Warfarin anticoagulation for liver fibrosis in patients transplanted for Hepatitis C virus infection

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Hepatitis C virus (HCV) persistently infects over 200 million people worldwide, causing inflammation in the liver leading to fibrosis or scarring,and eventually cirrhosis. The current available treatment is only successful in half of patients, is expensive, and can have unpleasant side effects.
Mice models of liver fibrosis have shown that mice who have a predisposed tendency to coagulate (thrombose) their blood (a prothrombotic tendency) develop liver fibrosis more rapidly than normal mice, and if given anticoagulation the rate of fibrosis is rapidly reduced. Patients who are genetically predisposed to coagulate their blood more rapidly than normal are also more likely to develop rapid liver fibrosis if infected with Hepatitis C virus.
Anticoagulation is widely used to treat a variety of conditions and has also been used to treat lung fibrosis, with a 50% reduction in mortality without any anticoagulation related complications. We believe anticoagulation may provide a simple and safe intervention to slow or prevent fibrosis in patients with Hepatitis C virus .
The study will be a multi-centre clinical trial of anticoagulation in patients transplanted for HCV infection. The treatment group will receive warfarin for 2 years, and liver biopsies will be performed annually, as per their routine clinical care. All patients will be screened for prothrombic tendencies. We will also evaluate non-invasive tests for liver fibrosis.
If anticoagulation safely prevents or slows liver fibrosis, this could lead to it being widely used in liver transplant recipients with HCV infection. Furthermore it may lead to its use as an anti-fibrotic irrespective of the aetiology of liver fibrosis in the future.

Technical Summary

Hepatitis C virus (HCV) persistently infects over 200 million people worldwide. The current available treatment is only successful in half of patients and where treatment fails the liver fibrosis may progress to cirrhosis and liver failure.
Genetic and acquired thrombophilia are reproducibly associated with accelerated liver fibrosis in patients with HCV infection. Furthermore, mice predisposed to thrombosis develop liver fibrosis more rapidly than normal mice. However mice given anticoagulation are resistant to chemically induced liver and lung fibrosis.
Warfarin anticoagulation is a safe and effective treatment widely used for deep vein thrombosis, pulmonary embolism and stroke. Recently warfarin has also been used to reduce the mortality from idiopathic pulmonary fibrosis.
The primary objective of this study is to evaluate the impact of anticoagulation on progression of liver fibrosis. Patients with chronic hepatitis progress by 1 fibrosis stage every 5 ? 7 years on average. An initial study in this group would not therefore be feasible. In patients with HCV after liver transplant 20% develop significant fibrosis within the first year. As only a small minority of these patients respond to anti-viral therapy and because these patients undergo routine annual liver biopsy they represent an optimal group in which to test the effect of warfarin on fibrosis.
The study will take the form of a prospective open labeled randomised controlled multi-centred clinical trial. Patients aged 18 to 70 years old will be recruited into the study within 2 months of their first transplant and randomized by gender and centre to either the treatment group (warfarin anticoagulation for a period of 2 years) or the control group (standard post-transplant care).
The primary endpoint will be the proportion of patients with an increase in their fibrosis score of 2 more after 2 years of anticoagulation compared to the control group. The secondary endpoints will be the stage of liver fibrosis on liver biopsy after one year of anticoagulation, the number activated stellate cells per high powered field on liver biopsy and the safety of anticoagulation as shown by number of adverse events.

Publications

10 25 50
 
Description Wellcome Training Fellowship
Amount £250,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Research Training Fellowship
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 09/2015