The Influence of Induction Therapy on Graft and Patient Survival in Patients with and without Hepatitis C after Liver Transplantation

Authors


*Corresponding author: Dilip Moonka, dmoonka1@hfhs.org

Abstract

We used the United Network for Organ Sharing Database to determine the influence of antibody-based induction therapy on patient and graft survival in orthotopic liver transplant (OLT) recipients with and without hepatitis C (HCV). We identified all initial OLT patients with HCV serology. Patients were divided into four groups: HCV positive without induction (17 362), HCV positive with induction (3479), HCV negative without induction (20 417) and HCV negative with induction (4357). Both HCV positive and negative patients who received induction did better than those who did not. For HCV positive patients, 5-year patient survival was 70.8% versus 68.7% (p = 0.004) and graft survival was 65.2% versus 62.1% (p < 0.001). For HCV negative patients, 5-year patient survival was 78.8% versus 76.7% (p < 0.001) and graft survival was 74.0% versus 70.8% (p < 0.001). On multivariate analysis, induction was associated with improved patient (HR = 0.91: p = 0.024) and graft (HR = 0.88: p < 0.001) survival in HCV positive patients and improved patient (HR = 0.87: p = 0.003) and graft survival (HR = 0.87: p < 0.001) in HCV negative patients. The benefit of induction occurred early and largely dissipated when patients with death within a year were censored. The benefit of induction therapy appeared most pronounced in patients with renal insufficiency or on organ-perfusion support at transplant.

Introduction

While the use of induction therapy, with lymphocyte depleting antibodies and interleukin-2 receptor antagonists (IL-2RA), in liver transplant recipients is less than in other organ transplant recipients; its use is growing (1). Induction therapy can be used to minimize exposure to corticosteroids (2) or to delay the introduction of calcineurin inhibitors (CNI) to facilitate recovery of renal function (3–5). Induction therapy has the potential to diminish the incidence of diabetes (2,6,7), osteoporosis, rejection (2,6,7) and renal impairment (3–5). However, the impact of these profound immunosuppressive agents on the severity of recurrent hepatitis C (HCV) after liver transplantation is not clear. While several studies have shown induction therapy (8,9) can have a deleterious effect on the progression of recurrent HCV, other studies have not shown this effect (6,10) or have shown benefit (7). The current study uses the United Network of Organ Sharing (UNOS) Public Use Database to evaluate the influence of induction therapy on patient and graft survival in both HCV infected and uninfected patients.

Materials and Methods

Patient populations

The study was approved by the institutional review board of the Henry Ford Health System. We used the UNOS Public Use Database updated as of August 20, 2008 to perform a retrospective cohort analysis. We evaluated all liver transplant recipients who were 18 years of age or older (N = 81 160) and excluded patients with prior transplant (N = 8517), multiorgan transplant (N = 3523), live donor transplant (N = 2495) and those with incomplete follow-up (N = 756). This left a total of 67 155 patients comprising Group 1.

We then divided patients in Group 1 into HCV positive and negative patients. HCV positive patients, Group 2 (N = 20 841), were those with a positive serologic test for hepatitis C testing including enzyme immunoassay, recombinant immunoblot assay or RNA. Patients with a negative test for hepatitis C made up the HCV negative cohort or Group 3 (N = 24 774). Patients who did not have any serologic results for HCV (N = 25 845) or who had conflicting results were not included in either Group 2 or 3. To guard against the possibility that the criteria for HCV positive patients were too strict, we defined a Group 4, which included patients with a UNOS code for HCV (N = 15 626). The codes for HCV included 4204 for ‘HCV postnecrotic cirrhosis’ (N = 12 141), 4206 for ‘postnecrotic cirrhosis type B and C’ (N = 296) and 4216 for ‘Laennec's cirrhosis and HCV’ (N = 3189). Data for Group 1 was collected starting September 30, 1987. Data for groups 2–4 included only patients transplanted after 1991.

All four groups were divided into patients who received induction therapy and those who did not. Antibody based-induction therapy was defined as the use of T-cell-depleting antibodies or IL-2RA agents (1). T-cell-depleting antibodies included alemtuzumab (campath-1H, Berlex Laboratories, Montville, NJ), muromonab-CD3 (OKT3, Orthobiotech, Bridgewater, NJ), horse antithymocyte globulin (ATGAM, Pharmacia and Upjohn, Kalamazoo, MI) or rabbit antithymocyte globulin (Thymoglobulin, Genzyme, Cambridge, MA). IL-2RA antibodies were basiliximab (Simulect, Novartis, East Hanover, NJ) and daclizumab (Zenapax, Roche, Nutley, NJ). The following codes were used to identify patients receiving induction: CAMPATHALEMTUZUMAB_IND, ALG_IND, ATG_IND, OKT3_IND, THYMOGLOBULIN_IND, ZENAPAX_IND and SIMULECT_IND. The database coding distinguishes between when these agents are used for induction or for rejection. Patients who were not identified in the database as having received induction were considered no induction patients.

Analysis

Within each Group (1–4), patients who received induction were compared to those who did not. The groups were compared for baseline demographic factors (Table 1) using chi-square tests for categorical variables and two-sample t-tests for continuous variables. Groups were also compared for ‘maintenance’ use of corticosteroids, mycophenolate mofetil (MMF), cyclosporin and tacrolimus at time of discharge. Kaplan–Meier (KM) estimates of patient and graft survival by induction status were calculated for each group and compared using the log-rank test (Table 2). The groups were also compared for rejection rates (Table 2) using the codes of ACUTE_REJ_EPI (acute rejection episode between transplant and discharge), REJ_ACUTE (recipient contributing cause of graft failure-acute rejection), TRTREJ6M (treated for rejection within six months) and TRTREJ1Y (treated for rejection within 1 year).

