Mycophenolate mofetil combination therapy improves long-term outcomes after liver transplantation in patients with and without hepatitis C

Authors

  • Russell H. Wiesner,

    Corresponding author
    1. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minn
    • Transplant Center, Mayo Clinic, 200 First St. SW, Rochester, Minn, 55905
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    • Telephone: 507-266-1586. Fax: 507-266-2810

    • Supported by Roche Laboratories, Inc. The analyses reported here were conducted in ProSanos Corporation facilities. Dr. Lake receives grant support from Roche Laboratories, Inc. Dr. Wiesner serves as an advisor to Roche Laboratories, Inc. Dr. Lake and Dr. Wiesner serve as consultants to ProSanos Corporation.

  • Jolene S. Shorr,

    1. ProSanos Corporation, La Jolla, Calif
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  • Bettina J. Steffen,

    1. ProSanos Corporation, La Jolla, Calif
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  • Alice H. Chu,

    1. ProSanos Corporation, La Jolla, Calif
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  • Robert D. Gordon,

    1. Medical Affairs, Roche Laboratories, Inc., Nutley, NJ
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  • John R. Lake

    1. Department of Medicine, University of Minnesota, and Liver Transplantation Program, Fairview University Medical Center, Minneapolis, Minn
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    • Supported by Roche Laboratories, Inc. The analyses reported here were conducted in ProSanos Corporation facilities. Dr. Lake receives grant support from Roche Laboratories, Inc. Dr. Wiesner serves as an advisor to Roche Laboratories, Inc. Dr. Lake and Dr. Wiesner serve as consultants to ProSanos Corporation.


Abstract

To evaluate the impact of mycophenolate mofetil (MMF) on long-term outcomes of tacrolimus and corticosteroids, we analyzed data reported to the Scientific Registry of Transplant Recipients for 11,670 adult patients (3463 with hepatitis C [HCV]) who underwent primary, single-organ, liver transplantation between 1995 and 2001. Patients who were discharged from the hospital on tacrolimus-based immunosuppression with (n = 4466; n = 1323 HCV) or without MMF (n = 7204; n = 2140 HCV) were included in the analysis. Recipients treated at discharge with MMF, tacrolimus, and corticosteroids had significantly increased patient survival (81.0% vs. 77.0% at 4 years, P < 0.0001) and graft survival (76.4% vs. 72.9%, P < 0.0001), and lower rates of acute rejection (29.0% vs. 33.4%, P < 0.001) as compared to recipients treated at discharge with tacrolimus and corticosteroids alone. A trend toward lower rates of death from infection was observed (6.1% at 4 years for MMF vs. 7.1% at 4 years for tacrolimus and corticosteroids, P = 0.0508), but this result did not reach statistical significance. In multiple regression analyses, MMF triple therapy at discharge was associated with a reduced risk of death (hazard ratio [HR] = 0.77, P < 0.001), graft loss (HR = 0.81, P < 0.001), acute rejection (HR = 0.89, P = 0.002), and death from infectious complications (HR = 0.80, P = 0.007). Outcomes were similar for the cohort with HCV.

In conclusion, the addition of MMF at discharge to tacrolimus-based immunosuppression is associated with improved long-term outcomes after liver transplantation in patients with and without HCV. (Liver Transpl 2005;11:750–759.)

According to the Organ Procurement and Transplantation Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) 2003 Annual Report, maintenance immunosuppression at hospital discharge included MMF for almost half of patients undergoing liver transplantation in the United States in 2002;1 this figure is nearly 70% higher than that reported for 2001. The efficacy of MMF administered in combination with cyclosporine and corticosteroids for reduction of acute rejection has been demonstrated relative to azathioprine;2 however, the impact of MMF on long-term outcomes has not been extensively studied.

