Research tackles liver transplant failure

Provided by MedicalXpress

November 7, 2013

The re-infection of transplanted livers with hepatitis C virus (HCV) – which can irreparably damage the new organ - could be halted by administering a drug which blocks the virus entering the liver, research from the University of Birmingham being presented at the Liver Meeting demonstrates.

People who receive a new liver to replace their own organ previously damaged by HCV infection are 95 per cent likely to experience recurrent infection after the transplant, where virus levels can surpass the pre-transplant levels within a few days. Importantly, viral replication and ensuing injury can be more aggressive after the transplantation.

This often means that the new liver becomes damaged, and to a level at which it can cease to function in just a few years. As many as a quarter of HCV infected patients who receive a transplant will experience liver failure, possibly leading to death, within ten years.

Until now, doctors have been unable to prevent HCV, which circulates in the bloodstream, from entering the new liver – however results from a trial at Birmingham evaluating a HCV entry inhibitor drug, ITX5061, given before, during and after the transplant dramatically slows down the progress of the virus re-infecting the liver. Although the drug did not clear HCV completely from the blood of the patients, the results of this research suggest that it could be used as a treatment in conjunction with more conventional strategies.

The trial involved 23 patients undergoing liver transplantation. Thirteen control patients did not receive the drug, and the remaining 10 patients were given ITX5061 on the day of their transplant and for a week afterwards. The levels of HCV in all participants' blood were measured at set time points, with a greater decline noted for all patients treated with ITX5061.

The trial was carried out by researchers at the Centre for Liver Research and NIHR Birmingham Liver Biomedical Research Unit at the University of Birmingham, in conjunction with colleagues at the Queen Elizabeth Hospital Birmingham.

Dr Ian Rowe, who presented the research, said: "This is the first trial in patients undergoing liver transplantation of a drug that blocks HCV entry into the new liver. Until now we have only been able to study this process in the laboratory and this study has allowed us to learn about this process as it happens in patients. ITX5061 treatment was safe and we hope that further studies of this drug in combination with others in development will improve the outcomes for this challenging group of patients."

The findings, Scavenger receptor B-I antagonist ITX5061 modulates early HCV kinetics in patients undergoing liver transplantation: results of a phase Ib clinical trial, were presented on Sunday (November 3) at the Liver Meeting, the Annual Meeting of the American Association for the Study of Liver Disease in Washington DC.

HCV is the second biggest cause of chronic liver disease leading to a transplant in the UK, and the leading cause in the USA. The Health Protection Agency (HPA) estimate that by 2020 15,840 individuals will be living with hepatitis C-related cirrhosis or cancer in England, more than 4,200 with decompensated cirrhosis or cancer for whom a liver transplant may be the only option.

Explore further: Aging hepatitis C population escalates demand for liver transplantation

Provided by University of Birmingham

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New Loyola Study on Hepatitis C Virus Entry Factor

Public release date: 10-Jun-2013
Contact: Stasia Thompson
thoms@lumc.edu
708-417-5036
Loyola University Health System

Loyola researchers identify disruption of iron uptake receptor

Hepatitis C virus (HCV) infects more than 170 million people worldwide. Approximately 80 percent of infections lead to chronic illness including fibrosis, cirrhosis, cancer and also hepatic iron overload. A new study completed by researchers at Loyola University Chicago Stritch School of Medicine reveals that HCV not only alters expression of the iron-uptake receptor known as transferrin receptor 1 (TfR1) but that TfR1 also mediates HCV entry.

"We have not yet discovered a cure for Hepatitis C, however discovering the relationship between HCV and TfR1 sheds more light on the complex, multistep process required for the virus to get into liver cells," said senior author Susan L. Uprichard, PhD, virologist and Director of Hepatology Research, Loyola. "This new knowledge reveals important insight into how the virus interacts with and changes our liver cells for its own benefit. As such, it may facilitate the development of entry inhibitors or treatments for HCV-associated iron overload." The research findings could also potentially be used in the clinical setting for the care of patients not only for those with chronic liver disease but also for post liver transplant where it might help prevent infection of a new liver or at least slow disease progression. Uprichard says her HCV research lays important groundwork. "This research is like finding one of the four corners of a puzzle," she said. "It creates a key building block toward finding a medical solution to Hepatitis C."

The new study is part of a project initially directed at understanding how HCV may disrupt cellular iron homeostasis. "TfR1 plays a role in HCV infection at the level of glycoprotein-mediated entry, acts after CD81 and is possibly involved in HCV particle internalization," said Danyelle Martin, the first author of the study who performed this research as part of her Ph.D work at University of Illinois at Chicago (UIC) and is now manager of the newly established Clinical Research Office Biobank at Loyola University Medical Center. "More studies will need to be done to determine if and how the interaction between TfR1 and HCV leads to the hepatic iron overload seen in HCV infected patients."

Results of the HCV study are published in the Proceedings of the National Academy of Sciences (PNAS) the week of June 10, 2013.

"The Hepatitis C Virus is fascinating and complex; we are still learning about the biology of the virus including the liver cell factors the virus needs to replicate and how these interactions cause the specific liver dysfunction observed in patients," said Uprichard, who also began the research while at UIC.

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Uprichard and Martin are members of the Division of Hepatology at Loyola University headed by Scott Cotler, MD and the Clinical Research Office led by Thomas Layden, MD.

Together with Harel Dahari, Ph.D, a mathematical modeler and another member of the Division of Hepatology, Dr. Uprichard co-directs a new Program for Experimental and Translational Modeling currently being established at Loyola to promote interdisciplinary research.

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