For the HCV-3 Study Group.
Corticosteroid-free immunosuppression with daclizumab in HCV+ liver transplant recipients: 1-year interim results of the HCV-3 study†
Article first published online: 29 OCT 2007
Copyright © 2007 American Association for the Study of Liver Diseases
Volume 13, Issue 11, pages 1521–1531, November 2007
How to Cite
Klintmalm, G. B.G., Washburn, W. K., Rudich, S. M., Heffron, T. G., Teperman, L. W., Fasola, C., Eckhoff, D. E., Netto, G. J. and Katz, E. (2007), Corticosteroid-free immunosuppression with daclizumab in HCV+ liver transplant recipients: 1-year interim results of the HCV-3 study. Liver Transpl, 13: 1521–1531. doi: 10.1002/lt.21182
See Editorial on Page 1500
- Issue published online: 29 OCT 2007
- Article first published online: 29 OCT 2007
- Manuscript Accepted: 12 MAR 2007
- Manuscript Received: 4 JAN 2007
This work is a 1-yr interim analysis of a prospective, randomized, multicenter trial evaluating the effect of corticosteroid-free immunosuppression on hepatitis C virus–positive (HCV+) liver transplant recipients following liver transplantation (LT). Patients received tacrolimus and corticosteroids (Arm 1; n = 80); tacrolimus, corticosteroids, and mycophenolate mofetil (MMF) (Arm 2; n = 79); or daclizumab induction, tacrolimus, and MMF (Arm 3; n = 153). At 1 yr, 64.1%, 63.4%, and 69.4% of patients achieved the composite primary endpoint of freedom from rejection, freedom from HCV recurrence, and freedom from treatment failure, respectively. Excellent patient and graft survival did not differ significantly among treatment arms. Freedom from HCV recurrence at 1 yr was 61.8 ± 6.2%, 60.1 ± 6.1%, and 67.0 ± 4.3% in Arms 1, 2, and 3, respectively (P = not significant). Freedom from rejection was significantly higher in Arm 3 compared to Arm 1 (93.0 ± 2.2% vs. 81.9 ± 4.4%; P = 0.011). Multivariate analysis identified acute rejection (hazard ratio = 2.692; P = 0.001) and donor age (hazard ratio = 1.015; P = 0.001) as significant risk factors for HCV recurrence. HCV recurrence was not influenced by recipient demographics, HCV genotype, or immunosuppression. In conclusion, these results suggest that a corticosteroid-free regimen of tacrolimus and MMF following daclizumab induction is safe and effective in HCV+ liver transplant recipients. Liver Transpl 13:1521–1531, 2007. © 2007 AASLD.
Chronic hepatitis C virus (HCV) infection is the most prevalent indication for liver transplantation (LT), accounting for at least 40% of all transplants performed in the United States.1, 2 Epidemiologic data suggest that, between 2000 and 2020, the incidence of HCV-associated cirrhosis will double, increasing the demand for LT through the year 2040.1, 3
Following transplantation, HCV reinfection of the liver allograft is universal, with HCV ribonucleic acid (RNA) detectable as early as 48 hours posttransplantation.4 Among nontransplant patients, cirrhosis develops in fewer than 20% of patients after 20 yr.5, 6 Following LT, the course of HCV disease is accelerated, with 20 to 40% of liver transplant recipients developing cirrhosis by 5 yr,7 and with median interval to the development of cirrhosis as short as 10 yr.5, 8–11
Several donor, recipient, and viral factors correlate with HCV disease severity following transplantation. Recipients of living donor grafts and those with high pre- or posttransplantation viral load may be more likely to develop severe recurrent disease.12 Patients infected with genotype 1 HCV and those who develop cytomegalovirus infection are also at increased risk for severe disease recurrence.12
Immunosuppressive agents, specifically corticosteroids and muromonab CD3, have also been identified as possible risk factors for HCV recurrence.13–15 Conflicting reports obscure the value of mycophenolate mofetil (MMF) in HCV+ liver transplant recipients.16–18 Few prospective, randomized clinical studies have determined the effects of different immunosuppressive regimens on the course of posttransplantation HCV disease.19–22
The HCV-3 study, a randomized, prospective, multicenter, open-label clinical trial, investigated the use of daclizumab in a corticosteroid-free maintenance regimen of tacrolimus and MMF following LT in patients with chronic hepatitis C. Recently, we reported the pharmacokinetics and pharmacodynamics of daclizumab in a subset of patients enrolled in the HCV-3 multicenter study.23 Based on the novel dosing used in the study, our findings confirmed high serum levels of the antibody in these patients, leading to effective therapeutic suppression of CD25+ T cells for at least 30 days following treatment.
