Hepatitis C virus kinetics after liver transplantation to study the role of a small molecule inhibitor of viral entry

Abstract

BackgroundAfter liver transplantation in patients infected with hepatitis C virus (HCV), reinfection of the transplanted liver is universal. The targeting of viral entry at the time of transplantation is therefore an attractive strategy. An understanding of the mechanisms and kinetics of this process will allow rational studies of small molecule inhibitors or neutralising antibodies that target HCV entry. MethodsAs part of a proof of concept study of ITX5061 (a small molecule antagonist of the HCV entry receptor, scavenger receptor B-I), we have studied detailed HCV kinetics. HCV RNA was quantified in plasma before and after liver transplantation. This study is registered with ClinicalTrials.gov, number NCT01292824. Findings13 patients were studied (median age 57 years, 11 male). Seven patients were infected with genotype 1, four with genotype 3, and one each with genotypes 2 and 4. During the period when no blood flowed through the liver there was a slow decline in plasma HCV RNA. After implantation of the donor liver there was a rapid decrease in HCV RNA in the plasma indicating entry of viral particles into the liver. Typically, there was a 90–99% decrease in HCV RNA at 4 h after implantation. This decrease continued until 12 h after implantation in all patients, and the initial rapidity of HCV RNA decline suggests the presence of specialised clearance systems in the liver. After this decrease, five patients showed a steady increase in plasma HCV RNA, which returned to baseline within 96 h indicating a rapid establishment of productive infection in the allograft. In the remaining eight patients there was a prolonged nadir for up to 21 days after transplant suggesting innate immune control in the transplanted liver. No differences in kinetics were observed between patients infected with different viral genotypes, or in the degree of liver injury at the time of transplantation. InterpretationThese marked differences in viral kinetics have major implications for trial design and probably have important biological significance in innate control of infection. FundingNational Institute for Health Research.