Table 1.  Patient demographics
 Group 1: AllGroup 2: HCV Pos by SerologyGroup 3: HCV Neg by SerologyGroup 4: HCV Pos by Coding
No Induc (N = 58 111)Induction (N = 9044)p-ValueNo Induc (N = 17 362)Induction (N = 3479)p-ValueNo Induc (N = 20 417)Induction (N = 4357)p-ValueNo Induc (N = 13 027)Induction (N = 2599)p-Value
  1. *Data presented as mean ± standard deviation.

  2. Hepatocellular carcinoma data are not provided for Group 4 because the database allows only one primary diagnosis per patient.

Recipient age (years)*50.7 ± 10.751.4 ± 10.2<0.00151.5 ± 7.951.5 ± 7.4NS51.2 ± 11.951.6 ± 11.8NS51.0 ± 7.850.9 ± 7.2NS
Female sex21 526 (37%)3154 (35%)<0.0014599 (26%)911 (26%)NS8656 (42%)1811 (42%)NS3530 (27%)707 (27%)NS
African-American4267 (7%)771 (9%)<0.0011386 (8%)320 (9%) 0.0171546 (8%)355 (8%)NS1013 (8%)235 (9%) 0.030
Donor age*38.0 ± 17.538.8 ± 17.0<0.00139.5 ± 17.039.2 ± 16.2NS39.4 ± 18.138.5 ± 17.4<0.00139.1 ± 16.939.1 ± 16.1NS
Follow-up in years*4.7 ± 4.53.5 ± 3.4<0.0013.6 ± 3.33.2 ± 3.1<0.0014.2 ± 3.83.7 ± 3.6<0.0013.8 ± 3.43.4 ± 3.2<0.001
Recipient diabetes8451 (19%)1577 (18%)NS2962 (18%)549 (16%) 0.0793841 (20%)836 (20%)NS2159 (17%)383 (15%) 0.033
Pre-MELD34 206 (59%)3176 (35%)<0.0018324 (48%)1108 (32%)<0.00110 814 (53%)1547 (36%)<0.0016822 (52%)884 (34.%)<0.001
MELD era23 905 (41%)5868 (65%) 9038 (52%)2371 (68%) 9603 (47%)2810 (64%) 6205 (48%)1715 (66%) 
Calculated MELD score*19.8 ± 9.220.7 ± 9.5<0.00118.7 ± 8.619.5 ± 9.2<0.00120.9 ± 9.721.9 ± 9.7<0.00119.5 ± 8.520.5 ± 9.1<0.001
Bilirubin at OLT*7.2 ± 9.87.8 ± 10.6<0.0015.5 ± 8.26.4 ± 9.7<0.0018.2 ± 10.68.9 ± 11.3 0.0015.7 ± 8.46.7 ± 9.7<0.001
Recipient CMV exposure19 676 (68%)4607 (70%) 0.0098551 (70%)1985 (72%) 0.0228726 (66%)2232 (68%)NS6252 (70%)1489 (73%) 0.030
Hepatocellular carcinoma7316 (13%)1352 (15%)<0.0013702 (21%)799 (23%) 0.0311924 (9%)399 (9%)NS   
Creatinine at OLT*1.3 ± 1.11.5 ± 1.2<0.0011.2 ± 0.91.4 ± 1.1<0.0011.3 ± 1.11.5 ± 1.2<0.0011.2 ± 0.91.4 ± 1.1<0.001
Creatinine ≥ 1.5 at OLT12 820 (22%)2828 (31%)<0.0013450 (20%)972 (28%)<0.0014740 (23%)1491 (34%)<0.0012706 (21%)799 (31%)<0.001
Dialysis at OLT1966 (4%)590 (7%)<0.001634 (4%)218 (6%)<0.0011096 (5%)346 (8%)<0.001498 (4%)185 (7%)<0.001
on organ-perfusion support4445 (8%)713 (8%)NS743 (4%)168 (5%)NS1829 (9%)445 (10%)0.010582 (4%)129 (5%)NS
Location at OLT: ICU8920 (16%)1303 (14%)<0.0011866 (11%)357 (10%)NS3531 (17%)761 (17%)<0.0011465 (11%)281 (11%)NS
Location: Hospital10 310 (18%)1347 (15%) 2766 (16%)537 (15%) 3577 (18%)632 (15%) 2170 (17%)421 (16%) 
Location: Home38 287 (67%)6368 (71%) 12 728 (73%)2585 (74%) 13 302 (65%)2964 (68%) 9391 (72%)1897 (73%) 
Cold ischemia time (hrs)*8.9 ± 4.67.9 ± 4.1<0.0018.0 ± 3.88.0 ± 4.4NS8.1 ± 3.97.8 ± 3.9<0.0018.0 ± 3.88.0 ± 4.3NS
Steroid maintenance47 198 (93%)6090 (77%)<0.00114 718 (93%)2172 (73%)<0.00117 420 (94%)3128 (79%)<0.00111 115 (93%)1667 (73%)<0.001
MMF maintenance20 175 (35%)4711 (52%)<0.0017871 (45%)1798 (52%)<0.0018954 (44%)2345 (54%)<0.0015668 (44%)1355 (52%)<0.001
Cyclosporine maintenance15 762 (27%)2250 (25%)<0.0012985 (17%)831 (24%)<0.0013657 (18%)989 (23%)<0.0012456 (19%)618 (24%)<0.001
Tacrolimus maintenance35 533 (61%)6326 (70%)<0.00112 941 (75%)2502 (72%) 0.00114 771 (72%)3115 (71%)NS9529 (73%)1876 (72%)NS
Table 2.  Patient and graft survival and rates of rejection as a function of induction
 Group 1: AllGroup 2: HCV Pos by SerologyGroup 3: HCV Neg by SerologyGroup 4: HCV Pos by Coding
No Induc (N = 58 111)Induction (N = 9044)p-ValueNo Induc (N = 17 362)Induction (N = 3479)p-ValueNo Induc (N = 20 417)Induction (N = 4357)p-ValueNo Induc (N = 13 027)Induction (N = 2599)p-Value
Patient survival
 1 year86.1%89.0%<0.00186.7%88.3% 0.00687.5%90.1%<0.00187.1%88.5% 0.024
 3 year78.2%81.4%<0.00176.2%78.8% 0.00281.6%84.4%<0.00177.4%79.6% 0.010
 5 year72.4%74.8%<0.00168.7%70.8% 0.00476.7%78.8%<0.00170.0%70.8% 0.078
Graft survival
 1 year80.9%85.1%<0.00181.8%84.8%<0.00182.5%86.2%<0.00182.3%85.3%<0.001
 3 year72.2%76.5%<0.00170.2%73.8%<0.00175.8%79.8%<0.00171.2%74.7%<0.001
 5 year66.2%69.5%<0.00162.1%65.2%<0.00170.8%74.0%<0.00163.3%65.2% 0.003
Rejection89941439NS2352516 0.0452952724<0.0011885393NS
(15.5%)(15.9%) (13.6%)(14.8%) (14.5%)(16.6%) (14.5%)(15.1%) 