Herein we report the results of the entire HCV-3 study at 1 yr of follow-up.
PATIENTS AND METHODS
This open-label, randomized, prospective, multicenter study compared the safety and efficacy of 3 immunosuppressive treatment regimens in HCV+ liver transplant recipients. The protocol was approved by the institutional review boards at each of the 18 participating centers across the United States. Follow-up is designed for 2 yr, with interim outcome assessment at 90 days and 1 yr. This report presents 1-yr interim results.
Primary adult liver transplant recipients (≥18 yr of age) with end-stage liver disease caused by chronic HCV infection were enrolled in the study. Prior to enrollment, each patient signed a consent form approved by each institutional review board.
Patients were excluded from the study if they had previously received or were receiving an organ transplant other than a liver. Those who received a liver from a hepatitis B core antibody–positive or a hepatitis C antibody–positive donor, or from an ABO blood group–incompatible organ donor, were also excluded. Patients with fulminant liver failure, positive for hepatitis B surface antigen, and those seropositive for human immunodeficiency virus were deemed ineligible. Patients restricted to the intensive care unit and those who could not be administered a calcineurin inhibitor within the first 72 hours following transplantation were not enrolled in the study.
A total of 312 patients were enrolled and randomized in a 1:1:2 ratio among 3 treatment groups: Arm 1: tacrolimus (Prograf; Astellas Pharma US, Deerfield, IL) and corticosteroids; Arm 2: tacrolimus, corticosteroids, and MMF (CellCept; Hoffmann-LaRoche, Nutley, NJ); and Arm 3: daclizumab (Zenapax; Hoffmann-LaRoche) induction, tacrolimus, and MMF (Fig. 1). A total of 80 patients were enrolled in Arm 1, 79 in Arm 2, and 153 in Arm 3. Randomization was stratified according to deceased or live donor source.
Tacrolimus was administered to patients in all treatment arms. The first dose was administered within 72 hours after transplantation. Target whole blood trough levels were 10–15 ng/mL within 72 hours of the initial dose and for the first 6 weeks, and 5–12 ng/mL thereafter. Toxicities were first managed by reducing the tacrolimus dose to the lower end of the desired target range. Lower target ranges may have been adhered to in cases of persistent toxicity.
Corticosteroids were administered to patients in Arms 1 and 2. The first dose was administered in the operating room (500–1,000 mg methylprednisolone or hydrocortisone IV or dexamethasone IV at equivalent doses), followed by an oral corticosteroid taper to 10 mg/day by day 30, and to 5 mg/day by day 90 following transplantation. Further corticosteroid tapering or discontinuation was permitted after 90 days, according to institutional protocol. No steroids were given to patients in Arm 3.
MMF was administered to patients in Arms 2 and 3, intravenously or orally at a dose of 2–3 gm/day in 2 divided doses for the duration of the study. The initial dose was given within the first 12 hours following transplantation. MMF dose adjustment for adverse events, including leukopenia (≤3,000 leukocytes/μL) and gastrointestinal complaints, was permitted.
Only patients in Arm 3 received daclizumab using a novel regimen of 3 doses. Dose calculations were based on the patient's pretransplantation weight. The first dose (2 mg/kg) was administered in the intensive care unit, within 12 hours of transplantation. Patients received the second dose on postoperative day 3 (2 mg/kg), and the third dose (1 mg/kg) on day 8.
Intravenous/oral ganciclovir/valganciclovir was administered for a minimum of 7 days posttransplantation as prophylaxis against cytomegalovirus infection. The same minimum of 7 days cytomegalovirus prophylaxis was given following rejection treatment. After 7 days, all patients were managed according to institutional protocol. No cytomegalovirus prophylaxis was given to the sero-negative donor/sero-negative recipient (D-/R-) combination. Prophylaxis for Pneumocystis carinii, fungal, and other bacterial infections was administered uniformly to all patients, according to institutional protocol. Hepatitis C antiviral prophylaxis was not permitted.
Assessment and Treatment of Acute Rejection
Biopsies were performed when 3 consecutive test results, prior to alteration in treatment, revealed serum aspartate aminotransferase/alanine aminotransferase levels elevated 1.5 times above the baseline or serum bilirubin elevated by >0.3 mg/dL. Histologic evaluation of rejection was done according to the Banff schema for liver rejection24 and defined for this study as grade ≥ 2 and rejection activity index score ≥4 (moderate and severe rejection). Mild rejection episodes were recorded but not used for analyzing rejection rate. All biopsies were read and evaluated by pathologists in the local participating centers for this interim 1-yr analysis. A central pathologist histological evaluation is to be obtained on all biopsies for the final 2-yr study analysis.
