A prospective randomized open study in liver transplant recipients: Daclizumab, mycophenolate mofetil, and tacrolimus versus tacrolimus and steroids

Abstract

This open-label, randomized study compared the efficacy of a regimen of corticosteroids and tacrolimus (standard therapy group, n ϭ 79) with a regimen of daclizumab induction therapy in combination with mycophenolate mofetil and tacrolimus (modified therapy group, n ϭ 78) in primary liver transplant recipients. The primary endpoint was biopsy-proven acute rejection (BPAR) at 24 weeks. Secondary endpoints included time to rejection and patient and graft survival. The incidence of BPAR was significantly reduced in the modified therapy group compared to the standard therapy group (11.5% versus 26.6%, respectively, P ϭ 0.017). The time to rejection was significantly shorter in the standard therapy group compared with the modified therapy group (P ϭ 0.044). There was no significant difference between groups in patient or graft survival. Hepatitis C virus-positive patients exhibited no differences from hepatitis C virus-negative patients with respect to the incidence of BPAR. A steroid-sparing regimen of daclizumab, mycophenolate mofetil, and tacrolimus was effective and well tolerated in the prevention of BPAR in adult liver transplant recipients in comparison with a standard regimen of tacrolimus and steroids. Liver Transpl 15:1542-1552, 2009. © 2009 AASLD. Received February 5, 2009 accepted May 26, 2009. Standard immunosuppressive therapy after liver transplantation is based on calcineurin inhibitors (CNIs) and corticosteroids.1 Although corticosteroids are still widely used as maintenance immunosuppression for most liver transplant recipients, tacrolimus has supplanted cyclosporine as the CNI of choice.1,2 In the United States alone, 89% of liver transplant recipients currently receive tacrolimus, whereas less than 10% receive cyclosporine. 1 However, both tacrolimus and corticosteroids are associated with serious side effects, including nephrotoxicity (tacrolimus) and hypertension and metabolic effects (corticosteroids).2 Thus, alternative immunosuppressive regimens that minimize the use of tacrolimus or corticosteroids have been sought. [3][4][5]

Induction immunosuppression in liver transplantation: a review

“…It is worth noting, however, that the absence of steroids did not result in a lower incidence of hepatitis C recurrence, except for one study, which found an increase in peri‐portal inflammation at 2 years post transplant in the steroid‐treatment arm . The adverse metabolic and infectious complications were noted in two studies reporting an increase in CMV, bacterial infections and diabetes in the steroid group , although most studies with follow‐up beyond the period of steroid treatment found no difference in metabolic complications between groups .…”

“…Each group received a single dose of intraoperative IV steroids. They found a significantly decreased incidence of ACR in the induction arm ( P = 0.017) with no difference in hepatitis C recurrence at 2 years post transplant (power > 80%) . Similarly, Klintmalm and colleagues reported a prospective, multicenter trial with patients randomized to receive tacrolimus and steroids ( n = 80), tacrolimus, steroids, and MMF ( n = 79) or daclizumab induction with tacrolimus and MMF ( n = 153) post‐OLT.…”

Renal dysfunction and the liver transplant recipient; novel strategies for determination of reversibility and renal protective therapies pretransplant and posttransplant

“…As compared to controls, patients on MMF had significantly less acute cellular rejection (30 vs. 46%), renal dysfunction (24 vs. 42%) and higher 1-year posttransplant eGFR (90 vs. 78 ml/min), P < 0.05. However, Otero et al [15] performed a similar analysis comparing standard-dose TAC þ corticosteroids with reduceddose TAC þ MMF þ daclizumab and found no effect. Reduced-dose patients had significantly less biopsyproven rejection compared with controls (11.5 vs. 26.6%), P < 0.05, but no difference in renal function as measured by serum creatinine 12 months or less posttransplant.…”

Long-Term Toxicity of Immunosuppressive Therapy

“…In addition, daclizumab was shown to be effective in reducing acute rejection episodes while avoiding steroid therapy. 61,62 However, basiliximab showed no significant improvement over a conventional immunosuppressive regimen. 63 In a meta-analysis of randomized trials on these interleukin--2 blockers, no evidence of increased infections or malignancies was noted at 1-year after transplantation.…”