In a separate analysis, patients who received individual induction agents were compared for survival to patients who did not receive induction. Three year survival numbers are reported because of the smaller groups (Table 3). Patients who received T-cell-depleting antibodies were pooled as were patients who received IL-2RA agents, and these groups were also compared to patients who did not receive induction. The p values here represent overall survival using log-rank tests.

Table 3.  Three-year patient and graft survival by specific induction medications
 Group 2: HCV Pos by SerologyGroup 3: HCV Neg by Serology
NumberPatientp-ValueGraftp-ValueNumberPatientp-ValueGraftp-Value
  1. Three-year survival is reported because of smaller patient numbers with individual agents.

  2. p-Values refer to overall differences in survival against the No Induction group using log-rank tests.

  3. HCV patients receiving Alemtuzumab were too small to interpret.

No Induction17 36276.2% 70.2% 20 41781.6% 75.8%NS
Alemtuzumab     25583.6%0.06982.1% 0.003
Antilymphocyte globulin2776.3%NS70.4%NS7884.9%NS81.5%NS
Antithymocyte globulin21284.1%0.03278.1% 0.02128689.3%0.06684.1% 0.041
OKT336678.6%NS71.2%NS49686.0%NS81.1%NS
Thymoglobulin100276.4%NS70.9%NS105485.1%0.07280.8% 0.008
All T-cell-depleting agents160878.3%NS72.3%NS215585.5%0.00581.6%<0.001
Basiliximab104477.0%NS72.7% 0.082130181.9%NS77.8%NS
Daclizumab83781.6%0.02277.7% 0.00190784.6%0.05778.5%NS
All IL-2RA agents187479.1%0.03375.0%<0.001220583.0%NS78.0%NS

The effect of induction on survival in HCV positive and negative patients was assessed using multivariable Cox regression models. Due to the large sample size, the decision was made to adjust for all of the following potential confounding factors in all models: recipient and donor age, gender, race, creatinine at transplant, pretransplant diabetes, dialysis the week prior to transplant, bilirubin at transplant, era of transplant (pre-MELD vs. MELD), organ-perfusion support and location of patient at transplant and cold ischemia time. The pre-MELD era patients received an OLT up to February 29, 2002 and the MELD era patients underwent transplant after this date. Models were fit for Groups 2, 3 and 4 (Table 4). Cytomegalovirus (CMV) status was not included because it was not a significant variable on univariate analysis and because a large number of patients had missing data. The MELD score was also not included in the final analysis because of missing data. Adjusted odds ratios and 95% confidence intervals were determined.

Table 4.  Multivariate analysis of factors affecting graft and patient survival after liver transplantation
 Group 2: HCV Pos by SerologyGroup 3: HCV Neg by SerologyGroup 4: HCV Pos by Codes
Patient (N = 15 536)p-ValueGraft (N = 15 536)p-ValuePatient (N = 17 606)p-ValueGraft (N = 17 606)p-ValuePatient (N = 11 651)p-ValueGraft (N = 11 651)p-Value
  1. Hazard ratios are with 95% confidence interval.