Acute rejection was treated by an intravenous bolus of 1.0 gm methylprednisolone followed by a conventional steroid taper of intravenous methylprednisolone or oral prednisone. Following treatment of rejection, further tapering of corticosteroids was left to investigator discretion, with the goal to return patients to their original immunosuppressive regimen as soon as possible. Mild rejection episodes were treated in a step process, first increasing tacrolimus trough levels and then increasing or adding antimetabolite (MMF or azathioprine), with no use of corticosteroids.
Corticosteroid-resistant rejection was defined as a biopsy-proven rejection episode treated with corticosteroids that led to repeat biopsy showing unchanged or worsening rejection. Antilymphocyte antibody therapy was permitted for treatment of corticosteroid-resistant rejection.
Assessment and Treatment of HCV Recurrence
Histological confirmation of HCV recurrence was defined in liver biopsy specimens as Batts-Ludwig25 fibrosis stage ≥2 or Batts-Ludwig inflammation grade ≥3 within the first yr. All biopsies were read and evaluated by pathologists at the local participating centers for this interim 1-yr analysis. A central pathologist histological evaluation is to be obtained on all biopsies for the final 2-yr study analysis. Protocol biopsies were performed after reperfusion, on day 90 and on day 365 following transplantation. Additional biopsies were performed as clinically indicated and the results of these biopsies were included in the analysis of the rate of HCV recurrence.
For the analysis of the primary endpoint, HCV recurrence was defined as histological confirmation of hepatic injury from HCV (as outline in the previous paragraph), resulting in the initiation of HCV antiviral therapy. Only the histological confirmation was used for all other analyses of HCV recurrence. Progression of the Batts-Ludwig stage or grade on liver biopsies obtained between day 90 and day 395 posttransplantation was defined as follows:
Stable/Regressive: no change or a lowering of Batts-Ludwig stage or grade
Progressive: 1 level increase in Batts-Ludwig classification.
Aggressive: ≥2 level increase in Batts-Ludwig classification.
The time to HCV recurrence was analyzed separately for Batts-Ludwig stage or grade criteria, based on the day the biopsy was obtained. The time to recurrence was defined as:
Early: day 0 to day 100
Intermediate: day 101 to day 180
Late: day 181 to day 395.
Currently, a log change in HCV RNA is reported as a parameter of viral replication.26 In the present study, HCV RNA serum levels were reported at baseline (prior to transplantation), and at day 90 and day 365 posttransplantation. Levels, which did not affect patient management decisions, were defined as:
Low: HCV RNA ≤2.4 million IU/mL
Intermediate: HCV RNA >2.4 to 4.7 million IU/mL
High: HCV RNA >4.7 million IU/mL
Log change analysis of HCV RNA over 2 yr will be part of the final study analysis.
A central laboratory analyzed samples. Treatment of HCV recurrence was based on institutional protocol.
New onset diabetes mellitus was defined as the use of insulin for ≥30 days within the first yr posttransplantation, among patients not having active diabetes prior to transplantation. New onset of hypertension or hyperlipidemia at baseline was defined as patients who presented either condition at the 1-yr follow-up visit and did not have the condition at baseline.
Data was analyzed by intention to treat. The primary endpoint was satisfied if all of the following criteria were met: freedom from treatment failure (death, graft loss, or study withdrawal by day 365), freedom from rejection, and freedom from HCV recurrence.
SAS for Windows (version 8.2; SAS Institute, Cary, NC) statistical software was used. All statistical tests were conducted at the 5% level of significance. However, for the primary endpoint, to maintain an overall 5% type 1 error rate, the significance level was adjusted for each of the pair wise comparisons between treatment groups. Therefore, significance was concluded when the P value was <0.013.
Demographic data is summarized using descriptive statistics. Continuous data are presented as the mean ± standard deviation (SD). Categorical data are presented as counts and percentages.
The Kaplan-Meier product-limit method was used to analyze patient and graft survival, time to first acute rejection and time to recurrence of HCV disease.27 The log-rank statistic was used to compare overall results among treatment arms, stratified by donor transplant source.28 For patient survival, living patients were censored at the time of last known follow-up. For graft survival, living patients with functioning allograft were censored at the time of last known follow-up; an allograft was considered lost in the event of death with function or retransplantation. For rejection, living patients and patients who died without acute rejection were censored at the time of last known follow-up or death, respectively. For the recurrence analysis, patients were censored at the last known time at which a biopsy showed no recurrence of hepatitis C infection, if the biopsy was conducted outside of a protocol biopsy visit window. If the last biopsy showing no recurrence was conducted within a protocol biopsy visit window, then the patient was censored on the last day of that visit window.
