Blocking liver rejection following a transplant procedure is not always an easy task for physicians. It typically requires a cocktail of immunosuppressive drugs aimed at preventing the body's immune system from attacking the new organ.¹ From 1992 to 2001, nearly 30% of patients who underwent liver transplantation eventually rejected their organ, though that trend is an improvement from a high of about 50% 10 years ago.²

Now, doctors in Philadelphia claim a new combination of drugs might result in even fewer rejection episodes in liver transplant patients compared to current therapies.³

A Drug with a Positive History
The therapy they tested is a monoclonal antibody known as basiliximab (bas-il-IX-ih-mab), an immunosuppressive drug already used in kidney transplantation. The therapy works by fending off the body's white blood cells that launch an advance against the newly transplanted organ.⁴ Basiliximab has traditionally been given by injection.

"… In general, a kidney transplant has a tendency to reject more aggressively than a liver transplant. Therefore, if this drug was proven to be successful in kidneys, I thought maybe we can achieve even better results in livers. And in fact, this was the case," explained Ignazio Marino, MD, head of the Division of Liver Transplantation and Hepato-biliary Surgery at Thomas Jefferson University Hospital in Philadelphia, and the study's chief investigator.

To test the hypothesis that basiliximab might also be beneficial for men and women undergoing liver transplant procedures, Marino and his fellow surgeons studied the results of 50 liver transplant operations they had performed from 2000 to 2002, using basiliximab as part of an anti-rejection treatment protocol that also included the traditional medication, tacrolimus (tuh-CRAW-lih-mus) and low doses of steroids.  Their study was the first to use this regimen in liver transplantation. In the end, the study team noted a much lower incidence of liver rejection.

"We were able to prove that with the combination of this drug with the standard immunosuppression regimen using tacrolimus, rejections dropped from the historical rate of 40% to 12%, which is really a striking difference," said Marino, who is also a professor of Surgery at Thomas Jefferson University.

The results also suggest that this immunosuppression protocol may help improve a patient's odds of survival. Eighty-eight percent of the patients on which the study team focused were alive three years after transplantation, Marino and his colleagues noted. That compares to survival odds for the general liver transplant population of 78% after three years.⁵

The trial, he says, marks the first time that the basiliximab protocol has been tested for its efficacy and safety in liver transplant procedures. Marino notes that in the past 15 months of using this combination of drugs for liver transplants at his hospital, the chances of survival after 1 year has been 100%. Another advantage is that high doses of tacrolimus can be toxic to the nervous system and kidneys, and supplementing that with doses of basilixmab can reduce that risk." We think we have much less toxicity in the short term because we use less tacrolimus," he explains. Fewer steroids are also used in this regimen, which decreases the risk of toxicity even further. As a result, Marino says he and his colleagues expect fewer steroid-related complications, which can include high blood pressure, osteoporosis, and diabetes.

How Immunosuppression Works
Tacrolimus is a drug that suppresses the immune system by inhibiting an enzyme that's necessary for the production of T-cells, which make up part of the immune system. In the last decade, Marino says, researchers at the University of Pittsburgh developed a tacrolimus-based protocol that was considered an advance in the use of post-liver transplant immunosuppression.⁶ Its use greatly decreased the reliance on steroids, which can produce unwanted side effects. But tacrolimus produces its own side effects, such as an increased risk of infection in some cases, and anemia, among others, as well as its potential toxicity. Basiliximab inhibits the function of interleukin-2 in the body—a chemical messenger that calls certain immune system cells into action against a foreign invader.

"With the standard dose of 20 milligrams of basiliximab given at the time of surgery, and another 20 milligrams four days afterwards, you can decrease the dose of tacrolimus, and actually, you can even postpone the time that you start tacrolimus," Marino explained.

The approach is "revolutionary", he maintained, because rather than treating patients with aggressive immunosuppression immediately following liver transplant, this approach is much less aggressive, but still effective.