To examine long-term efficacy and safety of maintenance immunosuppression including MMF, we used data from the Scientific Registry of Transplant Recipients (SRTR) to analyze patient survival, graft survival, acute rejection, and death due to infectious complications for patients undergoing primary liver transplantation. Because tacrolimus has replaced cyclosporine as the calcineurin inhibitor of choice for liver transplantation in the United States in recent years,3 we compared outcomes in patients who received tacrolimus-based immunosuppression with and without MMF. Due to concerns about the potential effects of excessive immunosuppression in patients with underlying hepatitis C (HCV) disease, we also compared survival outcomes and disease recurrence in the subset of patients with HCV.

Abbreviations

MMF, mycophenolate mofetil; HCV, hepatitis C virus; OPTN, Organ Procurement and Transplantation Network; SRTR, Scientific Registry of Transplant Recipients; ICU, intensive care unit; CMV, cytomegalovirus; HR, hazard ratio.

Methods

Data reported to the SRTR (October 2003) for adult patients between the ages of 18 and 80 years who underwent primary, single-organ, liver transplantation in the United States between January 1, 1995, and April 30, 2001, and were discharged from the hospital on tacrolimus-based immunosuppressive therapy were analyzed. Follow-up data were obtained from 6- and 12-month post-transplant reports, and annually thereafter, up to August 1, 2003, or as long as data were available.

Patients were divided into two groups based on their immunosuppressive regimens at discharge: MMF, tacrolimus, and steroids; and tacrolimus and steroids alone. Patient survival, graft survival, death-censored graft survival, acute rejection rates, and deaths due to infections were compared for the two treatment groups. Mean reciprocal serum creatinine values were compared at discharge and follow-up visits. In the subset of patients with a pre-transplant diagnosis of HCV, the effects of immunosuppression regimen on patient survival, graft survival, acute rejection, hepatitis recurrence, and death due to infection were compared.

In a sub-analysis, patients who received cyclosporine immunosuppression at discharge were analyzed and were divided into two groups: cyclosporine, MMF, and steroids; and cyclosporine and steroids alone. Patients who received other non-tacrolimus immunosuppression (758 patients) at discharge were excluded.

Due to limitations or the absence of data in the SRTR regarding liver biopsy results, acute rejection was defined as treatment for acute rejection or acute rejection reported as the cause of graft failure, and HCV recurrence was defined as graft failure or death attributed to HCV on follow-up reports. Infectious death was defined as an infection reported as the cause of death on follow-up reports.

Kaplan-Meier survival analyses were applied to each of the above endpoints. Differences between groups were compared using the log-rank test. Cox proportional hazards models were developed to investigate the independent effects of the following covariates on study endpoints: immunosuppression at discharge (MMF, tacrolimus, and steroids vs. tacrolimus and steroids); recipient age, race, underlying etiology of liver disease (non-cholestatic cirrhosis, acute hepatic necrosis [e.g., viral hepatitis, drug toxicity, toxin ingestion], other liver diseases [e.g., metabolic diseases, malignancies, congenital and vascular abnormalities] vs. cholestatic cirrhosis), pretransplant serum creatinine (≥ vs. < 2 mg/dL), and hospitalization status (in the intensive care unit [ICU], hospitalized, vs. not hospitalized); cytomegalovirus (CMV) donor and recipient status (CMV negative donor or recipient vs. CMV positive donor/negative recipient, positive donor/positive recipient, negative donor/positive recipient); donor age (for each decade vs. donor age between 11 and 20 years), and gender; cold ischemia time (≥ vs. < 12 hours), and transplant year (per year beyond 1995). Recipient age and transplant year were continuous variables; categorical covariates were transformed into sets of binary variables, with one variable from each set omitted to represent the reference group. Model for end-stage liver disease or Child-Turcotte-Pugh scores were not available for this analysis; therefore, hospitalization status at the time of listing was used as an estimate of pre-transplant liver disease severity. For cold ischemia time, a category for missing was included in the regression model. For the subgroup analysis of patients with HCV, underlying etiology of liver disease was excluded from the model. Complete model covariate data were available for more than 97% of patients; missing data were imputed for race (to other), pre-transplant diagnosis (to other liver disease), serum creatinine (to < 2 mg/dL), hospitalization status (not hospitalized), and donor age (mean donor age). Results of the Cox regression analysis for patient and graft survival endpoints for the subgroup of patients with HCV were reported previously as a part of a study examining outcomes based on underlying etiology of liver disease.4

