Rate of hepatitis C viral clearance by human livers in human patients: Liver transplantation modeling primary infection and implications for studying entry inhibition

• Published in: PloS one Vol. 12; no. 7; p. e0180719
• Main Authors: Hughes, Jr, Michael G, Tucker, William W, Reddy, Sreelatha, Brier, Michael E, Koch, David, McClain, Craig J, Jonsson, Colleen B, Matoba, Nobuyuki, Chung, Donghoon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.07.2017; Public Library of Science (PLoS)
• Subjects: Age; Aged; Allografts; Biology and Life Sciences; Blood Transfusion; Circulation; Drug therapy; Female; Half-life; Hepacivirus - physiology; Hepatitis; Hepatitis C; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - surgery; Hepatitis C, Chronic - virology; Hepatology; Humans; Immunosuppression; Immunotherapy; Infections; Inhibition; Interferon; Kinetics; Liver; Liver - virology; Liver cirrhosis; Liver Transplantation; Liver transplants; Male; Medicine and Health Sciences; Middle Aged; Models, Biological; Pathogenesis; Patients; Real-Time Polymerase Chain Reaction; Reperfusion; Research and analysis methods; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA, Viral - blood; Surgery; Time Factors; Toxicology; Transplantation; Transplants & implants; Variability; Viral Load; Virus Internalization; Viruses; United States > US; Kentucky
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0180719

To better understand the dynamics of early hepatitis C virus (HCV) infection, we determined how rapidly non-cirrhotic HCV-uninfected liver allografts clear HCV from the circulation of cirrhotic HCV-infected patients at the time of transplantation but before administration of immunosuppression. Specifically, we characterized serum HCV kinetics during the first 90 min of reperfusion for 19 chronically HCV-infected patients transplanted with an HCV-uninfected liver by measuring serum viral load immediately prior to reperfusion (t = 0) and then every 15 min for a total of 90 min (t = 90). Immunosuppression was withheld until all samples were taken to better model primary infection. During this period, rates of viral clearance varied more than 20-fold with a median rate constant of 0.0357 1/min, range 0.0089-0.2169; half-life (minutes) median 19.4, range 3.2-77.8. The majority of viral clearance occurred within the first 60 min. The amount of blood transfused during this 90-min period (a potential confounding variable of this human liver transplant model of primary infection) accounted for 53% and 59% of k (r = 0.53, p = 0.05) and half-life (r = 0.59, p = 0.03) variability, respectively. No other clinical variables tested (age, allograft weight, and degree of reperfusion injury as assessed by peak postoperative ALT or AST) accounted for the remaining variability (p>0.05). In a human liver transplant model of primary infection, HCV rapidly clears the bloodstream. With approximately 90% of clearance occurring in the first 90 minutes of reperfusion, studies of HCV entry inhibition could utilize rate of clearance during this early period as an outcome measure.