When it comes to suppressing organ rejection following liver transplantation, doctors have been prescribing steroid-based treatments for the past five decades. The immunosuppression regimens are aimed at avoiding these destructive immune system attacks against the new organ. But steroids pose significant risks to the patient, which include glucose intolerance, obesity, and osteoporosis.1 Additional side effects may include the risk of diabetes, arterial hypertension, bone diseases, and certain infections.2
A New Approach
As a result, doctors have been working in recent years to develop immune suppression interventions that are free of steroids, with the aim of avoiding many of these side effects3, as well as potentially preventing the risk of HCV recurrence after liver transplants, which can result from over-suppressing a patient's immune system.
Initial findings from one such study were unveiled at a recent medical conference in Seattle. The open-label trial is testing the efficacy and safety of a steroid-free immune suppression therapy that includes a medication known as mycophenolate mofetil, branded as CellCept4. So far, the results have suggested that the CellCept regimen is as safe and effective as a standard immunosuppression therapy that includes cyclosporine and corticosteroids.
In addition to helping prevent unwanted side effects, this unique immune suppressing protocol may help stave off hepatitis C recurrence after liver transplants. That's what earlier research has suggested, explained Goran Klintmalm, MD, the principal investigator in the latest study, and Chief and Chairman of the Baylor Regional Transplant Institute at Baylor University Medical Center in Dallas.
"The question has always been: how do we achieve the right balance of immunosuppression to prevent acute rejection without over-suppressing the immune system, which would allow [the] hepatitis C virus to rapidly replicate?" Klintmalm said. "In our study, the steroid-free CellCept regimen demonstrated comparable efficacy, without increasing the risk of hepatitis C recurrence. We are encouraged by these trends at one year."
Testing a New Protocol
CellCept was approved about 10 years ago for use with cyclosporine and corticosteroids to prevent organ rejection in transplant procedures. It was approved specifically for liver transplant patients in 2000.
In the open-label, prospective trial—in which both patients and clinical staff are aware of the individual immune-suppressing regimen being tested—patients were selected at random to receive one of three therapies: the standard treatment of tacrolimus and prednisone (a commonly used steroid); CellCept, tacrolimus, and prednisone; or CellCept, tacrolimus, and doses of daclizumab (Zenapax). The latter protocol completely excluded steroids. The physicians designed a novel three-dose protocol for daclizumab in hopes of boosting its efficacy, Klintmalm stated, due to evidence in earlier research that suggested this medication was not as effective in liver transplant patients.
Klintmalm's team then compared any differences in the numbers of acute rejections and/or the numbers of patients with hepatitis C recurrence after transplant between the three groups.
Effective Outcomes Seen Early On
After one year since the start of the study, they found that more patients experienced liver rejection in the group given standard tacrolimus combined with prednisone. Only 9 percent and 5 percent of the patients in the CellCept/tacrolimus/prednisone and CellCept/tacrolimus/daclizumab groups had acute rejections, respectively.
Additionally, the rates of hepatitis C recurrence were found to be comparable in all three groups, Klintmalm and his colleagues reported. Further, the regimens that included CellCept were comparable to the steroid-based treatments in terms of organ or patient survival, or the incidence of side effects like infections, malignancies, and diabetes.
"These patients have done exceptionally well with almost no rejections whatsoever," Klintmalm told Priority Healthcare. "And the rejections we have had have been extremely mild."
While there hasn't been much of a difference in the risk of HCV recurrence for patients using CellCept, the investigators did discover that recurrences in the CellCept group have been less aggressive. For instance, test results on liver histology (the health of the liver's tissue) have been similar between all three groups; however, liver function tests have shown greater improvement in the group of patients who had been given CellCept regimens, Klintmalm added.
Larger Study Plans
Due to the positive findings, CellCept maker Hoffmann-La Roche Pharmaceuticals, is sponsoring its own open-label, prospective trial involving a larger number of patients. "We came up with this protocol that we took to Roche … and suggested this study. They thought it was sufficiently interesting for them to fund it," said Klintmalm.
The new CellCept clinical trial will evaluate its safety in two treatment regimens—combined with either the standard immunosuppressant sirolimus, or calcineurin inhibitors (CNI)—another group of standard immune-suppressing medications. Researchers plan to evaluate the therapies' effect on kidney function, as well as their ability to prevent acute rejection, organ loss, and patient death.
Initially, the trial was designed to test CellCept's effectiveness in preventing HCV recurrence after transplantation, Klintmalm explained. But he and his colleagues wanted to take the study a step further and determine if CellCept could be an effective substitute for steroids in these immunosuppression treatments.
Steroid-Free Immunosuppression is the Aim
Successfully performing transplant procedures without the use of steroids in immune suppression regimens has been the aim of physicians for many years, Klintmalm explained. But "it never seemed to be feasible," he said. "This is the first study ever where not a single milligram of steroids is being given during the entire study. That has never been done before."
The trial is expected to recruit some 340 patients at 35 transplant centers in the United States and Canada.
While medical science hasn't quite reached the point at which steroid-free immunosuppression can be prescribed routinely, trials such as this are strongly suggesting that certain non-steroid protocols can be "an extremely efficacious and safe way of treating patients," Klintmalm said. But he added it's still too early to determine the long-term effects of a CellCept regimen on the risk of hepatitis C recurrence.
Trials like these will likely lead to other questions, as well, he explained. For example, pegylated interferon/ribavirin therapy is not successful in a proportion of hepatitis patients.5 But in some instances, liver transplant patients who don't respond to hepatitis treatment were previously given steroid-based immunosuppression that resulted in aggressive HCV recurrence. Would it then follow that if such patients were given steroid-free immunosuppression, their recurrence may not be as aggressive and, in turn, their interferon/ribavirin therapy might be more successful? That and other questions remain to be answered, Klintmalm said.
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2. Reding R. Steroid withdrawal in liver transplantation: benefits, risks, and unanswered questions. Transplantation 2000 Aug 15;70(3):405-10.
3. Lerut JP. Avoiding steroids in solid organ transplantation. Transpl Int 2003 Apr;16(4):213-24. Epub 2003 Apr 2.
4. 2005 American Transplant Congress. 2005 May 21-25. Seattle, WA.
5. Trepo C. Genotype and viral load as prognostic indicators in the treatment of hepatitis C. J Viral Hepat 2000 Jul;7(4):250-7.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