The incidence of infectious death overall and by type of infection (bacterial, viral, or fungal, as determined from reported cause of death) was calculated, and differences between groups were compared using a chi-square test. Demographic data and baseline clinical characteristics were summarized with descriptive statistics. All analyses were based on the intent-to-treat population (i.e., immunosuppression regimen at hospital discharge). MMF use and discontinuation of steroids based on 6-, 12-, and 24-month post-transplantation follow-up reports were summarized. Analyses were performed using SAS Release 8.2 (Windows XP).

Results

Patient Population

A total of 11,670 patients (4466 MMF, tacrolimus, and steroids; 7204 tacrolimus and steroids) between the ages 18 and 78 years (mean age 49.7 ± 10.8) were included in the study. The population was predominantly male (61.2%) and white (86.6%). The two treatment groups were well matched in terms of recipient and donor characteristics (Table 1). Only a small percentage of patients underwent living donor transplantation (4.3% MMF, tacrolimus, and steroids; 2.7% tacrolimus and steroids). Median length of follow-up was 2.9 years for patients who received MMF, tacrolimus, and steroids and 3.0 years for patients treated with tacrolimus and steroids alone; maximum length of follow-up was 7.9 and 8.3 years, respectively. The study included 3463 patients with HCV (1323 MMF, tacrolimus, and steroids; 2140 tacrolimus and steroids). Demographic and clinical characteristics for the subgroup of patients with HCV were similar to the overall study population (data not shown).

Table 1. Demographic and Baseline Clinical Characteristics
VariableTacro + Steroids (n = 7204)MMF + Tacro + Steroids (n = 4466)P-Value
  • 1

    Includes viral hepatitis, drug toxicity, toxin ingestion.

  • 2

    Includes metabolic diseases, malignancies, and congenital and vascular abnormalities.

Recipient   
Age (years)   
 Mean ± SD49.8 ± 10.849.5 ± 10.70.140
 Minimum18.018.0 
 Maximum78.077.0 
Gender   
 Female2808 (39.0%)1725 (38.6%)0.704
 Male4396 (61.0%)2741 (61.4%) 
Race   
 Caucasian6256 (86.8%)3853 (86.3%)0.382
 African American478 (6.6%)371 (8.3%)<0.001
 Other race470 (6.6%)242 (5.4%)0.015
Weight (kg; mean ± SD)79.5 ± 18.482.1 ± 19.0<0.001
Pretransplant liver disease   
 Non-cholestatic cirrhosis4929 (68.4%)3002 (67.2%)0.176
 Cholestatic cirrhosis/liver disease1034 (14.4%)614 (13.7%)0.362
 Acute hepatic necrosis1540 (7.5%)436 (9.8%)<0.001
 Other liver disease2701 (9.7%)414 (9.3%)0.411
Pretransplant serum creatinine ≥2 mg/dL939 (13.0%)689 (15.4%)<0.001
Pretransplant hospitalization status   
 In ICU1519 (21.1%)1095 (24.5%)<0.001
 Hospitalized1440 (20.0%)744 (16.7%)<0.001
 Not hospitalized4245 (58.9%)2627 (58.8%)0.912
Donor   
Age (years)   
 Mean ± SD37.44 ± 17.3437.67 ± 17.040.482
 Minimum1.001.00 
 Maximum87.0086.00 
Gender   
 Female2894 (40.2%)1825 (40.9%)0.459
 Male4310 (59.8%)2641 (59.1%) 
Type   
 Deceased7006 (97.3%)4276 (95.7%)<0.001
 Living198 (2.7%)190 (4.3%) 

