Sirolimus Reduces the Risk of Significant Hepatic Fibrosis After Liver Transplantation for Hepatitis C Virus: A Single-Center Experience

doi:10.1016/j.transproceed.2013.04.011

Transplantation Proceedings

Volume 45, Issue 9, November 2013, Pages 3325-3328

https://doi.org/10.1016/j.transproceed.2013.04.011 Get rights and content

Abstract

Introduction

Hepatitis C virus (HCV) recurrence following orthotopic liver transplantation is an expected outcome in all patients transplanted for a primary diagnosis of HCV. HCV recurrence has been shown to be associated with graft fibrosis and graft loss. Recent studies suggest that sirolimus (SRL) therapy may slow or inhibit hepatic fibrosis following liver transplant in patients positive for HCV at the time of transplant.

Methods

Among 313 patients who underwent orthotopic liver transplantation for HCV between 2000 and 2009, 251 qualified for inclusion in the study. Per protocol liver biopsies were performed on all patients at 1 year following liver transplantation and/or at the time of a clinical diagnosis of HCV recurrence. Biopsies were scored for fibrosis using the Batts-Ludwig staging system (0–4); significant fibrosis was defined as fibrosis ≥ stage 2.

Results

Overall, there was no difference in overall survival or graft loss in the SRL compared with the control group. Multivariate analysis revealed SRL therapy to be associated with decreased odds of significant hepatic fibrosis at year 1 postoperatively and over the study duration.

Conclusions

This retrospective, single-center study showed sirolimus-based immunosuppression to be associated with a lower risk of significant graft fibrosis, both at year 1 and throughout the study period, following liver transplantation in HCV-infected recipients.

Section snippets

Methods

After institutional review board approval, reviewed retrospectively our database from January 2000 to July 2009 seeking to identify HCV-infected recipients who received SRL within 3 weeks of OLT as part of their initial immunosuppressive regimen. SRL we excluded retransplants or deaths within 30 days of OLT. were excluded. The SRL cohort received 2 mg of SRL daily without a loading dose within 3 weeks of OLT in addition to tacrolimus. The indications for SRL were either tacrolimus intolerance

Results

From January 2000 to July 2009, we performed OLT for HCV on 313 patients. After applying exclusion criteria, 251 HCV-infected OLT recipients met the study criteria. Seventy-nine had received SRL for primary immunosuppressive (SRL cohort) and the remaining 172, the control group.

Discussion

Hepatitis C recurrence is a considerable, inevitable outcome following OLT that leads to graft fibrosis and loss. Immunosuppressive regimens that prevent or slow progression of collagen deposition in the allograft, that lead to hepatic fibrosis in HCV recipients, is an attractive target. Several in vivo studies have shown that SRL inhibits the function of hepatic stellate elements, the cells responsible for collagen production in the liver.¹ Additionally, many in vitro animal studies in rats

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Chronic hepatitis C (HCV) infection has a high incidence in patients with end-stage renal disease and affects between 11% and 49% of the kidney transplant (KT) recipients. After transplantation, HCV infection course is accelerated compared to the general population, and is associated with significant reduction in patient and graft survival. The unfavorable impact of HCV infection on KT survival is mainly related to an accelerated liver disease induced by the use of immunosuppression drugs and specific HVC-related renal disease, including graft glomerulopathy, posttransplant new-onset diabetes, glomerulonephritis, and higher risk of acute and chronic graft rejection. Therefore, the choice of adequate immunosuppression regimen and of antiviral treatment before and after transplantation both play a critical role in HCV-positive KT recipient.
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Citation Excerpt :
Targeting PDGFR signaling using tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec®) and sorafenib (Nexavar®), has been proven to be effective in preclinical models of liver fibrosis [26,27]. Of particular relevance in this context is also the demonstration that the mTOR inhibitor, rapamycin, inhibits progression of hepatic fibrosis in rat model [28], because treatment with this drug has been shown to delay time to progression of liver fibrosis in HCV-transplanted recipients [29]; in addition it seems to favor the clinical course of HCV infection through anti-HCV action [30]. It has been further demonstrated that pathways downstream of mTOR activation, including mTOR complex 1 (mTORC1) and p70S kinases, could be involved in hepatic fibrosis and could represent a suitable therapeutic target [31].
Fibrosis represents a response to chronic injury, aimed at maintaining organ integrity. Hepatic fibrosis is mainly related to chronic viral hepatitis B or C (HBV or HCV), alcoholic and nonalcoholic steatohepatitis (NASH), and biliary diseases. A deep understanding of the cellular and molecular mechanisms underlying liver fibrosis has enabled the development of ‘pathogenetic tailored’ therapeutic interventions. However, effective drugs to prevent or revert hepatic fibrosis are still lacking. In this review, we discuss the cellular populations and the molecular pathways involved in liver fibrogenesis as well as the novel approaches currently being tested in clinical trials.
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Progress in transplantationLiver transplantationSirolimus Reduces the Risk of Significant Hepatic Fibrosis After Liver Transplantation for Hepatitis C Virus: A Single-Center Experience

Abstract

Introduction

Methods

Results

Conclusions

Section snippets

Methods

Results

Discussion

Gastroenterology

J Hepatol

J Biol Chem

Am J Transplant

Progress in transplantation
Liver transplantation
Sirolimus Reduces the Risk of Significant Hepatic Fibrosis After Liver Transplantation for Hepatitis C Virus: A Single-Center Experience