by John C. Martin
Article Date: 10-01-04

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.