Follow-up Immunosuppression

Follow-up immunosuppression at 6, 12, and 24 months was reported, respectively, for 97.6%, 88.3%, and 84.9% of patients discharged on MMF, tacrolimus, and steroids and 98.0%, 85.5%, and 81.0% of patients discharged on tacrolimus and steroids. Continuation of MMF was reported at 6, 12, and 24 months for 61.0%, 40.2%, and 23.3% of patients with follow-up data, respectively. Discontinuation of steroids 6, 12, and 24 months post-transplantation was noted, respectively, for 13.8%, 24.6%, and 52.2% of patients discharged on MMF, tacrolimus, and steroids and 18.4%, 27.3%, and 51.1% of patients discharged on tacrolimus and steroids. Findings were similar for patients with HCV (data not shown), with the exception that discontinuation of steroids by 2 years post-transplantation was higher (57.4% of patients discharged on MMF, tacrolimus, and steroids groups and 57.9% of patients discharged on tacrolimus and steroids).

Patient Survival

Patient survival was significantly higher for patients treated at discharge with MMF, tacrolimus, and steroids compared to tacrolimus and steroids alone (81.0% vs. 77.0% at 4 years, respectively; P < 0.0001; Figure 1A). Cox regression analysis confirmed that MMF at discharge contributed independently to a decreased risk of death (HR = 0.77, P < 0.001). Additional risk factors for death included underlying etiology of liver disease, donor age > 40 years, pre-transplant ICU hospitalization or hospital stay, serum creatinine ≥ 2 mg/dL, African American race, cold ischemia time ≥ 12 hours, year of transplant, and older recipient age (Table 2).

Figure 1.

Kaplan-Meier analysis of patient survival in liver transplant recipients overall (A) and with hepatitis C (B) following treatment at discharge with MMF, tacrolimus, and corticosteroids; or tacrolimus and corticosteroids alone.

Table 2. Cox Regression Analysis: Covariates for Death for Overall and Hepatitis C Transplant Populations
VariableOverallHepatitis C
HR95% CIPHR95% CIP
Treatment at Discharge      
 MMF + tacrolimus + steroids0.770.71–0.84<0.0010.770.66–0.89<0.001
Recipient Factors      
 Recipient age1.011.01–1.02<0.0011.011.004–1.020.004
 African American race1.361.19–1.56<0.0011.301.01–1.680.041
 Other race0.720.60–0.86<0.0010.530.36–0.77<0.001
 Non-cholestatic cirrhosis1.331.18–1.52<0.001
 Other liver disease1.851.57–2.17<0.001
 In ICU1.451.31–1.60<0.0011.351.12–1.620.002
 Hospitalized1.261.14–1.40<0.0011.231.02–1.480.027
 Pretransplant serum creatinine ≥2 mg/dL1.411.27–1.57<0.0011.371.12–1.680.002
Donor Factors      
 Donor age ≤10 years1.210.91–1.610.1880.990.53–1.850.977
 Donor age 31–40 years1.140.99–1.310.0641.230.95–1.590.125
 Donor age 41–50 years1.341.17–1.52<0.0011.711.35–2.17<0.001
 Donor age 51–60 years1.331.16–1.53<0.0011.841.44–2.36<0.001
 Donor age >60 years1.751.52–2.02<0.0011.921.47–2.50<0.001
Transplant Factors      
 Cold ischemia time ≥12 hours1.151.03–1.290.011.080.89–1.320.440
 Transplant year1.041.02–1.070.0011.000.95–1.040.872

Hepatitis C

Patient survival was significantly higher for HCV-infected recipients whose treatment included MMF at discharge compared to treatment with tacrolimus and steroids alone (P = 0.002), with 4-year survival rates of 79.5% vs. 73.8%, respectively (Figure 1B). Cox regression analysis demonstrated that MMF at discharge contributed independently to a reduction in the risk of death (HR = 0.77, P < 0.001). The strongest risk factor for death in patients with HCV was the age of the donor, with the highest risk when donors were older than 60 years, although the risk was significantly increased starting when donors were older than 40 years. Additional risk factors for death included serum creatinine ≥ 2 mg/dL, pre-transplant ICU hospitalization or hospital stay, African American race, and older recipient age (Table 2).

