Hepatitis C-induced hepatic allograft injury is associated with a pretransplantation elevated viral replication rate

Abstract

Hepatitis C virus (HCV) allograft infection after liverEnd-stage liver disease associated with hepatitis C virus (HCV) infection is the leading indication for liver transplantation. 1 Although the recurrence of posttransplantation viremia is nearly universal, 2-4 the rate and extent of HCV-induced allograft injury is variable. 5 At present, mechanisms of injury and reliable predictors of aggressive allograft injury induced by HCV remain elusive.HCV is a positive-sense, single-strand RNA virus that presumably requires a negative-strand RNA-replicative intermediate. Previous nontransplantation studies have demonstrated intra-and extrahepatic replication determined by the presence of negative-strand HCV RNA. 6-12 Evaluation of HCVreplicative intermediates has suggested that persistent infection may be partly the result of intrahepatic viral replication. 13 Others have shown an association of HCV-replicative status with outcomes after interferon alfa therapy. 14,15 The association of pre-or posttransplantation HCV replication and long-term outcome following liver transplantation remains unclear. Because there is an initial decrease in serum HCV viral load within the first 2 days after transplantation, followed by a marked elevation over pretransplantation quantities, a rapid turnover of virions over the first posttransplantation days has been proposed. 16 However, although intrahepatic HCV replication is noted to occur as early as 7 days after liver transplantation, viral replication in the early posttransplantation period is not associated with the development of recurrent hepatitis. 17 Others have demonstrated a correlation between the extent of allograft fibrosis with the rate of posttransplantation HCV replication at the time of biopsy. 18 The association of viral replication with increased propensity for allograft infection has been firmly established for hepatitis B virus. [19][20][21][22] Whether pretransplantation HCV viral replication rate predicts progression of liver disease remains to be determined. Although recognizing HCV and hepatitis B virus are clearly different, previous experience with hepatitis B lead to the hypothesis that pretransplantation, and possibly posttransplantation, HCV intrahepatic replication status would be associated with outcome. The purpose of the present study was to prospectively evaluate the differences in pre-and posttransplantation intrahepatic HCV replication in a cohort of HCV liver-transplant recipients undergoing protocol biopsies. PATIENTS AND METHODSPatients and Clinical Monitoring. The University of Virginia Human Investigation Committee approved this study. Informed consent in writing was obtained from patients as approved by our hospital practices committee in conformation with the ethical guidelines of the 1975 Declaration of Helsinki. Twenty-four liver transplantations in 23 consecutive patients with end-stage liver disease caused by Abbreviations: HCV, hepatitis C virus; RT-PCR, reverse-transcriptase polymerase chain reaction; Eq, equivalent(s).

Dynamics of Hepatitis C Virus Replication in Human Liver

“…If the suppressed T cell function promotes viral production and increases intrahepatic viral load (V L ), a larger number of HCV is released to circulating blood resulting in a higher serum titer (V B ). Our study and others 37 demonstrate that intrahepatic HCV loads, V L , are not different between immunosuppressed and immunocompetent patients. Alanine aminotransferase levels are positively correlated with the half-life of infected cell death.…”

Morphological and biochemical characterization of a human liver in a uPA‐SCID mouse chimera†‡

“…High viremia of this magnitude can be observed, however, when HCVinfected patients are undergoing immune suppressive therapy after transplantation. [22][23][24] Histological analysis of the liver of an HCV-infected mouse showed that most human hepatocytes were infected. Despite careful electron microscopic analysis, no viral or subviral particles could be identified in human hepatocytes.…”

Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation

“…6 Several variables have been associated with a more severe HCV disease recurrence after LT, such as a high pretransplantation viral load, old donor age, the presence of significant graft steatosis, and the administration of steroid boluses. 4,[7][8][9] It is important to state, however, that most studies are retrospective and that there is a lack of homogeneity in the definition of severe HCV recurrence after LT.…”