Recipient Age (per 10 years)1.14 (1.10–1.19)<0.0011.03 (0.998–1.07) 0.0681.27 (1.23–1.30)<0.0010. (1.07–1.13)<0.0011.13 (1.07–1.18)<0.0011.01 (0.97–1.05) 0.709
Sex: Male vs. Female0.83 (0.77–0.89)<0.0010.85 (0.80–0.90)<0.0011.09 (1.02–1.17) 0.0081.09 (1.03–1.15) 0.0050.81 (0.75–0.88)<0.0010.83 (0.77–0.89)<0.001
Race: AA vs. Caucasian1.44 (1.29–1.60)<0.0011.42 (1.30–1.56)<0.0011.43 (1.28–1.61)<0.0011.34 (1.21–1.48)<0.0011.39 (1.23–1.57)<0.0011.39 (1.25–1.55)<0.001
Donor age (per 10 years)1.17 (1.15–1.19)<0.0011.19 (1.17–1.21)<0.0011.05 (1.03–1.07)<0.0011.09 (1.07–1.10)<0.0011.18 (1.15–1.20)<0.0011.19 (1.17–1.22)<0.001
Creatinine at OLT (per 1 mg/dL)1.09 (1.05–1.12)<0.0011.07 (1.04–1.10)<0.0011.06 (1.03–1.09)<0.0011.03 (1.00–1.05) 0.0561.09 (1.05–1.12)<0.0011.06 (1.02–1.09) 0.001
Dialysis 1 week before OLT1.07 (0.90–1.27) 0.4311.07 (0.92, 1.25) 0.3731.43 (1.24–1.64)<0.0011.36 (1.20–1.54)<0.0011.04 (0.86–1.25) 0.7061.04 (0.87–1.23) 0.691
Recipient diabetes1.05 (0.88, 1.25) 0.5800.98 (0.84–1.14) 0.7611.33 (1.14–1.54)<0.0011.19 (1.04–1.36) 0.0141.00 (0.80–1.25)0.9970.97 (0.80–1.18) 0.772
Total bilirubin1.003 (0.999–1.0) 0.1301.00 (0.997–1.00)0.8200.998 (0.99–1.00) 0.2510.998 (0.99–1.00) 0.2941.00 (0.999–1.01) 0.0921.00 (0.997–1.01) 0.691
Induction: Yes vs. No0.91 (0.83–0.99) 0.0240.88 (0.81–0.95)<0.0010.87 (0.80–0.95) 0.0030.87 (0.80–0.94)<0.0010.94 (0.86–1.04) 0.2580.89 (0.82–0.98) 0.014
Organ-perfusion support at OLT1.38 (1.18–1.62)<0.0011.46 (1.27–1.68)<0.0011.43 (1.26–1.62)<0.0011.38 (1.23–1.54)<0.0011.55 (1.30–1.86)<0.0011.59 (1.35–1.86)<0.001
Medical condition at OLT
 In ICU1.16 (1.03–1.31) 0.0041.09 (0.98–1.21) 0.1091.32 (1.18–1.48)<0.0011.24 (1.12–1.37)<0.0011.15 (1.01–1.32) 0.0391.10 (0.98–1.24) 0.115
 In hospital, not ICU1.19 (1.09–1.30)<0.0011.15 (1.07–1.24)<0.0011.29 (1.18–1.41)<0.0011.21 (1.13–1.31)<0.0011.20 (1.09–1.33)<0.0011.17 (1.071.27)<0.001
 Not in hospitalReference Reference Reference Reference Reference Reference 
Cold ischemic time (per 1 hour)1.01 (1.00–1.02) 0.0131.01 (1.01–1.02)<0.0011.01 (1.01–1.02) 0.0011.02 (1.01–1.02)<0.0011.01 (1.00–1.02) 0.0431.01 (1.01–1.02)<0.001
ERA: After 2/2002 vs. before1.06 (0.98, 1.14) 0.1251.01 (0.94, 1.07)0.8440.93 (0.86–1.01) 0.0710.91 (0.85–0.98) 0.0101.06 (0.97–1.15) 0.2121.01 (0.94–1.09) 0.815

Patient and graft survival were evaluated separately for groups of particular interest (Table 5). The influence of induction and HCV was evaluated in patients with hepatocellular carcinoma (HCC) and in patients transplanted before and after implementation of the MELD allocation system. To determine if the influence of induction on outcome was most pronounced early or late after transplantation, a separate analysis was done of patients with at least 1 year of follow-up.

Table 5.  Patient and graft survival as a function of induction and HCV in specific populations
 Group 2: HCV Pos by SerologyGroup 3: HCV Neg by Serology
No InducInductionp-ValueNo InducInductionp-Value
  1. p-Values refer to overall differences in survival between No Induc and Induction groups using log-rank tests.

Patient Survival: HCC (No. = 6824)1 year86.9%87.4%NS87.7%90.2%NS
3 year71.7%76.1% 76.2%75.4% 
5-year62.6%69.7% 69.1%66.7% 
Graft Survival: HCC (6824)1 year82.9%83.5%NS84.1%88.4%NS
3-year66.4%70.6% 72.4%73.4% 
5-year57.2%63.5% 65.6%62.4% 
Patient Survival: No HCC (38 791)1 year86.7%88.5%NS87.5%90.1% 0.011
3-year77.1%79.4% 82.0%85.0% 
5-year69.7%71.3% 77.2%79.6% 
Graft Survival: No HCC (38 791)1 year81.5%85.2%0.00382.4%86.0%<0.001
3-year70.8%74.6% 76.0%80.1% 
5-year62.9%65.8% 71.0%74.6% 
Patient Survival: Pre-Meld (21 793)1 year86.7%88.2%NS87.2%90.6%NS
3-year77.1%79.9% 81.5%85.8% 
5-year69.6%72.3% 76.7%80.6% 
Graft Survival: Pre-Meld (21 793)1 year81.0%84.8%0.06081.7%85.7% 0.016
3-year70.2%74.4% 75.4%80.6% 
5-year62.3%66.3% 70.4%75.3% 
Patient Survival: MELD (23 822)1 year86.6%88.3%0.02087.9%89.9% 0.036
3-year74.9%77.9% 81.5%83.0% 
5-year67.0%69.8% 76.3%76.7% 
Graft Survival: MELD (23 822)1 year82.5%84.8%0.00783.5%86.4% 0.002
3-year69.6%73.2% 76.1%78.7% 
5-year61.0%64.5% 70.6%71.5% 
Patient Survival: at least 1 year follow-up (31 745)3-year87.9%89.2%NS93.2%93.6%NS
5-year79.2%80.3% 87.7%87.4% 
Graft Survival: at least 1 year follow-up (31 745)3-year85.7%87.0%NS91.9%92.5%NS
5-year75.9%76.9% 85.7%85.9% 

Finally, an effort was made to determine specific patient populations who benefited most from induction. The interaction between induction and specific patient characteristics was assessed in a separate Cox regression model (Table 6) for patients positive (Group 2) and negative for HCV (Group 3). Patients were divided into two exclusive populations based on variables of interest. Hazard ratios with 95% confidence intervals were calculated to determine the influence of induction therapy versus no induction on outcome within the patient population. For continuous variables, including age, creatinine, bilirubin and MELD score, patients were divided into those below and above the median. SAS version 9.2 (SAS Institute, Cary, NC) was used for all analyses.