A Cox proportional hazards model29 was used to assess the impact of known or suspected risk factors on HCV recurrence at day 395 (1 yr + 30 day visit window). Donor organ source was included in the Cox model as a stratification variable. Candidate covariates included treatment group, donor and recipient age and gender, recipient race, HCV genotype, HCV viral load at baseline and at day 90, acute rejection, and antibody therapy. HCV viral load, rejection, and antibody therapy were included in the model as time-dependent covariates.
Stepwise regression began with all covariates included in the model, followed by backward elimination of covariates without significant contribution (P > 0.10). Treatment group and donor organ source were included in all models.
Demographics and Disposition
Recipient and donor characteristics are summarized in Table 1. The majority of recipients were men, infected with HCV genotype 1.
|Arm 1 (tacrolimus + corticosteroids) (n = 80)||Arm 2 (tacrolimus + corticosteroids + MMF) (n = 79)||Arm 3 (daclizumab + tacrolimus + MMF) (n = 153)|
|Male (%)||56 (70.0)||60 (75.9)||109 (71.2)|
|Female (%)||24 (30.0)||19 (24.1)||44 (28.8)|
|Recipient age, mean ± SD (yr)||51.7 ± 7.2||51.4 ± 7.8||51.5 ± 7.4|
|Recipient race and ethnicity|
|Caucasian (%)||59 (73.8)||57 (72.2)||106 (69.3)|
|Hispanic (%)||14 (17.5)||15 (19.0)||24 (15.7)|
|Oriental (%)||1 (1.3)||1 (1.3)||6 (3.9)|
|African American (%)||4 (5.0)||3 (3.8)||16 (10.5)|
|Other (%)||2 (2.5)||3 (3.8)||1 (0.7)|
|Recipient weight, mean ± SD (kg)||81.8 ± 16.7||87.0 ± 16.9*||86.1 ± 18.4|
|HCV genotype||n = 73||n = 70||n = 135|
|HCV-1 (%)||54 (74.0)||59 (84.3)||105 (77.8)|
|Non HCV-1 (%)||19 (26.0)||11 (15.7)||30 (22.2)|
|MELD score, mean ± SD||20.5 ± 6.6||21.5 ± 6.2||21.0 ± 7.3|
|Deceased donor (%)||72 (90.0)||68 (86.1)||135 (88.2)|
|Living donor (%)||8 (10.0)||11 (13.9)||18 (11.8)|
|Cold ischemia time, median (range)(hours)||7.5 (0.5–12.6)||7.1 (0.9–18.8)||6.9 (0.5–14.4)|
|HLA mismatch, mean ± SD (deceased donor)||5.2 ± 0.9||4.9 ± 0.9||4.7 ± 1.0†|
|Donor age >55 yr (%)||19 (23.8)||11 (13.9)||30 (19.6)|
|Male (%)||53 (66.3)||57 (72.2)||82 (53.6)‡|
|Female (%)||25 (31.3)||22 (27.8)||67 (43.8)|
|Unknown (%)||2 (2.5)||0||4 (2.6)|
There were no significant differences in recipient gender, recipient or donor age, mean Model for End-Stage Liver Disease score or cold ischemia time among patients in Arms 1–3. Racial and ethnic distribution of patients was equivalent.
Recipient weight was significantly higher in Arm 2 compared to Arm 1 (P = 0.045), and there were significantly fewer human leukocyte antigen mismatches in patients receiving deceased donor organs in Arm 3 compared to Arm 1 (P = 0.011). There were proportionately more male donors in Arm 2 (72.2%) compared to Arm 3 (53.6%; P = 0.012). There were significantly more patients with blood type AB in Arm 1 (13.8% vs. 2.5% and 3.3% in Arms 2 and 3, respectively), and significantly more recipients with blood type B in Arm 3 (12.4% vs. 5.0% and 6.3% in Arms 1 and 2, respectively). The difference in distribution of recipient blood type between Arm 1 and Arm 3 was statistically significant (P = 0.015).
There were no withdrawals from Arm 1. Over the first yr of follow up, 4 patients withdrew from Arm 2, and 7 from Arm 3. In Arm 2, 3 of the 4 patients withdrew consent, while 4 of 7 patients in Arm 3 were lost to follow-up (Fig. 1).
