Date Published: July 21, 2017
Publisher: Public Library of Science
Author(s): Michael G. Hughes, William W. Tucker, Sreelatha Reddy, Michael E. Brier, David Koch, Craig J. McClain, Colleen B. Jonsson, Nobuyuki Matoba, Donghoon Chung, Eve-Isabelle PECHEUR.
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). Conclusion: 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.
The study of HCV pathogenesis is complicated by the lack of relevant animal models. Chimpanzee, murine, and a murine model with hepatocytes of human origin susceptible to HCV infection have been developed; unfortunately, all have limitations. Despite established HCV infection in individuals undergoing liver transplantation for HCV, the previously uninfected allograft is not infected until after reperfusion. Therefore, transplant represents a primary infection of that organ. Liver transplantation, therefore, represents the only model to ethically and prospectively study infection of a human liver in humans.
The purpose of the current study was to better understand how rapidly hepatitis C virus (HCV) clears the bloodstream. As the only ethical way to infect a human liver in a human patient is by transplanting an HCV-uninfected liver into an HCV-infected recipient, we calculated the rates of viral clearance from the bloodstream during liver transplant as a surrogate for viral entry. To more accurately model primary infection, immunosuppression was withheld during the study period. This is a key difference from other published studies on HCV kinetics during liver transplantation.
With most HCV clearance occurring in the first 90 minutes of transplantation, we believe that liver transplantation represents a prime opportunity to study the impact of HCV entry inhibitors.