Table 6.  Effect of induction on patient and graft survival stratified by patient populations
 Group 2: HCV Pos by SerologyGroup 3: HCV Neg by Serology
PatientGraftPatientGraft
HR (95% CI)p-ValueHR (95% CI)p-ValueHR (95% CI)p-ValueHR (95% CI)p-Value
  1. aGroup 2 median age = 51; Group 3 median age = 53.

  2. bGroup 2 median donor age = 40; Group 3 median donor age = 39.

  3. cGroup 2 and 3 median creatinine = 1.0.

  4. dGroup 2 median MELD Score = 16.77; Group 3 median MELD Score = 19.2.

  5. dGroup 2 median bilirubin = 2.8; Group 3 median bilirubin = 3.8.

Gender: Male0.93 (0.85–1.02)NS0.89 (0.83–0.97) 0.0050.93 (0.85–1.02)NS0.89 (0.83–0.98) 0.011
 Female0.91 (0.80–1.04)NS0.91 (0.81–1.02)NS0.87 (0.78–0.98) 0.0210.84 (0.76–0.93) 0.001
Race: AA0.90 (0.72–1.11)NS0.96 (0.79–1.16)NS0.71 (0.55–0.93) 0.0130.81 (0.65–1.00) 0.054
 Non-AA0.92 (0.85–0.99) 0.0360.88 (0.83–0.95)<0.0010.93 (0.86–1.00) 0.0490.88 (0.82–0.94)<0.001
Patient age: ≥ mediana1.13 (0.84–1.52)NS1.06 (0.81–1.38)NS0.97 (0.68–1.38)NS0.83 (0.59–1.17)NS
  <median0.91 (0.85–0.98) 0.0200.89 (0.83–0.95)<0.0010.91 (0.84–0.98) 0.0090.88 (0.82–0.94)<0.001
Donor age: ≥ medianb0.89 (0.81–0.99) 0.0250.88 (0.81–0.96) 0.0050.88 (0.79–0.98) 0.0190.86 (0.79–0.94) 0.001
  <median0.97 (0.87–1.08)NS0.92 (0.84–1.02)NS0.94 (0.85–1.04)NS0.91 (0.83–0.99) 0.035
Organ-perfusion support: Yes0.66 (0.49–0.87) 0.0040.64 (0.50–0.84) 0.0010.72 (0.59–0.87)<0.0010.70 (0.59–0.83)<0.001
  No0.94 (0.87–1.01)NS0.91 (0.85–0.98) 0.0070.93 (0.86–1.00) 0.0520.89 (0.83–0.96) 0.001
Medical condition: ICU0.73 (0.60–0.90) 0.0030.71 (0.59–0.86)<0.0010.75 (0.65–0.88)<0.0010.72 (0.63–0.83)<0.001
 In hospital: not ICU1.01 (0.85–1.19)NS1.02 (0.88–1.18)NS0.92 (0.77–1.09)NS0.90 (0.78–1.05)NS
 Not in hospital0.95 (0.87–1.03)NS0.91 (0.84–0.98) 0.0160.97 (0.88–1.07)NS0.93 (0.85–1.01)NS
Creat at OLT: ≥ medianc0.87 (0.79–0.95) 0.003 0.86 (0.79—0.93)<0.0010.84 (0.77–0.92)<0.0010.82 (0.76–0.89)<0.001
  <median0.95 (0.85–1.08)NS 0.92 (0.82—1.02)NS0.96 (0.85–1.09)NS0.93 (0.84–1.04)NS
Dialysis: Yes0.62 (0.46–0.81)<0.001 0.56 (0.43—0.73)<0.0010.67 (0.53–0.84)<0.0010.65 (0.53–0.80)<0.001
 No0.94 (0.87–1.01)NS0.91 (0.85–0.97) 0.0070.91 (0.84–0.98) 0.0150.88 (0.82–0.94)<0.001
Bilirubin: ≥ mediane0.91 (0.82–1.00) 0.0550.88 (0.80–0.96) 0.0040.89 (0.81–0.99) 0.0300.86 (0.78–0.94)<0.001
 <median0.94 (0.84–1.05)NS0.92 (0.83–1.01)NS0.93 (0.84–1.03)NS0.90 (0.82–0.99) 0.033
MELD score: ≥ mediand0.83 (0.72–0.94) 0.0040.82 (0.73–0.92) 0.0010.83 (0.72–0.95) 0.0090.83 (0.73–0.93) 0.002
  <median0.95 (0.83–1.10)NS0.92 (0.81–1.04)NS0.93 (0.79–1.08)NS0.88 (0.77–1.00) 0.055
Diabetes: Yes1.02 (0.71–1.48)NS0.91 (0.64–1.29)NS0.91 (0.67–1.23)NS0.86 (0.65–1.15)NS
 No0.92 (0.85–1.00) 0.0550.89 (0.83–0.96) 0.0030.89 (0.81–0.97) 0.0060.87 (0.81–0.94)<0.001
HCC: Yes0.86 (0.72–1.02)NS0.89 (0.76–1.04)NS0.92 (0.71–1.18)NS0.85 (0.67–1.07)NS
 No0.94 (0.87–1.02)NS0.90 (0.84–0.97) 0.0040.91 (0.84–0.98) 0.0130.88 (0.82–0.94)<0.001
CMV: Positive0.96 (0.87–1.07)NS0.93 (0.85–1.02)NS0.89 (0.79–0.99) 0.0380.86 (0.78–0.95) 0.003
 Negative0.85 (0.71–1.01)NS0.89 (0.77–1.03)NS0.98 (0.83–1.15)NS0.94 (0.82–1.09)NS
Transplant: Pre-MELD0.95 (0.86–1.05)NS0.91 (0.83–1.00) 0.0530.92 (0.84–1.02)NS0.90 (0.83–0.98) 0.015
  MELD0.88 (0.79–0.98) 0.0200.88 (0.80–0.97) 0.0100.88 (0.79–0.99) 0.0310.86 (0.78–0.94) 0.002

