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Wednesday May 1, 5:18 pm Eastern Time
Press Release
SOURCE: Hoffmann-La Roche Inc.
New Investigational Studies Report on CellCept Use in Patients Who Are Re-Infected With Hepatitis C After a Liver Transplant
WASHINGTON, May 1 /PRNewswire/ -- The immunosuppressive drug CellCept® (mycophenolate mofetil) positively altered the course of hepatitis C re-infection after liver transplantations in three investigational studies reported this week at the American Transplant Congress, a joint meeting held annually by the American Society of Transplantation (AST) and the American Society of Transplant Surgeons (ASTS).
The first study evaluated the benefit of CellCept used as an induction therapy (given immediately after transplant surgery) in the evolution of hepatitis C. The second study evaluated the effect of long-term CellCept treatment in patients with hepatitis C recurrence after a liver transplant. The third study examined use of CellCept in a steroid-free combination therapy with Zenapax® (daclizumab) and tacrolimus in patients with hepatitis C pre-transplant.
Approximately four million Americans are infected with hepatitis C, a blood-borne infectious disease of the liver. Hepatitis C is a leading cause of cirrhosis and liver cancer, and is the number-one reason in the United States why patients need liver transplants. In fact, 70 percent of people with hepatitis C will develop chronic liver disease, which may lead to liver failure and the need for a transplant, according to the Centers for Disease Control and Prevention (CDC).
In addition, of all patients who undergo liver transplants related to hepatitis C infection, more than 95 percent are re-infected as early as four weeks after transplant surgery because hepatitis C often remains in the bloodstream and re-attacks the new liver.
High Dose of CellCept and Hepatitis C Re-Infection
"Hepatitis C re-infections are one of the most common contributors to liver dysfunction and eventual recurrence of fibrosis after liver transplantation," said Carlos Fasola, M.D., transplant surgeon, Baylor University Medical Center, Dallas, TX. "In our study, when used at higher doses (greater than or equal to 1.5 g/day) for at least one year post-liver transplantation, CellCept reduced the severity of hepatitis C re-infection, extended patient survival, and improved long-term outcomes."
The study analyzed outcomes from hepatitis C post-liver transplants during 1995-2000. Three groups were examined, including 132 patients on calcineurin inhibitors (cyclosporine or tacrolimus) plus prednisolone, 29 patients on calcineurin inhibitors, prednisolone and CellCept (<1.5 g/day) and 21 patients on calcineurin inhibitors, prednisolone and a higher dose of CellCept (>1.5 g/day).
At one year after transplantation, results showed no incidence of hepatitis C recurrence in 62 percent (n=21) of patients in the group treated with the higher dose of CellCept (>1.5 g/day); 52 percent (n=15) of those treated with the <1.5 g/day CellCept dose; and 33 percent (n=132) of patients who were not treated with CellCept. Seven patients (33 percent) that were treated with the higher dose of CellCept had moderate hepatitis C recurrences, as compared with 10 patients (31 percent) treated with the <1.5 g/day CellCept dose, and 70 patients (53 percent) who were not treated with CellCept.
At year two, there was less severe fibrosis in the transplanted livers of patients given higher doses of CellCept (seven percent CellCept >1.5 g/day, 22 percent CellCept <1.5 g/day, 33 percent no CellCept, although due to the small sample size the differences were not statistically significant, p=0.15).
CellCept's Impact on the Rate of Hepatitis C Development
The goal of this retrospective study, presented by M. Bahara of Virchow-Clinics, Berlin, Germany, was to evaluate the effect of CellCept treatment on outcomes in 40 patients with histologically proven hepatitis C recurrence after a liver transplant. Immunosuppression consisted of CellCept in combination with tacrolimus (n=34), cyclosporine (n=5) or rapamune (n=1). CellCept dosage ranged from 500 to 2000 mg/day. Liver biopsies were performed routinely and histological changes were scored for inflammation and fibrosis. Mean follow-up was 24 months.
Most of the patients in this study showed a normalization of transaminases -- liver cell enzymes, which, when elevated indicate cellular injury and liver inflammation. Of those treated with CellCept for re-infection, 71 percent (n = 25) had normalization of transaminases, 83 percent (n = 6) of those treated with CellCept for acute rejection had normalization of transaminases.
Comparisons of fibrosis and inflammation showed no degradation of histology during CellCept treatment. In this study, CellCept showed positive results for the treatment of acute rejection without steroid application in five of six patients. Although no direct antiviral effects of CellCept could be observed, CellCept seemed to improve the clinical course of hepatitis C re-infection after liver transplantation.
Steroid-Free Combination Therapy: CellCept, Zenapax and Tacrolimus in Liver Transplant
The objective of this multicenter open label study presented by Francisco J. Suarez, M.D., Ph.D., of Hospital Juan Canlejo, La Corunia, Spain, was to evaluate the efficacy of a combination therapy of CellCept, Zenapax and tacrolimus for the prevention of acute rejection episodes in liver transplant recipients. In this study, 102 patients (34 percent with hepatitis C) received 2 g/day of CellCept and Zenapax in a 2 mg/kg dose six hours after surgery followed by one dose (1 mg/kg) of Zenapax on the seventh day post transplantation. The targeted trough level of tacrolimus was 5-15 ng/ml during the first month after transplantation and 5-10 ng/ml from the first to the sixth month.
Treatment of rejection consisted of up to two full courses of high-dose steroids (up to 1 g/day given over three days). Eighteen patients prematurely withdrew from the trial (four deaths, one retransplantation, 11 adverse events and two protocol violations). Ten patients suffered from biopsy proven acute rejection (five mild and five moderate in severity). Only four moderate rejections required steroid treatment. The incidence of rejection did not differ significantly between the hepatitis C positive and hepatitis C negative groups (8 and 10 percent, respectively).
The study concluded that therapy with this combination of CellCept, Zenapax and tacrolimus without steroids was effective, with only 9.8 percent of patients developing acute rejection episodes and no increase in opportunistic infections (including hepatitis C) or mortality.
About CellCept
CellCept is an immunosuppressant or "anti-rejection" drug to be used in combination with other immunosuppressive drugs (cyclosporine and corticosteroids) for the prevention of rejection in patients receiving heart, kidney and liver transplants. CellCept received FDA approval for the prevention of organ rejection in kidney (May 1995), heart (February 1998), and liver (July 2000).
The principal adverse events associated with the administration of CellCept (in combination with cyclosporine and corticosteroids) include diarrhea, leukopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections. A higher proportion of renal transplant patients in the active treatment groups experienced one or more opportunistic infections compared with patients receiving placebo. Cytomegalovirus tissue invasive disease was more common in patients receiving 3 g/day.
Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal, cardiac or hepatic transplant patients should use CellCept. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.
There are no adequate and well-controlled studies in pregnant women. However, CellCept has been shown to have teratogenic effects in animals; it may cause fetal harm when administered to a pregnant woman. Therefore, CellCept should not be used in pregnant women unless the potential benefit justifies the potential risk to the fetus.
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