Targeting Hepatitis C
Another significant side effect of liver transplantation can be potentially avoided through the use of basiliximab: hepatitis C recurrence. "We suspect that the recurrence of HCV is lower, though we don't have enough data to confirm this," Marino explains. Typically, patients who undergo liver transplantation for hepatitis experience high rates of recurrence postoperatively.⁷ Perhaps basiliximab possesses some unique mechanism that blocks HCV replication, or the ability of the virus to make copies of itself, Marino says. That and other drugs that target interleukin-2 have hinted that they may be able to reduce the risk of recurrence.

"If this observation can be confirmed, it's important news because 60 percent of the patients we transplant are diagnosed with HCV," said Marino. "This would mean an immunosuppression that can delay the recurrence of HCV on top of having fewer episodes of rejection and toxicity than before."

While Marino would be interested in examining the mechanisms that underlie basiliximab's ability to keep HCV recurrence at bay, there is another clinical trial he has in mind first; one that would test the use of basiliximab alone, then adding tacrolimus after the transplant, without the use of steroids. "We are going to start this study soon with this aim," he said.

1. United Network for Organ Sharing (UNOS).
2. Scientific Registry of Transplant Recipients. University Renal Research and Education Association. University of Michigan. Trends in incidence of rejection at 1 year in liver transplant recipients.
3. Marino I, Doria C, Scott V et al. Efficacy and safety of basiliximab with a tacrolimus-based regimen in liver transplant recipients. Transplantation 2004 Sep 27;78(6):886-91.886-91.
4. Pascual J, Marcen R, Ortuno J. Anti-interleukin-2 receptor antibodies: basiliximab and daclizumab. Neprhol Dial Transplant 2001 Sep;16(9):1756-60.
5. Transplant Liver Registry. United Network for Organ Sharing (UNOS).
6. Abu-Elmagd K, Fung J, Todo S et al. The current status of hepatic transplantation at the University of Pittsburgh. Clin Transpl 1995;145-70.
7. Davis GL. Chronic hepatitis C and liver transplantation. Rev Gastroenterol Disord 2004 Winter;4(1):7-17.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.

http://www.hepatitisneighborhood.com/content/in_the_news/archive_2071

 

Docs Zero In on HCV Re-Infection After Transplant

 

by John C. Martin

 

Article Date: 09-23-04

 

Re-infection with the hepatitis C virus (HCV) is not uncommon following

liver transplantation,1 but doctors are now setting their sights on the

specific factors associated with HCV recurrence in transplant patients. In a

new study,2 physicians in Spain claim hepatitis C recurrence is more severe

in patients who receive liver transplants from living donors compared to

those who receive them from cadavers. But they add that the reasons for this

aren't currently known.

 

"Our data, though limited to a single center, show that living donor liver

transplantation is a strong and independent predictor of severe HCV disease

recurrence following transplantation," wrote the study authors in Barcelona,

Spain. "Accordingly, the 2-year probability of presenting severe recurrence

was significantly higher [as well] in living donor liver transplantation

compared to cadaveric liver transplantation."

 

Still, critics charge that doctors shouldn’t write off the obvious benefits

of living donor liver transplants before "premature" decisions about the

risk of HCV recurrence are made.

 

A Tough Fight

 

Hepatitis C recurrence after liver transplantation is hard to avoid, experts

say, occurring in nearly all patients who undergo the procedure. Nearly a

third of patients develop severe hepatitis and cirrhosis, even after

undergoing an operation designed to rescue a patient from end-stage liver

disease.3

 

To better understand the factors associated with recurrence, researchers led

by Xavier Forns, MD, at Hospital Clinic in Barcelona investigated donor

characteristics on the outcomes of HCV patients undergoing liver transplant

procedures. They followed 116 patients who underwent transplant operations

for end-stage liver disease between the years 2000 and 2003. The majority

had received livers from cadavers, while 22 received livers from living

donors.

