Jefferson liver transplant surgeons show less rejection, better survival with drug regimen
Transplant surgeons at Thomas Jefferson University Hospital in Philadelphia have found that a new combination of drugs results in fewer incidences of rejection in liver transplant patients than do current treatments.
Surgeons, led by Ignazio Marino, M.D., director of the Division of Liver Transplantation and Hepato-biliary Surgery at Thomas Jefferson University Hospital, analyzed the results of 50 liver transplant procedures they performed between 2000 and 2002. To try to prevent or lessen the severity of rejection, Dr. Marinos group used a monoclonal antibody, basiliximab, as part of a group of drugs that included tacrolimus, a standard anti-rejection agent, and low doses of steroids. Basiliximab, which ties up an important immune system cell (IL-2) receptor, has been used for kidney transplantation.
The group found a much lower incidence of liver rejection.
"When we added basiliximab, the rate of rejection dropped dramatically to 12 percent," says Dr. Marino, who is also professor of surgery at Jefferson Medical College of Thomas Jefferson University and the interim director of the Division of Transplantation at Thomas Jefferson University Hospital. He notes that the rate, which is after one year, is comparable to a French study that showed that 38 percent of patients had a rejection episode in the first year. Another trial conducted by the University of Pittsburgh had a 45 percent rejection rate after one year. "The big advantage [of this combination of drugs] is that the incidence of rejection is significantly decreased," he says. "These results could change the standard of care for liver transplant recipients."
The study findings appear Sept. 27, 2004 in the journal Transplantation. The results show that the drugs may have helped improve survival as well. Of the 50 patients who received transplants, 88 percent were alive three years later (The actuarial survival rate at three years was 88 percent.). According to the Transplant Liver Registry of the United Network for Organ Sharing, approximately 78 percent of those who receive liver transplants live for at least three years.
Dr. Marino notes that in the past 15 months of using this combination of drugs for liver transplants at Jefferson, the one-year patient survival is 100 percent.
According to Dr. Marino, in the 1990s at the University of Pittsburgh, surgeons developed a tacrolimus-based drug combination that changed the face of liver transplantation. Its use greatly decreased the reliance on steroids, which can produce nasty side effects, but high doses of the drug caused neurotoxicity and kidney toxicity. In the last decade, surgeons began using antibodies that were given to the patient initially before surgery in an attempt to reduce side effects from high doses of tacrolimus.
Tacrolimus is a drug that suppresses the immune system by inhibiting an enzyme (calcineurin) crucial for T-cell proliferation, which is important in the immune process. The Jefferson surgeons trial marks the first time anyone had evaluated the effectiveness and safety of basiliximab and tacrolimus to suppress the immune system to prevent the bodys rejection of a liver. "We think we have much less toxicity in the short term because we use less tacrolimus," he says. They also expect less toxicity in the long term as well because they used fewer steroids. As a result, he says, they expect fewer complications associated with long-term steroid use, which includes hypertension, osteoporosis and diabetes.
Dr. Marino has also discovered that basiliximab may affect hepatitis C virus (HCV) recurrence. "We also suspect that the recurrence of HCV is lower, though we dont have enough data to confirm this," he says. Typically, immunosuppressed liver transplant patients experience high rates of HCV recurrences, Dr. Marino notes, because the virus has fewer restrictions on its growth. Perhaps, he says, the anti-IL2 monoclonal has some mechanism affecting the replication of the HCV.
"If this observation can be confirmed, its important news because 60 percent of the patients we transplant are diagnosed with HCV. 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 Dr. Marino says that he would like to continue to investigate whether these drugs indeed reduce the recurrence of HCV, he has another clinical trial in mind. "We would like to begin a new study with no steroids – just two doses of this new drug at the time of the liver transplant and then tacrolimus for life," he says. "We think in the long term, we need to shift the paradigm of immune suppression," he says. "We may someday be able to wean patients away from immune suppression."
Steve Benowitz | EurekAlert!