Graft Survival and Death-Censored Graft Survival

Patients treated at discharge with MMF, tacrolimus, and steroids had significantly higher rates of graft survival (76.4% vs. 72.9%; P < 0.0001) compared to those treated at discharge with tacrolimus and steroids alone; this finding was confirmed by the multivariable analysis (HR = 0.81, P < 0.001). Increasing donor age, underlying liver disease, pre-transplant ICU hospitalization or hospital stay, serum creatinine ≥ 2 mg/dL, African American race, cold ischemia time ≥ 12 hours, year of transplant, and older recipient age were significant risk factors for graft loss (Table 3).

Table 3. Cox Regression Analysis: Covariates for Graft Loss for Overall and Hepatitis C Transplant Populations
VariableOverallHepatitis C
HR95% CIPHR95% CIP
Treatment at Discharge      
 MMF + tacrolimus + steroids0.810.75–0.88<0.0010.840.72–0.960.013
Recipient Factors      
 Recipient age1.0041.0003–1.01<0.0321.001.00–1.010.493
 African American race1.271.12–1.45<0.0011.281.003–1.630.047
 Other race0.760.64–0.900.0020.570.39–0.820.003
 Non-cholestatic cirrhosis1.201.07–1.340.002
 Other liver disease1.581.36–1.83<0.001
 In ICU1.391.26–1.53<0.0011.221.02–1.460.027
 Hospitalized1.191.08–1.31<0.0011.160.97–1.380.098
 Pretransplant serum creatinine ≥2 mg/dL1.301.17–1.44<0.0011.341.11–1.630.003
 No CMV0.870.79–0.970.010.850.70–1.030.100
Donor Factors      
 Donor age ≤10 years1.331.03–1.730.031.100.62–1.950.744
 Donor age 31–40 years1.191.05–1.350.0091.220.95–1.550.116
 Donor age 41–50 years1.331.17–1.50<0.0011.671.34–2.09<0.001
 Donor age 51–60 years1.441.26–1.64<0.0011.861.48–2.34<0.001
 Donor age >60 years1.951.71–2.22<0.0012.211.73–2.81<0.001
Transplant Factors      
 Cold ischemia time ≥12 hours1.161.05–1.280.0051.120.93–1.340.244
 Transplant year1.051.02–1.07<0.0011.000.96–1.050.821

Death-censored graft survival was significantly increased in patients treated at discharge with MMF, tacrolimus, and steroids compared to tacrolimus and steroids alone (86.1% vs. 83.4% at 4 years; P = 0.0015). The Cox regression model for death-censored graft loss (data not shown) was similar to the model for graft loss, with the exceptions that non-cholestatic cirrhosis, serum creatinine ≥ 2 mg/dL, cold ischemia time ≥ 12 hours, and CMV status no longer were statistically significant. When censored for death, the risk of graft loss was reduced for patients treated at discharge with MMF (HR = 0.80, P < 0.001), and there was a strengthened association between increasing donor age and the risk of graft loss (HR = 1.25 [P = 0.012], 1.39, 1.64, and 2.50 [P < 0.001] for donors 31–40, 41–50, 51–60, and > 60 years of age, respectively).

Hepatitis C

Graft survival for HCV-infected patients treated at discharge with MMF, tacrolimus, and steroids was significantly better than for patients treated at discharge with tacrolimus and steroids (P = 0.024; 74.9% vs. 69.5% at 4 years); the multivariable analysis confirmed a reduced risk of graft loss associated with MMF at discharge (HR = 0.84; P = 0.013). Donor age > 40 years, serum creatinine ≥ 2 mg/dL, African American race, and pre-transplant ICU hospitalization were significant risk factors for graft loss in patients infected with hepatitis C (Table 3).

Acute Rejection

The addition of MMF at discharge to tacrolimus and steroids was associated with significantly lower rates of acute rejection compared to tacrolimus and steroids alone (29.0% vs. 33.4% at 4 years, respectively; P < 0.001), and a reduction in the risk of acute rejection, based on multivariable analysis (HR = 0.89, P = 0.002). African American race was the only other factor associated with an increased risk of acute rejection (Table 4).