Exposure to Maintenance Immunosuppressive Agents
Doses of all maintenance immunosuppressive agents and tacrolimus trough levels are presented in Table 2. At day 8 following transplantation, tacrolimus dosing was significantly lower in Arm 3 compared to Arms 1 and 2, and remained significantly lower, compared to Arm 1, at day 30 following transplantation. By 1 yr, there were no significant differences in mean tacrolimus dose among treatment arms. There were no significant differences in dosing of the other maintenance agents at any time following transplantation.
|Arm 1 (tacrolimus + corticosteroids) (n = 80)||Arm 2 (tacrolimus + corticosteroids + MMF) (n = 79)||Arm 3 (daclizumab + tacrolimus + MMF) (n = 153)|
|Mean tacrolimus dose (mg/day ± SD)|
|Day 8||9.4 ± 4.2||9.9 ± 6.0||7.2 ± 5.1*|
|Day 30||8.5 ± 5.0||7.8 ± 4.8||7.2 ± 5.5†|
|Day 90||6.9 ± 4.1||7.1 ± 5.2||6.4 ± 3.7|
|Day 365||4.2 ± 2.4||4.7 ± 3.7||4.8 ± 3.2|
|Mean tacrolimus trough level (ng/mL ± SD)|
|Day 8||10.0 ± 3.7||10.9 ± 6.6||10.8 ± 5.0|
|Day 30||12.3 ± 5.8||10.8 ± 4.4||11.1 ± 4.6|
|Day 90||9.7 ± 4.7||10.9 ± 5.7||9.7 ± 3.7|
|Day 365||8.4 ± 4.7||8.7 ± 3.1||9.1 ± 4.3|
|Mean MMF dose (mg/day ± SD)||n = 8||n = 48||n = 93|
|Day 365||1750.0 ± 462.9||1458.3 ± 581.9||1435.5 ± 608.9|
|Oral corticosteroid dose (mg/day ± SD)||n = 26||n = 25||n = 7‡|
|Day 365||5.1 ± 5.9||5.9 ± 8.0||7.1 ± 6.2|
There was no significant difference in the achievement of the primary efficacy endpoint, namely, freedom from rejection, freedom from HCV recurrence, and freedom from treatment failure (defined as death, graft loss, or study withdrawal), among patients in the 3 treatment arms (Fig. 2).
Patient and graft survival at 1 yr were equivalent (Fig. 2). A total of 8 patients in Arm 1, 8 in Arm 2, and 11 in Arm 3 died within the first yr of follow-up. Overall, HCV recurrence was listed as the primary cause of death for 2 patients, 1 each in Arms 1 and 3. Massive intraoperative coagulopathy, possibly due to pulmonary embolism, was listed as cause of death in 1 patient in Arm 3. Two patients in Arm 3 developed sepsis, and uncontrolled gastrointestinal bleeding was responsible for the death of 1 patient in Arm 1. One patient in Arm 2 succumbed to a cerebrovascular accident.
Graft loss occurred in 12, 9, and 15 patients in Arm 1, Arm 2, and Arm 3, respectively. The principal causes of graft loss were patient death, hepatic artery thrombosis, recurrent HCV, bile duct complications, liver failure, and infection. There were no significant differences among treatment arms.
From a total of 867 biopsy specimens collected from 312 patients, 40 specimens from 22 patients were missing Batts-Ludwig staging or grading data. Therefore, we evaluated 827 samples from 290 patients.
Kaplan-Meier time-to-event analysis revealed no significant difference in freedom from HCV recurrence across treatment arms (Fig. 3). At 1 yr, freedom from recurrent HCV was 61.8 ± 6.2%, 60.1 ± 6.1%, and 67.0 ± 4.3% in arms 1, 2, and 3, respectively (P = not significant). There was no significant effect of deceased or living donor organ source on HCV recurrence (data not shown).
At baseline, the vast majority of patients in each treatment arm had low (≤2.4 × 106 IU/mL) serum titers of HCV RNA (Table 3). On day 90 the distribution of the HCV RNA titers changed, with about one-half of the patients with low titer and about one-third with high HCV RNA titer (Table 3). No difference between the 3 treatment arms was observed in the HCV RNA titer. By day 365, there were no significant differences in the proportion of patients with high titers of HCV RNA (>4.7 × 106 IU/mL), aggressive progression of HCV disease, or in the timing of HCV recurrence (Table 3), although the percentage of recipients with low titers of HCV decreased markedly as compared to pre-orthotopic LT values. This was consistent across all 3-treatment arms.
