the molecular mechanism of action of Civacir. Inhibition of HCV infection was studied using infectious HCV models including HCV pseudoparticles (HCVpp) and cell culture-derived HCV viruses (HCVcc) containing patient-derived viral envelope glycoproteins from 22 HCV variants isolated from patients before and after LT.(2) Additionally, we studied neutralization of different HCV genotypes and of DAA-resistant viruses. Our results indicate that Civacir potently, broadly and dose-dependently neutralizes all tested patient variants in HCVpp and HCVcc assays including variants displaying resistance to host neutralizing antibodies and anti-viral monoclonal antibodies. The half maximal inhibitory concentrations were independent of the phenotype of the viral variant indicating that virus neutralization by Civacir is not affected by viral selection. Furthermore, Civacir is equally active against tested DAA-resistant HCV isolates in cell culture.
Collectively, these results demonstrate broad neutralizing activity of Civacir against resistant viruses and support its further clinical development for prevention of liver graft infection. The broad neutralizing activity of Civacir is likely due to synergy between anti-HCV antibodies derived from different plasma donors. This article is protected by copyright. All rights reserved.