Results

Patient characteristics

Of the 67 155 patients who met inclusion and exclusion criteria, 9044 received induction (13%) and 58 111 (87%) did not. Seventeen percent of patients received induction in the HCV positive by serology (3479 of 20 841) group and the HCV positive by code group (2599 of 15 626). Induction was used in 18% of HCV negative patients (4357 of 24 774). Induction use rose from 8.5% in the pre-MELD period to 19.7% in the MELD era.

Table 1 compares patients who did not receive induction to those who did within Groups 1–4. There are no consistent differences in recipient and donor age, gender, diabetes, organ-perfusion support, patient location or cold ischemia time. The most consistent difference in those who received induction is diminished renal function. Across Groups 2–4, patients who received induction had a higher creatinine (p < 0.001), higher calculated MELD score (p < 0.001) and a greater percentage of patients with a creatinine > 1.5 mg/dL (p < 0.001) and on dialysis (p < 0.001). Patients who received induction also had a higher bilirubin. HCV patients receiving induction had higher rates of CMV and HCC. The only consistent differences in immunosuppression across groups were the increased use of MMF and the decreased use of corticosteroids in patients receiving induction. The follow-up period is shorter for patients receiving induction presumably because of its greater use in the MELD era. There are no major differences in patients HCV positive by serology (Group 2) opposed to those HCV positive by code (Group 4).

Patient survival

Liver transplant recipients with negative HCV serology had better 5-year patient (77.1% vs. 69.0%: p < 0.001) and graft survival (71.3% vs. 62.6%: p < 0.001) than those who were positive (Figure 1A, B). Patients who received induction therapy had better 5-year (Table 2) patient (74.8% vs. 72.4%: p < 0.001) and graft (69.5% vs. 66.2%: p < 0.001) survival than those who did not (Figure 1C, D). Figure 2 compares patient and graft survival as a function of both HCV and induction status. Both HCV positive and negative patients who received induction fared better than those who did not. HCV negative patients who received induction had 5-year patient survival of 78.8% versus 76.7% (Table 2) in those who did not (p < 0.001) and 5-year graft survival of 74.0% versus 70.8% (p < 0.001). For the HCV positive patients, the survival benefit appeared more pronounced for grafts than for patients (Table 2). HCV positive by serology (Group 2) patients who received induction had a 5-year patient survival of 70.8% versus 68.7% (p = 0.004) and 5-year graft survival of 65.2% versus 62.1% (p < 0.001). For HCV positive by code patients (Group 4), the survival benefit with induction was significant for graft (p = 0.003) but not patient survival.

Figure 1.

Part (A) represents 5-year patient survival in patients who are HCV negative (77.1%) and HCV positive (69.0%) and part (B) represents the 5-year graft survival (71.3% vs. 62.6%). Part (C) represents 5-year patient survival in patients who received induction (74.8%) versus those who did not (72.4%) and part (D) represents the 5-year graft survival (69.5% vs. 66.2%). The numbers for patient and graft survival are similar because the database censors patient survival after graft loss.

Figure 2.

Part (A) demonstrates the influence of HCV and induction on patient survival and part (B) on graft survival. Patients without HCV who received induction versus those who did not had 5-year patient survival of 78.8% versus 76.7% (A) and 5-year graft survival of 74.0% versus 70.8% (B). Patients with HCV with and without induction had 5-year patient survival of 70.8% versus 68.7% (A) and graft survival of 65.2% versus 62.1% (B). The numbers for patient and graft survival are similar because the database censors patient survival after graft loss.

When individual agents are compared to patients receiving no induction (Table 3), survival is higher for all induction agents but the difference in patients with HCV is significant for patient and graft survival only for antithymocyte globulin (p = 0.032 and p = 0.021) and daclizumab (p = 0.022 and p = 0.001). In HCV negative patients (Group 3), thymoglobulin is associated with improved graft survival (p = 0.008). When agents are pooled into T-cell-depleting agents and IL-2RA agents and compared to no induction patients, the IL-2RA are associated with improved patient (p = 0.033) and graft survival (p < 0.001) in HCV positive patients and T-cell-depleting agents in HCV negative patients (p = 0.005, <0.001).