|Arm 1 (tacrolimus + corticosteroids)||Arm 3 (daclizumab + tacrolimus + MMF)|
|HCV RNA levels (IU/mL)|
|Low: ≤2.4 × 106 n (%)||72 (98.6)||137 (98.6)|
|Low: ≤2.4 × 106 (%)||48.1||56.1|
|Intermediate: >2.4 × 106 to 4.7 × 106 (%)||17.3||15.3|
|High: >4.7 × 106 (%)||34.6||28.6|
|Low: ≤2.4 × 106 (%)||67.9||68.4|
|Intermediate: >2.4 × 106 to 4.7 × 106 (%)||15.1||11.2|
|High: >4.7 × 106 (%)||17.0||20.4|
|Batts-Ludwig progression*||Grade (n = 24)||Stage (n = 24)||Grade (n = 24)|
|Timing of HCV recurrence∥||Grade (n = 63)||Stage (n = 36)||Grade (n = 54)|
|Early: day 0 to day 100 (%)||65.1||36.1||70.4|
|Intermediate: day 101 to day 180 (%)||14.3||5.6||14.8|
|Late: day 181 to day 395 (%)||20.6||58.3||14.8|
A Cox proportional hazards model was used to identify the risk factors for HCV recurrence. Data were analyzed with all covariates (full model; see Patients and Methods), and with backward elimination of covariates not contributing significantly to the regression model (P > 0.010). In both models, acute rejection and donor age emerged as highly significant risk factors for HCV recurrence (Table 4), although the effect of donor age was not nearly as profound as that of acute rejection. African American race approached statistical significance in the backward elimination model. There was no effect of maintenance immunosuppressive therapy or antibody treatment for rejection on HCV recurrence in either model.
|Hazard ratio (95% CI)||P value|
|Full Cox proportional hazards model|
|Acute rejection||2.692 (1.520–4.768)||0.001|
|Donor age (yr)||1.015 (1.000–1.030)||0.048|
|Backward elimination model|
|Acute rejection||2.547 (1.458–4.449)||0.001|
|Donor age (yr)||1.014 (1.000–1.027)||0.050|
|African American race||1.878 (0.971–3.633)||0.061|
Freedom from Rejection
Compared to patients randomized to treatment Arm 1, a significantly greater proportion of those in Arm 3 remained free from rejection through 1 yr (81.9 ± 4.4% vs. 93.0 ± 2.2%; P = 0.011; Fig. 4). The statistical significance of this finding was retained when the combined results from Arms 1 and 2 were compared with those in Arm 3 (P = 0.033). No severe rejection episodes were recorded in Arm 3, compared to 10.5% (2/19 episodes) in Arm 1 and 25.0% (3/12 episodes) in Arm 2. Mild rejection episodes were recorded in 26.3%, 33.3%, and 52.4% in Arms 1, 2, and 3, respectively (P = not significant). Donor source had no statistically significant effect on the incidence of acute rejection.
Laboratory Values at 1 Yr
Results of kidney and liver function tests are reported in Table 5. Median serum creatinine values were 1.1, 1.1, and 1.2 mg/dL in Arms 1, 2, and 3, respectively. While mean serum creatinine was significantly higher among patients in Arm 3 compared to those in Arm 2 (P = 0.033), values in all treatment arms remained below 1.5 mg/dL. There were no significant differences in blood urea nitrogen, aspartate aminotransferase, or alanine aminotransferase among treatment arms. The mean total bilirubin level in Arm 3 was significantly lower than the value for Arms 1 and 2 combined (P = 0.025). Finally, the 1-yr mean alkaline phosphatase level was significantly lower in Arm 3, compared to Arm 1 (P = 0.046).
|Arm 1 (tacrolimus + corticosteroids)||Arm 2 (tacrolimus + corticosteroids + MMF)||Arm 3 (daclizumab + tacrolimus + MMF)|
|SCr (mg/dL)*||n = 68||n = 63||n = 127|
|1.3 ± 0.7||1.1 ± 0.4||1.3 ± 0.5|
|BUN (mg/dL)||n = 68||n = 62||n = 127|
|24.4 ± 18.7||21.6 ± 7.1||23.4 ± 8.5|
|Total bilirubin (mg/dL)†||n = 68||n = 63||n = 127|
|2.3 ± 4.1||1.6 ± 2.4||1.0 ± 1.0|
|AST (U/L)||n = 68||n = 63||n = 127|
|100.2 ± 101.1||85.1 ± 91.2||77.9 ± 75.3|
|ALT (U/L)||n = 68||n = 62||n = 127|
|101.3 ± 107.3||96.3 ± 100.6||87.8 ± 82.1|
|Alkaline phosphatase (U/L)‡||n = 68||n = 63||n = 127|
|205.7 ± 158.1||175.6 ± 188.7||155.0 ± 99.5|
One-yr Kaplan-Meier estimates of freedom from infection were 68.4%, 68.5%, and 71.7% in Arms 1, 2, and 3, respectively (Table 6). Freedom from malignancy was estimated to be 95.8%, 94.4%, and 97.0%, respectively. The incidence of new onset diabetes was highest among patients in treatment Arm 2. In contrast, new onset hyperlipidemia occurred more frequently in Arm 1. None of these differences achieved statistical significance.