Table 4. Cox Regression Analysis: Covariates for Acute Rejection in Overall Liver Transplant Population
VariableHR95% CIP
Treatment at Discharge   
 MMF + tacrolimus + steroids0.890.82–0.960.002
Recipient Factors   
 Recipient age0.990.988–0.994<0.001
 African American1.331.18–1.50<0.001
 Non-cholestatic cirrhosis0.810.74–0.89<0.001
 Other liver disease0.720.62–0.83<0.001
Transplant Factors   
 Transplant year0.970.95–0.99<0.001

Hepatitis C

HCV patients treated at discharge with MMF, tacrolimus, and steroids had significantly lower rates of acute rejection compared to patients treated with tacrolimus and steroids alone (27.3% vs. 32.1% at 4 years, P = 0.047); however, this finding did not persist in the multivariable analysis (HR = 0.93, P = 0.324). Transplantation after 1995 was associated with a reduced risk of acute rejection in patients infected with HCV (HR = 0.997, P < 0.001).

Renal Function

Mean reciprocal serum creatinine values in the two treatment groups were similar over an 8-year period, with median values of 1.01 at post-transplantation hospital discharge, and generally stabilizing at approximately 0.8 thereafter (data not shown).

Hepatitis Recurrence Leading to Graft Loss or Death

The addition of MMF at discharge to tacrolimus and steroids did not affect the risk of graft loss or death attributed to HCV recurrence (P = 0.917; event-free survival was 92.6% for MMF, tacrolimus, and steroids vs. 92.1% for tacrolimus and steroids; HR = 1.03, P = 0.843). The risk of HCV recurrence leading to graft loss or death was most notably associated with the age of the donor: the risk increased with each decade of donor age starting with donors 31–40 years, and was more than fourfold greater than the reference group (donors between 11 and 20 years of age) when donors were older than 60 years (see Figure 2). The only other significant risk factor for hepatitis recurrence was pre-transplant hospitalization (HR = 1.46, P = 0.035).

Figure 2.

Relative risk of hepatitis C recurrence leading to graft loss or death in patients based on the age of donor (*P = 0.027, **P < 0.001 vs. donor age 11–21 years).

Death Due to Infection

The overall incidence of death secondary to infection was significantly lower for patients treated at discharge with MMF, tacrolimus, and steroids compared to tacrolimus and steroids alone (5.6% vs. 6.8%, respectively; P = 0.012). Bacterial infection was the most common cause of infection-related death, and significantly more patients in the tacrolimus and steroids group died due to bacterial infection compared to patients who received these medications in combination with MMF (4.1% vs. 3.2%, respectively; P = 0.011). The incidence of death due to viral (1.6% vs. 1.7%, respectively, P = 0.775) or fungal infection (1.1% vs. 0.7%, P = 0.084) did not differ significantly for the two groups.

Rates of death due to infection were slightly lower for patients who at discharge received MMF, tacrolimus, and steroids compared to those who received tacrolimus and steroids alone (6.1% vs. 7.1% at 4 years); this difference approached statistical significance (P = 0.0508). Cox regression analysis demonstrated that MMF at discharge contributed independently to a reduced risk of death due to infection (HR = 0.80; P = 0.007). The risk of death due to infection increased with each decade of donor age (donors 31–40 years: HR = 1.46, P = 0.005; 41–50 years: HR = 1.78, P < 0.001; 51–60 years: HR = 1.73, P < 0.001, > 60 years: HR = 2.18, P < 0.001). Additional significant risk factors for death due to infection included serum creatinine ≥ 2 mg/dL (HR = 1.81, P < 0.001), pre-transplant ICU (HR = 1.75) or hospital stay (HR = 1.47, P < 0.001), liver disease classified as other (HR = 1.62, P = 0.003) or non-cholestatic cirrhosis (HR = 1.43, P = 0.004), and African American race (HR = 1.29, P = 0.049).

