Author: Neighborhood Reporter
Author Date: 1/17/2003

A liver transplant is often the only life-saving treatment available to
people whose livers have failed -- and thousands die each year waiting
for a donor.

Now U.S. researchers are testing an artificial liver, one that could
provide a bridge to transplantation or even help seriously ill patients
survive long enough for their own livers to regenerate.

"It would be the dream of 40 years of research to have a machine that
can replace the liver," says Dr. Andres T. Blei, a liver expert at
Northwestern University Medical School in Chicago who is studying the new
device.

Normally, the liver removes toxins from the blood. When it stops
working, toxins accumulate in the bloodstream, damaging nerves, kidneys and
other organs, and increasing pressure on the brain, ultimately
culminating in death.

The artificial liver, known as the Molecular Adsorbent Recirculating
System, cleanses blood of these poisons.

Developed in the early 1990s by two kidney specialists in Germany, the
device works on the same principle as a kidney dialysis machine. Blood
is pumped slowly from the body and filtered through a thin membrane
coated with albumin, a protein that removes the large, fatty toxins
normally filtered out by the liver.

Patients with liver failure are kept on the machine round-the-clock,
until they feel better or receive a transplant.

In Germany, the device was first tested on 26 seriously ill patients
with chronic liver disease. Of those, nine died, but 17 survived without
a transplant.

"Normally, all of them would have died," says Dr. Jan Stange, a
co-inventor of the system who is now at UC San Diego in La Jolla. "The machine
allowed them to live long enough to recover."

Since it became commercially available in Europe and Asia in 1998, the
system has been used on more than 2,500 patients who are waiting for
transplants, are in comas induced by toxins in the bloodstream and brain,
or have acute liver failure caused by ingestion of a substance toxic to
the liver, such as acetaminophen (the active ingredient in Tylenol) or
mushrooms.

It was first used in the U.S. in the late 1990s on 20 desperately ill
patients.

Two of the patients, who suffered acute liver failure, survived long
enough to recover their liver function.

The remaining 18 showed improvement, and six received a liver
transplant.

"This encouraged us to study people who were less sick in hopes of
getting even better results," says Dr. Robert H. Bartlett, a surgery
professor at the University of Michigan in Ann Arbor who did the research.

Since then, a study of 70 patients whose liver failure has put them in
a coma has gotten underway at five hospitals across the country,
although results won't be available for at least a year.

"The question is whether we can help patients recover their mental
status and reverse the coma quickly," says Dr. Robert J. Fontana, medical
director of liver transplantation at the University of Michigan Medical
Center, who is helping conduct this study.

"Potentially, this device could be a bridge to other interventions,
like a life support for patients in liver failure."

(INFOBOX)

When a liver fails

Liver failure is generally divided into two types: sudden, more
commonly known as "acute," and chronic.

Acute liver failure occurs when an otherwise healthy person ingests
chemicals toxic to the liver (found in some mushrooms and medications) or
as a complication of acute hepatitis. Sometimes the liver can recover
by itself but often a liver transplant is required.

Chronic liver failure is much more common, affecting an estimated 4
million to 5 million Americans. It occurs during the end stage of
long-term liver problems caused by prolonged alcohol or substance abuse,
chronic hepatitis or other infections.

People with chronic liver problems can lead normal lives until an
averse reaction to something such as a viral infection or a fatty diet
pushes them over the edge into liver failure. Although medication and a
restricted diet can help eliminate liver toxins, if the liver is too
damaged, a transplant may be the only alternative.

Copyright 2003 Los Angeles Times

PEG-Intron Plus Ribavirin Is Effective for Hepatitis C Recurrence in Treatment-naïve Liver Transplant Recipients

Abstract Summary

Recurrent HCV in the liver recipients is a major concern. Researchers at the University of Miami presented preliminary data using PEG-Intron (peginterferon alfa-2b) and ribavirin in naïve HCV-R patients.

Patients underwent PEG-Intron (1.5mcg/kg) and ribavirin (400-600mg/d) therapy for at least 24 weeks. Side effects recorded: neutropenia (<750 cells), anemia (hemoglobin <8 grams), thrombocytopenia and depression. Definition of HCV-R: increase in liver chemistries, histopathologic findings with inflammation along with COBAS AMPLICORÔ Hepatitis C virus Test, version 2.0 (HCV RNA Qualitative PCR) and COBAS AMPLICOR HCV MONITOR TEST-version 2.0 (HCV RNA quantitative PCR) assays. Immunosuppression: tacrolimus with steroid tapering by week 12-20.