Multivariate analysis

Patient characteristics previously associated with diminished patient survival after liver transplant were found to be so in our models (Table 4). These included increasing recipient and donor age, African-American race, elevated creatinine, dialysis, organ-perfusion support at transplant, location in the hospital or ICU at transplant and increased cold ischemia time. Diabetes was associated with worse outcomes in the HCV negative group but not the HCV positive groups whereas female sex was associated with improved survival in the HCV negative group but worse survival in the HCV positive group. HCV negative, but not HCV positive, patients did better in the MELD era than in the pre-MELD era. Induction was associated with improved patient and graft survival in both the HCV positive and negative by serology groups. In the HCV positive patients (Group 2), the risk of dying was 9% lower among HCV positive patients who received induction compared to those who did not with a hazard ratio (HR) of 0.91 (95% CI: 0.83–0.99) and a p-value of 0.024. For graft survival the HR was 0.88 (0.81–0.95) with a p-value <0.001. For the HCV negative group, the HR for patient survival was 0.87 (0.80–0.95) with a p-value of 0.003 and for graft survival the HR was 0.87 (0.80–0.94) with a p-value <0.001. For the HCV positive by code group (Group 4), induction was not associated with improved patient survival but was associated with improved graft survival (p = 0.014).

Patient groups of specific interest were analyzed separately to determine the influence of induction (Table 5). The p-values reflect overall survival using log-rank tests. While patients with HCC had slightly higher survival with induction, the difference was not significant. Because patients with HCV did not do better in the MELD era than in the pre-MELD era (Table 4) despite the higher use of induction in the MELD era, we evaluated patients transplanted in the MELD era separately. Both HCV positive and negative patients in the MELD era had clear improvement in both patient and graft survival with induction. A multivariate analysis similar to that in Table 4 was done only with patients in the MELD era. In this model, induction was associated with improved patient survival in HCV patients with a HR of 0.86 (0.76–0.97) and a p-value of 0.016 and improved graft survival with a HR of 0.86 (0.77–0.96) and p-value of 0.005. Induction was not associated with improved patient survival in HCV negative patients but was associated with improved graft survival with a HR of 0.89 (0.80–0.99) and a p-value of 0.047.

Figures 1 and 2 suggest that the influence of induction on patient and graft survival occurs early. To test this observation, a separate survival analysis was done censoring patients lost in the first year. Survival numbers are shown in Table 5 and a modified KM curve is shown in Figure 3. When patients with death within a year are removed, the difference in survival in patients with and without hepatitis C widens over time. However, within patients with HCV, the difference in patient and graft survival at 5 years in patients who received induction versus those who did not is stable at about 1%. In patients without HCV, induction and no induction lines are essentially superimposed.

Figure 3.

This figure is an analysis of the patient cohort with at least 1 year of survival. Part (A) demonstrates the influence of HCV and induction on patient survival and (B) on graft survival. In this analysis, patients without HCV who received induction versus those who did not had 5-year patient survival of 87.4% versus 87.7% (A) and 5-year graft survival of 85.9% versus 85.7%. Patients with HCV with and without induction had 5-year patient survival of 80.3% versus 79.2% (B) and graft survival of 76.9% versus 75.9%.

In order to identify specific patient populations within the HCV positive and negative groups who benefited most from induction therapy, patients were stratified by gender, race, recipient and donor age, organ-perfusion support, location at transplant, renal function, bilirubin, MELD score, diabetes, HCC and CMV status and era of transplant (Table 6). Hazard ratios were computed to demonstrate the influence of receiving induction versus not receiving induction within these populations. In both the HCV positive and negative groups, the patient populations who had the most striking benefit from induction therapy were those with renal insufficiency and those who were on organ-perfusion support or in the ICU at time of transplant. HCV positive patients on dialysis who received induction had a HR for patient survival of 0.62 (p < 0.001), those with a creatinine above median had a HR of 0.87 (p = 0.003) and those with a calculated MELD score above median had a HR of 0.83 (p = 0.004). HCV positive patients on organ-perfusion support who received induction therapy had a HR for patient survival of 0.66 (p = 0.004) and those in the ICU at transplant had a HR of 0.73 (p = 0.003). In HCV positive patients, the presence of CMV, HCC or diabetes did not appear to have an impact on the benefit of induction. The benefit of induction therapy in HCV positive patients, but not negative patients, seemed more pronounced in the MELD era for both patient and graft survival.

Discussion

Antibody-based induction therapy has the potential to delay introduction of CNIs, minimize steroid use and decrease rejection. Induction has grown in popularity in liver transplantation but its use is still below the level of other organ transplants. The rate of induction use in liver transplant has increased steadily from 7% in 1997 to 21% in 2003–2004 but is still below the 72% use in kidney transplantation (1). Perhaps part of the reluctance to use induction therapy in OLT is the concern that it might exacerbate the severity of recurrent HCV with subsequent graft or patient loss.

Two early reports suggested just that. A report by Rosen et al. in 1997 (8) found that of 19 HCV positive patients who received OKT3, 26.3% had cirrhosis at 2 years compared to 6% in 33 matched historic controls. It should be noted OKT3, in this analysis, was used for steroid resistant rejection and not for induction. It is possible that some patients had either co-existing recurrent HCV at the time of OKT3 therapy or recurrent HCV instead of rejection. In addition, the OKT3 was administered at least three months after transplant. HCV RNA levels are low in the peri-transplant period (11) but increase three months later. Perhaps antibody-based immunosuppression is tolerated when HCV RNA levels are low but not when high. Nelson et al. (9) also found accelerated disease in 21 HCV positive patients who received daclizumab induction. Those patients had higher HCV RNA levels and bridging fibrosis or cirrhosis at 1 year than historic matched controls who did not receive induction (45% vs. 26%).

Several more recent, prospective, randomized trials showed no adverse outcomes in patients with HCV who received induction (6,7,10). A United States multicenter trial of HCV patients compared daclizumab induction without steroids to tacrolimus and steroid based regimens and found less rejection and comparable 1 year survival (6). An international multicenter trial compared 65 HCV positive patients randomized to receive basiliximab induction to 69 patients who did not (7). Patients receiving basiliximab did better when ‘problem free transplant’ was incorporated as an endpoint. Problem free transplant includes the absence of graft or patient loss, acute rejection or recurrent HCV.