|Arm 1 (tacrolimus + corticosteroids)||Arm 2 (tacrolimus + corticosteroids + MMF)||Arm 3 (daclizumab + tacrolimus + MMF)|
|Freedom from infection (Kaplan-Meier estimate)||68.4 ± 5.2%||68.5 ± 5.3%||71.7 ± 3.7%|
|Freedom from malignancy (Kaplan-Meier estimate)||95.8 ± 2.4%||94.4 ± 2.8%||97.0 ± 1.5%|
|New onset diabetes mellitus n (%)*||7 (11.9)||9 (17.3)||8 (8.0)|
|New onset hypertension n (%)†||24 (44.4)||15 (28.8)||38 (39.6)|
|New onset hyperlipidemia n (%)†||22 (35.5)||17 (31.5)||37 (37.0)|
The HCV-3 clinical trial is the largest prospective, randomized, multicenter study to assess the impact of immunosuppressive regimens on the recurrence of HCV infection following LT. Overall a very small number of patients withdrew from the study; no patient withdrew from arm 1, 4 withdrew from arm 2, and 7 from arm 3. The 1-yr results clearly demonstrate the safety and efficacy of a corticosteroid-free regimen, using daclizumab induction, in HCV+ liver transplant recipients. Although no clear benefit was observed at 1 yr in HCV disease progression or recurrence, likely due to the short follow-up for these parameters, the results reveal a significant benefit in acute rejection under a daclizumab-induction, corticosteroid-free, maintenance immunosuppression comprised of tacrolimus and MMF. Furthermore, we have identified acute rejection and (to a lesser degree) donor age as significant risk factors for HCV recurrence.
The fact that 1-yr primary composite endpoint was achieved to an equivalent degree in each treatment arm suggests that the impact of different immunosuppressive regimens on this patient population is more subtle and requires detailed analysis of multiple factors. Longer follow-up may be necessary to detect differences in the primary composite endpoint.
The recurrence of HCV disease is a frequent complication following LT.2, 12, 13 It is estimated that 75% of HCV+ patients develop acute lobular hepatitis within the first 3 months following transplantation, with greater than 80% experiencing chronic allograft injury secondary to viral infection by 5 yr.30
The effects of current immunosuppressive regimens on HCV disease recurrence are unclear. However, multiple reports of the negative impact of corticosteroids on HCV disease outcome,31–33 have led to several corticosteroid avoidance or minimization studies.
A prospective study of a larger series of 140 HCV+ patients maintained on cyclosporine-plus-azathioprine revealed no significant difference in histologic recurrence of disease.20 However, that study reported a significantly higher incidence of rejection in the group not receiving corticosteroids. This finding underscores the importance of using an adequate replacement for corticosteroids, such as daclizumab. Indeed, in the present study, there was a significant reduction in the incidence of acute rejection among patients in Arm 3, treated without corticosteroids, but with daclizumab induction.
Other corticosteroid-free maintenance immunosuppression regimens have been investigated in several relatively small series of HCV+ patients.21, 22, 34–36 Reported benefits include suppression of HCV RNA levels,21, 35 reduced incidence of advanced fibrosis,36 and less severe recurrence of hepatitis C.22 In this study the corticosteroid-free treatment regimen for mild rejection episodes in the 3 treatment arms, provided another important approach for corticosteroid minimization in HCV+ liver recipients.
Our findings that are consistent with those of some other studies reveal no detectable impact of corticosteroid avoidance on HCV recurrence 1 yr after transplanation.20, 36, 37 Although acute rejection was found, in this study and others,38, 39 to be a significant risk factor for recurrence of hepatitis C, the significantly reduced incidence of acute rejection in Arm 3 (with concomitant reduction in total steroid exposure) failed to translate to reduction in HCV disease recurrence. A larger number of patients, longer follow-up, and further modifications to the immunosuppressive regimen in HCV recipients may be necessary to demonstrate any effect of reduced acute rejection incidence on HCV disease recurrence. An additional limitation of our current study is the possible bias introduced by analysis based on local pathology reports, as opposed to central pathologist evaluation.
Reports of the influence of MMF on the recurrence of HCV disease have been controversial.16, 18 One report cited MMF as a risk factor for HCV disease progression.40 In contrast, a recent analysis of the Scientific Registry of Transplant Recipients separately assessed rejection, death, graft loss, or HCV recurrence, and demonstrated the significant advantage of a 3-drug regimen containing MMF for all 3 endpoints at 4 yr posttransplantation.17 In the present study the impact of MMF on recurrence of HCV remains unclear, again likely due to the effect of the short follow-up on the assessment of this endpoint. No difference was found so far in recurrence of HCV between Arm 1 (no MMF) and Arm 2 or 3 (with MMF).