Thirty OLT recipients were included in the study. Mean age was 54 yrs, mean time from OLT was 29.2 months, Hispanics (57%) Caucasians (40%) and African Americans (3%). Eight out of 30 patients (27%) became HCV non detectable.

The following dose adjustments were required: PEG-IFN was reduced in 12 out of 30 (40%) and 13 out of 30 patients had (43%) to decrease in ribavirin dosage. Therapeutic interventions were: 3/30 (10%) received blood transfusions, 6/30 (20%) received erythropoietin and 13/30 (43%) had to receive Neupogen. Clinical depression with medical therapy was seen in 13/30 (43%).

Conclusions: Combination PEG-IFN with ribavirin appears to effective therapy in HCV-R. The frequency of side effects necessitating cessation of treatment was greater than generally reported in the non-transplant setting.

This data, although preliminary, reveals the difficulty and caution that must be considered when treating HCV-R liver transplant recipients with combination pegylated interferon and ribavirin therapy.                                                                 

03/28/03

Reference
GW Neff and others. TREATMENT OF NAÏVE HEPATITIS C RECURRENCE (HCV-R) IN LIVER TRANSPLANT RECIPIENTS WITH PEGYLATED INTERFERON ALPHA-2B AND RIBAVIRIN. Abstract 4449.00. Abstracts of the 38^th Annual Meeting of the European Association of the Study of the Liver (EASL).

PEG-Intron Plus Ribavirin in Liver Transplant Patients with Recurrent HCV Non Responsive to Rebetron

Abstract Summary

Recurrent HCV in liver recipients is a major concern. Researchers ant the University of Miami presented data from a prospective trial of pegylated interferon and ribavirin combination treatment in recurrent HCV nonresponder (HCV-NR).

Treatment: PEG-Intron (pegylated interferon-2b 1.5 mcg/kg/wk) and ribavirin (400-600 mg/d) therapy. Side effects recorded: anemia, neutropenia, thrombocytopenia and depression. T HCV-R was defined: increase in liver chemistries, histopathologic findings consistent with inflammation along with viral recurrence and HCV viremia. HCV RNA serology was done using COBAS AMPLICOR Hepatitis C virus Test, version 2.0 (HCV RNA Qualitative PCR) and COBAS AMPLICORÔ HCV MONITOR TEST-version 2.0 (HCV RNA quantitative PCR) assays.

Thirty-two OLT patients were given combination treatment. 8 Hispanics (25%), 24 Caucasians (75%). Mean time from transplant (24.2 mos) and Mean age was 53.1yrs. Biochemical improvements was seen in 16/32 (50%) and 6/32 (18%) became HCV nondetectable.

Side effects included; clinical depression 16/32 (50%), neutropenia 14/32 (43%), reduced pegylated interferon dosing 19/32 (60%), reduced ribavirin 9/32 (28%) and blood transfusions related to ribavirin 2/32 (6%). Combination therapy had to be discontinued secondary to drug intolerance in 9 out of 32 patients (28%).

Conclusions: Although treatment of HCV-NR with combination PEG-Intron and ribavirin was beneficial in 18% of patients, several transplant recipients suffered from depression, neutropenia, thrombocytopenia or anemia.

Safety data that we obtained from this study has prompted us to start HCV liver transplant recipients with lower doses of pegylated interferon-2b and ribavirin and increase in escalating dosages if tolerated by the recipient.

03/28/03

Reference
GW Neff and others. PRELIMINARY TREATMENT RESULTS OF PEGYLATED INTERFERON ALPHA 2B AND RIBAVIRIN IN LIVER TRANSPLANT RECIPIENTS WITH RECURRENT HEPATITIS C VIRUS NONRESPONSIVE TO INTERFERON ALPHA2B AND RIBAVIRIN. Abstract Number: 4447.00. Abstracts of the 38^th Annual Meeting of the European Association of the Study of the Liver (EASL).

Abstract Summary

The effectiveness (sustained virological response, SVR) of combination therapy (CT) with interferon and ribavirin in patients (pts) with recurrent hepatitis C after liver transplantation (LT) is low (10-30%). The pegylated interferons (IFN) have increased SVR in non-transplanted pts with chronic hepatitis C.

This ongoing study, conducted in Turin, Italy, is investigating the tolerance, safety and efficacy of PEG-Intron (pegylated interferon alfa-2b) and ribavirin in recurrent hepatitis C after LT.