 

The physicians took nearly 30 factors into account that could boost the risk

of HCV recurrence following surgery, including the age and gender of the

recipient, the HCV genotype, and pre-transplantation viral load. According

to experts, men, those under age 49, those receiving a donor liver less than

40 years of age, those with a hepatitis genotype other than 1, and those

with lower viral levels prior to surgery have better odds of fending off

hepatitis recurrence after a transplant.4

 

After the operations, the researchers followed up clinically with each

patient, performing liver biopsies when possible. The investigators

concluded that severe recurrence had occurred when they spotted evidence of

liver cirrhosis, or when patients experienced a rapid decline in their

health along with evidence of portal hypertension, an abnormal increase in

blood pressure in the  portal vein that feeds into the liver. The study team

then made comparisons to determine which of these factors was associated

with a higher incidence of hepatitis C recurrence postoperatively.

 

Factors Linked to HCV Recurrence

 

After an average of about 2 years of follow-up, 26 of the 116 patients

developed severe HCV recurrence. Of 95 patients who received livers from

cadavers, 18 percent had severe recurrence. But the same was true for 41

percent of 22 patients who had received their new livers from living donors.

According to the investigators, predictors of severe re-infection included

receiving a liver from a living donor, significant necroinflammation (a form

of hepatocyte necrosis), and postoperative biliary complications.

 

Two years after transplantation, patients who received a liver from a

cadaver likely faced about a 22% risk of developing severe recurrent

hepatitis C, the study investigators concluded. But the probability more

than doubled to 45% in the same timeframe for those who received livers from

living donors, the study investigators concluded.

 

While the reasons for the higher risk after living donor liver transplants

aren't clear, the researchers theorize that either biliary complications or

liver regeneration might accelerate liver fibrosis. It's known that the

regeneration of the liver can sometimes result in fibrosis.5

 

"In summary, our data indicate that living donor liver transplantation is a

strong predictor of severe HCV recurrence after transplantation," Forns and

his colleagues wrote. "Although the data need to be validated, the more

aggressive course of HCV infection in living donor compared to cadaveric

transplantation should be considered in living donor liver transplant

programs, since it may ultimately compromise graft and patient survival."

 

A Critical Viewpoint

 

An accompanying editorial in the same journal in which the study was

published6 had praise for the study's design, but points out that its

conclusion conflicts with other similar studies, and suggests that the

findings may not apply to all hepatitis C patients who undergo transplant

procedures.

 

"The benefits of living donor liver transplantation should not be overlooked

" insisted Roshan Shrestha, MD, a professor of Medicine, and Mark Russo, MD,

an assistant professor of Medicine, both at the University of North Carolina

 

 

Those benefits, they say, "must be considered before making a premature

decision about the risk of recurrent hepatitis C with living donor liver

transplantation."

 

Similar studies with conflicting findings included one published earlier

this year by doctors at the Mayo Clinic.7 In a group of 29 patients who

underwent HCV-related liver transplantation, there were no significant

differences found in the severity of hepatitis C recurrence, nor in the

health of each patient's liver tissue (histology), regardless of whether

they received livers from a living donor or a cadaver.

 

1. Davis GL. Chronic hepatitis C and liver transplantation. Rev

Gastroenterol Disord 2004 Winter;4(1):7-17.

 

2. Garcia-Retortillo M, Forns X, Llovet JM et al. Hepatitis C recurrence is

more severe after living donor compared to cadaveric liver transplantation.

Hepatology 2004 Sep;40(3):699-707.

 

3. Neumann UP, Berg T, Bahra M et al. Long-term outcome of liver transplants

for chronic hepatitis C: a 10-year follow-up. Transplantation 2004 Jan 27

77(2):226-31.

 

4. Porter SB, Reddy KR. Factors that influence the severity of recurrent

hepatitis C virus following liver transplantation. Clin Liver Dis 2003 Aug

7(3):603-14.

 

5. Bisgaard HC, Thorgeirsson SS. Hepatic regeneration. The role of

regeneration in pathogenesis of chronic liver diseases. Clin Lab Med 1996

Jun;16(2):325-39.

 

6. Russo MW, Shrestha R. Is severe recurrent hepatitis C more common after

adult living donor liver transplantation? Hepatology 2004 Sep;40(3):524-6.

 

7. Rodriguez-Luna H, Vargas HE, Sharma P et al. Hepatitis C virus recurrence

in living donor liver transplant recipients. Dig Dis Sci 2004 Jan

49(1):38-41.

 

 

 

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.