The current study supports the hypothesis that antibody-based induction is not associated with worse outcomes in HCV patients. In fact, both OLT recipients with and without HCV, who received induction, had remarkably similar improved graft and patient survival at 5 years (Figure 2). This is despite the fact that demographic data suggest induction therapy was administered preferentially to patients with diminished renal function, higher bilirubin and MELD scores and higher rates of HCC and CMV (Table 1). On multivariate analysis, induction was associated with improved outcomes in all patients and in those who were HCV positive. The benefit appeared early and was slightly more pronounced for graft survival than patient survival. The benefit of IL-2RA seemed more prominent in patients with HCV and the benefit of T-cell-depleting agents appeared more prominent in uninfected patients (Table 3).

While the current analysis is neither randomized nor prospective, its major advantages over previous studies are the number of patients evaluated and the length of follow-up. While the survival advantage in patients who received induction in this analysis is significant, the percent difference in 5-year survival of 2–3% is relatively small and is unlikely to have been recognized in studies of several hundred patients as opposed to 67 155 patients. As a comparison, numerous single center studies did not demonstrate a survival difference in liver transplant patients with HCV compared to uninfected patients (12–14), but an analysis of the UNOS database clearly did (15). In addition, most randomized studies of induction therapy focus on outcomes at 1 year after transplant or less (2,5,6,7). The current analysis allows comparisons at 5 years. Finally, the size of the UNOS database facilitates a relatively robust multivariate analysis that allows for the isolation of confounding patient variables and the identification of pertinent ones.

There are pitfalls to the analysis. A large number of patients were excluded because of the absence of HCV serologic data. This group was analyzed for UNOS diagnostic codes. Of these, 16.8% carried a primary diagnosis of HCV and are included in Group 4. 15.8% had alcoholic cirrhosis, 12.6% had cryptogenic cirrhosis and 8.0% had primary biliary cirrhosis. No other diagnosis exceeded 5%. In addition, HCV antibody markers may be false positive. Here we relied on the precedent of Forman et al. (15) who argue that a more stringent laboratory definition of HCV is less error-prone and that the positive predictive value of a positive EIA in the transplant population is high. However, we did do an alternative analysis of patients with HCV using UNOS codes (Group 4). In this group, patient survival was no longer improved in patients who received induction therapy (Table 4) on multivariate analysis. However, even in this group, graft survival was improved in patients who received induction (p = 0.014) and there was no evidence induction was associated with a worse outcome.

The mechanisms for improved outcomes in patients receiving induction therapy are not clear but the data point to several possibilities. The data suggest the benefit of induction therapy occurs relatively early after transplant. If the survival data is censored for patients who die within the first year (Table 5, Figure 3), the difference in survival, in patients receiving induction, largely dissipates. This suggests the influence of induction on survival is not primarily due to recurrent hepatitis C. When patient and graft loss is due to recurrent HCV, as is presumably the case when HCV positive and negative patients are compared, differences in survival widen over time (Figure 1A, B).

One group of patients that may explain the early benefit from induction therapy are those with renal insufficiency. HCV positive patients with a creatinine above median (Table 6) benefit from induction with a HR of 0.87 (p = 0.003) and those on dialysis have a striking benefit with a HR of 0.62 (p < 0.001). Several studies have suggested that antibody based induction can improve outcomes in patients with renal insufficiency (3–5) presumably by delaying the introduction of CNI. The current data supports that hypothesis and suggests the benefit of induction in patients with renal insufficiency may be especially pronounced in patients with HCV.

Another group of patients that may explain the early benefit of induction are those in the ICU or on organ-perfusion support at transplant. These patients have marked beneficial hazard ratios associated with induction therapy (Table 6). Antibody-based induction directly targets T lymphocytes. Because T lymphocytes mediate a myriad of immune and inflammatory pathways, it is likely that induction therapy has protean effects that are not fully appreciated. Patients in the ICU, on organ-perfusion support, may have a variety of ongoing inflammatory processes mediated by acute phase reactants, cytokines or microbial endotoxins that are blunted by induction therapy. While this hypothesis is speculative, there is evidence that induction, with rabbit antithymocyte globulin, diminishes lymphocyte mediated reperfusion injury and organ apoptosis (16) by blocking adhesion and activation markers and the resulting cytokine cascade.

Acute rejection is associated with poor outcomes in patients with hepatitis C (12) and some studies have suggested that induction reduces the incidence of rejection (2,6,7). We actually observed an increased incidence of rejection in both HCV positive and negative by serology patients who received induction (Table 2). However, studies have suggested that induction therapy has a more pronounced effect on the incidence of moderate to severe rejection than mild rejection (2,6). It is possible that severe rejection has a more pronounced influence on recurrent HCV than mild rejection and that induction therapy diminishes these more severe episodes. The current analysis does not distinguish between the severity of rejection episodes.

In summary, utilizing the UNOS Public Use Database, antibody-based induction therapy is not associated with worse patient and graft survival in either patients with HCV or without HCV. On multivariate analysis, induction is associated with improved outcomes in both hepatitis C positive and negative patients. The benefit persisted in HCV patients in the MELD era. The benefit appeared early and was slightly more prominent for graft survival than patient survival. The benefit of induction therapy on survival was restricted to those with impaired renal function at the time of transplant, defined either by an elevated creatinine or the need for dialysis.

Acknowledgments

This work was supported in part by Health Resources and Services Administration contract 234–2005-370011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. There are no funding sources or conflicts of interest to disclose.

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