Outcomes of immunosuppression minimization and withdrawal early after liver transplantation

Abstract

The Immune Tolerance Network ITN030ST A-WISH assessed immunosuppression withdrawal in liver transplant recipients with hepatitis C or nonimmune nonviral liver disease. Of 275 recipients enrolled before transplantation, 95 were randomly assigned 4:1 to withdrawal (n = 77) or maintenance (n = 18) 1- to 2-years posttransplant. Randomization eligibility criteria included stable immunosuppression monotherapy; adequate liver and kidney function; ≤Stage 2 Ishak fibrosis; and absence of rejection on biopsy. Immunosuppression withdrawal followed an 8-step reduction algorithm with ≥8 weeks per level. Fifty-two of 77 subjects (67.5%) reduced to ≤50% of baseline dose, and 10 of 77 (13.0%) discontinued all immunosuppression for ≥1 year. Acute rejection and/or abnormal liver tests were treated with increased immunosuppression; 5 of 32 rejection episodes required a methylprednisolone bolus. The composite end point (death or graft loss; grade 4 secondary malignancy or opportunistic infection; Ishak stage ≥3; or >25% decrease in glomerular filtration rate within 24 months of randomization) occurred in 12 of 66 (18%) and 4 of 13 (31%) subjects in the withdrawal and maintenance groups. Early immunosuppression minimization is feasible in selected liver recipients, while complete withdrawal is successful in only a small proportion. The composite end point comparison was inconclusive for noninferiority of the withdrawal to the maintenance group.

Keywords: clinical research/practice; clinical trial; immunosuppression/immune modulation; immunosuppressive regimens - minimization/withdrawal; infection and infectious agents - viral: hepatitis C; liver transplantation/hepatology; tolerance.

Conflict of interest statement

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.

Figures

Figure 1:

Disposition of enrolled subjects. All subjects who were assessed for eligibility for random assignment, as well as those who were replaced, are included.

Figure 2:

Percent of subjects who successfully completed each protocol-specified dose reduction. Subjects withdrew from immunosuppression at protocol-specified levels with the target dose indicated on the horizontal axis. Four subjects withdrew off all immunosuppression temporarily but restarted at a median time of 165 days later.

Figure 3:

Disposition of subjects randomly assigned to immunosuppression withdrawal who were non-tolerant. Those with or without elevated LFTs, and who did or did not undergo biopsy, are indicated. Those whose elevated LFTs did or did not resolve, and who had modification of immunosuppression, are also indicated. Liver function tests included gamma-glutamyl transferase, ALT, aspartate aminotransferase, bilirubin, and alkaline phosphatase. a Liver function tests are considered elevated if any of the five tests were increased more than 150% from the higher of the value at random assignment or the upper limit of normal. Liver function tests were considered resolved when all tests were less than 150% from the higher of the value at randomization or the upper limit of normal. IS, immunosuppression; LFT, liver function tests

Figure 4:

Subject dosing information at random assignment and last reported follow-up. The 18 subjects assigned to immunosuppression maintenance are depicted in the left panel. The 67 non-tolerant subjects and the 10 tolerant subjects among those assigned to immunosuppression withdrawal are shown in the middle and right panels respectively. Dosing units are as follows: 1 unit is equal to a tacrolimus 1 mg, cyclosporine 100 mg, sirolimus 1 mg, mycophenolate mofetil 1000 mg, mycophenolic acid 720 mg, azathioprine 50 mg, or prednisone 5 mg. Any antibody use equalled 20 units. Unit scores based on Vasudev B, et al. [22].