Transplant Trial Watch

Outcomes of immunosuppression minimization and withdrawal early after liver transplantation.

Shaked A, DesMarais MR, et al.

Am J Transplant. 2018; [record in progress].

To determine the outcomes of immunosuppression minimization and withdrawal starting within 2 years after liver transplantation in recipients with hepatitis C (HCV) or nonimmune nonviral (NINV) causes of liver failure.

Eligible patients receiving immunosuppression with corticosteroids and a calcineurin inhibitor and/or antimetabolite following transplantation were randomized (4:1) to either immunosuppression withdrawal or to immunosuppression maintenance at 1 and 2 years post transplantation. Patients assigned to immunosuppression maintenance were assessed for 2 years. Patients assigned to immunosuppression withdrawal were assessed for 2 years after immunosuppression withdrawal concluded. Biopsies were obtained on the day of transplant, at evaluation of randomization eligibility (12-24 months post-transplant) and at 24 and 36 months post-transplant. Additional protocol biopsies were obtained for HCV patients at 6 and 12 months post-transplant. Liver biopsies were also planned when allograft dysfunction was detected or as clinically indicated.

95 patients were randomized 4:1 to immunosuppression withdrawal (n=77) or maintenance (n=18). Randomization was stratified by HCV or NINV status.

The primary composite endpoint was defined as the occurrence of death or graft loss, grade 4 secondary malignancy, grade 4 opportunistic infection, stage 3 or higher fibrosis, or a decrease in renal function. All outcomes were assessed at 2 years post randomization except renal function that was assessed at 24 months to 36 months post randomization. Secondary endpoints were eligibility for random assignment, immunosuppression withdrawal completion, immunosuppression-free duration, hepatitis C viral load, fibrosis and graft loss or death.

Up to 3 years post transplantation.

CET Conclusions
This interesting study investigated attempted immunosuppression withdrawal in highly selected liver transplant recipients with HCV or non-immune causes of failure. Of the 275 recipients enrolled, 95 eligible patients were randomized in a 4:1 ratio to attempted minimization/withdrawal or maintenance. Immunosuppression was successfully withdrawn in 10 patients, with 52 reduced to <50% baseline dose. No difference was seen in the primary composite outcome (death, graft loss, malignancy/infection, 25% fall in GFR, fibrosis). This study provides some useful insights into immunosuppression withdrawal and operational tolerance in this patient group. Only a small proportion of enrolled patients were able to achieve complete withdrawal, although minimization was successful in a larger number. Of note, 23% of enrolled patients withdrew consent post-transplant before randomization, suggesting that many patients do not have the appetite for taking risk when clinically stable. The initial sample size calculation over-estimated the number of patients who would be eligible for randomization, and so the study is ultimately underpowered to demonstrate non-inferiority of this strategy compared to immunosuppression maintenance.

Jadad score

Data analysis
Per protocol analysis

Allocation concealment

Trial registration - NCT00135694

Funding source
Non-industry funded