Hepatitis C

In patients with HCV, there were no differences between groups in the rates of death due to infection (P = 0.716; 8.3% vs. 8.8% at 4 years for MMF, tacrolimus, and steroids vs. tacrolimus and steroids, respectively). MMF at discharge did not significantly affect the risk of infectious death in the multivariable analysis (HR = 0.96, P = 0.782). The risk of death due to infection was increased significantly for patients who received organs from donors between the ages of 41–50 (HR = 2.39), 51–60 (HR = 2.27), and > 60 years (HR = 2.65; P < 0.001). Patients who were in the ICU (HR = 1.86, P < 0.001) or hospitalized (HR = 1.50, P = 0.014) prior to transplantation also had an increased risk of death due to infection.

Cyclosporine-Based Immunosuppression

A total of 3998 patients (1729 MMF, cyclosporine, and steroids; 2269 cyclosporine and steroids) were analyzed. Although there was slightly higher patient survival (78.3% vs. 76.7% at 4 years, P = 0.5) and graft survival (74.9% vs. 72.2%; P = 0.21) for patients treated at discharge with MMF, cyclosporine, and steroids compared to cyclosporine and steroids alone, these results did not reach statistical significance. The addition of MMF at discharge to cyclosporine and steroids was associated with equivalent rates of acute rejection compared to tacrolimus and steroids alone (34.8% vs. 34.4% at 4 years, respectively; P = 0.55).

Discussion

This study provides a first look at long-term outcomes of MMF used in combination with tacrolimus and corticosteroids in a large population of primary liver transplant recipients. In this analysis, we demonstrated that the addition of MMF at discharge to tacrolimus-based immunosuppression was associated with superior patient and graft survival compared to tacrolimus and corticosteroids alone both in the overall liver transplant population and in patients with underlying HCV disease. Treatment at discharge with MMF also was associated with a reduction in the risk of acute rejection in the overall liver transplant population. Although the rate of acute rejection was lower in patients with HCV, MMF at discharge did not contribute independently to a reduction in the risk of acute rejection in this subgroup of patients.

Treatment with MMF at discharge was associated with a 20% reduction in the risk of death due to infection in the overall liver transplant population and, importantly, was not associated with an increased risk of infectious death in patients with underlying HCV disease. In general, concerns over the potential impact of excessive immunosuppression in patients with HCV were not supported by these analyses. Although these concerns are based largely on the negative impact of additional immunosuppression used to treat acute cellular rejection,5, 6, 7, 8 questions regarding the potential contribution of MMF as maintenance immunosuppression in combination with other potent immunosuppressants have been raised.9, 10 The benefits of treatment with MMF at discharge observed in this study in terms of patient and graft survival in patients with HCV were not offset either by an increase in death from infection or by an increased rate of HCV recurrence leading to graft loss or death. Because of limitations of data available in the SRTR (as of October 2003), we were required to use surrogates for infection and HCV recurrence outcomes in this study. HCV recurrence leading to graft loss or death represents an underestimation of actual disease recurrence based on histological confirmation of disease, capturing only the final outcome of disease recurrence. Nevertheless, if the concern is that excessive immunosuppression would result in more aggressive recurrence, we would have expected to see differences between the two groups in terms of the rates of these outcomes, as well. Findings from this analysis support previous studies that demonstrated no significant differences in histologically defined HCV recurrence in patients treated with MMF compared to azathioprine2 or to tacrolimus and corticosteroids alone.11 Within the subgroup that received cyclosporine-based immunosuppression, treatment with MMF at discharge was associated with similar but non-significant trends toward higher rates of patient and graft survival, and equivalent rates of rejection.