16 treatment-naive pts, mean age 54 yrs (34-62), 81% males, 62% genotype 1, with recurrent hepatitis C after LT, histology at baseline: acute hepatitis in 3 pts, chronic hepatitis in 13, mean grading 7/18 (4-12), mean staging 2/6 (1-3), were treated with PEG-Intron 1 mcg/kg weekly plus ribavirin 800 mg/d for 12 months (mo). Median time LT to treatment was 10 mo (3-74). The primary end-points are HCV RNA negative (by PCR, Roche Monitor) at end of treatment (ETVR) and at 24 week of follow-up (SVR).

Seven pts (44%) discontinued therapy for side effects at a median of 4 mo (1-6) after initiation: 2 pts before 3 mo, 5 before 6 mo. The causes of discontinuation were: important psychiatric or influenza-like symptoms in 5 pts; 2 pts developed severe jaundice (with negative HCV RNA). Fourteen (88%) of pts need PEG-Intron dose reduction for leukopenia (< 2500 109/l); but none of pts who continued therapy >3 mo tolerated the full dosage. ETVR was obtained in 7/16 pts (43, 7%), 3 of them with normal ALT level. Follow-up to evaluate SVR is ongoing.

Conclusions: PEG-Intron can improve ETVR and hopefully SVR in recurrent hepatitis C after LT. Tolerance is lower than conventional CT and the dose reduction may influence efficacy. Longer follow-up and close monitoring side effects will determine the real efficacy or limitations of current available therapy.

03/28/03

Reference
B Lavezzo and others. PRELIMINARY RESULTS OF NAIVE COMBINATION THERAPY WITH 12KDA PEG-IFN α-2B AND RIBAVIRIN IN RECURRENT HEPATITIS C AFTER LIVER TRANSPLANTATION (LT). Abstract 4157.00. Abstracts of the 38^th Annual Meeting of the European Association of the Study of the Liver (EASL).

Impact of immunosuppressive therapy on recurrence of hepatitis C.
Liver Transpl 2002 Oct;8(10 Suppl 1):S19-27 (ISSN: 1527-6465)
Everson GT
Hepatology, University of Colorado School of Medicine, Denver, CO 80262, USA. greg.everson@ucshc.edu.
1. Approximately 10% to 25% of hepatitis C virus-infected recipients of liver allografts will develop cirrhosis within 5 years of transplantation; this acceleration of the natural history of hepatitis C is caused in part by immunosuppression. 2. Risk factors for aggressive recurrence, graft loss, and death are treated acute cellular rejection, methylprednisolone pulse therapy, and use of OKT3. There appears to be no consistent difference between cyclosporine and tacrolimus in their effects on hepatitis C. 3. The benefit of steroid withdrawal, although commonly practiced in transplant recipients with hepatitis C, has not been proven. 4. Mycophenolate mofetil may show synergistic antiviral properties when used with interferon; however, posttransplantation use has not been associated with consistent beneficial or deleterious effects. 5. Effects of other agents, such as sirolimus or interleukin-2-receptor antibodies, have not been adequately defined. Early reports suggest that disease activity may be more aggressive when these agents are constituents of the immunosuppressive regimen.
Major Subject Heading(s) Minor Subject Heading(s) CAS Registry / EC Numbers
# Hepatitis C, Chronic [drug therapy] [immunology]
# Immunosuppressive Agents [therapeutic use]
# Mycophenolic Acid [analogs & derivatives]
# Cyclosporine [therapeutic use]
# Disease Progression
# Glucocorticoids, Synthetic [therapeutic use]
# Hepatitis C, Chronic [mortality] [surgery]
# Liver Cirrhosis [immunology]
# Liver Transplantation [immunology]
# Muromonab-CD3 [therapeutic use]
# Mycophenolic Acid [therapeutic use]
# Receptors, Interleukin-2 [immunology]
# Recurrence
# Risk Assessment
# Sirolimus [therapeutic use]
# Tacrolimus [therapeutic use]
# 0 (Glucocorticoids, Synthetic)
# 0 (Immunosuppressive Agents)
# 0 (Muromonab-CD3)
# 0 (Receptors, Interleukin-2)
# 109581-93-3 (Tacrolimus)
# 128794-94-5 (mycophenolate mofetil)
# 24280-93-1 (Mycophenolic Acid)
# 53123-88-9 (Sirolimus)
# 59865-13-3 (Cyclosporine)
Indexing Check Tags: Human
Language: English
MEDLINE Indexing Date: 200212
Publication Type: Owner: NLM; Status: Completed
Publication Type: Journal Article; Review; Review, Tutorial
PreMedline Identifier: 0012362294
Unique NLM Identifier: 22249245
Journal Code: IM