Daclizumab has been used in induction regimens in liver transplant recipients to spare calcineurin inhibitor exposure in patients with impaired renal function, and, as in our study, to spare corticosteroids.35–37, 41 In 2001, Nelson et al.42 reported significantly accelerated progression of HCV disease among patients treated with daclizumab and MMF. However, demographic imbalances and lack of a concurrent timeframe in transplantation of the comparator group renders the investigators' conclusions questionable. In the present randomized, controlled study, we found that daclizumab, used in a novel 3-dose regimen, replaced corticosteroids safely and effectively. The overall impact of daclizumab induction therapy in a corticosteroid-free regimen on the timing or severity of HCV disease recurrence will be assessed in this ongoing 2-yr trial.
Consistent with the results of other studies, we have identified acute rejection and advancing donor age as significant risk factors for HCV disease recurrence.40, 43–45 Our data reveal a notable imbalance in the relative impact of these factors. While each decade of advancing donor age is expected to increase the risk of recurrence by approximately 10%, a single episode of acute rejection is accompanied by a 270% increase in risk of HCV recurrence. Therefore, we believe that avoidance of acute rejection should be a priority in managing HCV+ liver transplant recipients.
Although there have been reports of more aggressive progression of posttransplantation HCV disease associated with liver grafts from living donors,46–49 we found no significant effect of donor source on the rate of progression or recurrence of HCV disease. In addition, we failed to demonstrate any effect of demographic differences on outcomes in our patient population. Full data, including the influence of donor source, await the results of the 2-yr analysis.
The 1-yr analysis presented in this report failed to show benefit of a corticosteroid-free regimen on the rate of posttransplantation infections, malignancy, hypertension, diabetes, or hyperlipidemia. Longer follow-up may be necessary to demonstrate this benefit. It is also possible that calcineurin inhibitor therapy is a more important cause for these postoperative complications than steroids when used at the current doses.
The interim findings of our study, presented here, suggest that a corticosteroid-free maintenance regimen with daclizumab induction and tacrolimus and MMF maintenance, is safe and effective. The corticosteroid-free regimen did not affect the rate or the time to onset of HCV recurrence, although some improvement in liver function tests was observed at 1 yr. Benefits of this regimen included a significantly reduced incidence of acute rejection, potentially important because of its demonstrated association with HCV disease recurrence. We await the final results of the study at 2 yr of follow-up, to evaluate the full benefit of corticosteroid avoidance in HCV+ liver transplant recipients.
We thank David McCollum, MS, for his assistance in the statistical analysis, and Carolynn E. Pietrangeli, PhD, for her critical contribution in preparing this manuscript. This manuscript was prepared in part by CTI Clinical Trial and Consulting Services. We thank the principal investigators and study coordinators of the HCV 3 Study Group for their dedication and hard work in completing this study: Linda Sher, MD, and Chris Romero from the University of Southern California, Los Angeles, CA; David Douglas, MD, and Joyce Wisbey from Mayo Clinical Hospital, Phoenix, AZ; Robert S. Brown, Jr., MD, PhD, and David Zimmerman from New York Presbyterian Hospital, New York, NY; John M. Ham, MD, and Claudia Stone from Oregon Health and Science University, Portland, OR; Lewis W. Teperman, MD, and Orit Neuderfer from New York University Medical Center, New York, NY; John Roberts, MD, and Abdel Rahmaoui from the University of California, San Francisco, San Francisco, CA; Michael J. Millis, MD, and Katie Wherity from the University of Chicago, Chicago, IL; Michael Charlton, MD, and Sharleen Cartney from the Mayo Clinic, Rochester, MN; Prabhakar Baliga, MD, and Carolyn Dawkins from the Medical College of South Carolina, Charleston, SC; Timothy L. Pruett, MD, and Terry Ryan from the University of Virginia, Charlottesville, VA; Elizabeth Pomfret, MD, and Agnes Trabucco from Lahey Clinic Medical Center, Burlington, MA; Baburao Koneru, MD, and Rakesh Arora from the University of Medicine and Dentistry of New Jersey, Newark, NJ; Michael Abecassis, MD, and Patrice Al-Saden from Northwestern University, Chicago, IL. We also thank the study coordinators at the authors' centers: Sharon Bruer, Cyndi Tourtellot, Mike Alonzo, Laurel Davis, and Patti Wilson.
- 1Chronic hepatitis C and liver transplantation. Rev Gastroenterol Disord 2004; 4: 7–17..
- 29Regression models and life tables. J Royal Stat Soc Ser B Stat Methodol 1972; 34: 187–220..