A relationship between older donor age and decreased patient and graft survival in the general liver transplant population has been noted previously.12 The focus of more recent research has been on the impact of older donor allografts in patients with HCV,10, 13, 14 where accelerated post-transplantation fibrogenesis and donor age have been linked.10, 15, 16 In this study, in which we examined the impact of donor age by decade, we confirmed the contribution of older donor age to poor outcomes in both the general transplant population and in patients with HCV, as reported previously.4 The risk of death, graft loss, and death due to infection each were increased considerably (HR = 1.75, 1.95, and 2.18, respectively) in patients who received organs from donors older than 60 years; these effects were magnified in patients with HCV, with relative risks of 1.92, 2.21, 2.65 for death, graft loss, and death due to infection, respectively. In the overall population, the risk of death was statistically significantly increased starting with donors > 40 years of age. Although a significant association between graft loss, death-censored graft loss, and infectious death was observed starting when donors were older than 30 years, the relative risk tended to increase as the age of the donor increased. Nevertheless, donor age greater than 60 stood alone in terms of the degree of risk, even compared to donors 51–60 years of age. In patients who received organs from donors older than 60 years, the relative risks for death, graft loss, death-censored graft loss, and infectious death increased by 32%, 35%, 52%, and 23%, respectively, compared to patients whose donors were between 51 and 60 years old. By far, the most striking effect of donor age in this analysis was its impact on graft failure or death attributed to HCV recurrence. The risk of graft failure or death due to HCV recurrence was more than 4 times greater for patients who received allografts from donors older than 60 years compared to those who received allografts from younger donors (i.e., 11 and 20 years old).

In interpreting findings from this retrospective analysis of registry data from the SRTR, the following caveats must be considered. The most obvious limitation of this study is the inability to make any claims regarding dosing of or duration of exposure to the treatments compared. The SRTR database does not contain information on drug dosing. Furthermore, as an intent-to-treat analysis based on immunosuppression at hospital discharge, we did not attempt to analyze outcomes based on the duration of the initial immunosuppression regimen. Thus, from this study, we cannot determine whether early or continued exposure to MMF contributes to the differences in outcomes observed. In this study population, less than one-half of patients discharged on MMF remained on MMF at 12 months, a finding consistent with practice, in which MMF tends to be discontinued within 4 to 6 months following transplantation. Likewise, we cannot determine any effects that might be attributable to continuation, tapering, or withdrawal of tacrolimus or corticosteroids. Because of the historical nature of this sample, potential long-term corticosteroid use in earlier years also may have contributed to the treatment benefit in patients with HCV.17, 18

Another important potential source of bias in this study involves the contribution of differences in practice by individual transplant centers. It could be that maintenance immunosuppression with triple-drug therapy is more commonly used at better and more experienced transplant centers, thus resulting in more favorable outcomes in the MMF group. Information on individual transplant centers was not available for this study. Controlling for transplant center experience could be beneficial in the interpretation of findings from future analyses.

Another consideration regarding this analysis relates to the accuracy and completeness of registry data. A recent study demonstrated that aggregate patient survival data reported to OPTN by individual transplant centers was accurate compared to OPTN data supplemented by mortality data from the Social Security Death Master File.19, 20 Completeness of data from OPTN is determined by comparing expected follow-up to reported follow-up reports and, where appropriate, the SRTR uses supplemental sources to try to provide more complete follow-up data.19, 20 Finally, individual reporting bias by transplant centers may result in underreporting or overreporting of outcomes; however, it is reasonable to expect that this would occur equally for both treatment groups compared in this study and, therefore, would not affect overall implications of the data.

In conclusion, immunosuppression with MMF at discharge in combination with tacrolimus and steroids is associated with improved long-term patient survival, graft survival, and lower rates of acute rejection relative to tacrolimus and corticosteroids alone in primary liver transplant recipients as a whole, as well as in patients with HCV. Furthermore, the addition of MMF to tacrolimus and corticosteroids at discharge was not associated with an increased risk of death due to infectious complications, even in patients with HCV, suggesting that these patients, in general, were not overimmunosuppressed.

Acknowledgements

The data reported here have been supplied by the United Network for Organ Sharing and University Renal Research and Education Association under contract with the Department of Health and Human Services. The interpretation and reporting of these data are the responsibility of the authors and do not represent an official policy or interpretation of the United States government or any of its representatives. This work was presented in part at the 2004 American Transplant Congress Annual Meeting, Boston, Mass; the 10th Annual Congress of the International Liver Transplantation Society, Kyoto, Japan; and the 55th Annual Meeting of the American Association for the Study of Liver Diseases, Boston, Mass.

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