Interleukin-2 receptor antibody (basiliximab) for immunosuppressive induction therapy after liver transplantation: A protocol with early elimination of steroids and reduction of tacrolimus dosage
A prospective evaluation was performed to study the potential benefits of the use of interleukin-2 receptor antibody (IL-2Rab) in the induction therapy with early elimination of steroid and reduction of tacrolimus dosage in liver transplant recipients among whom 94% had chronic hepatitis B infection. Thirty-one liver transplant recipients who underwent right-lobe live donor (n = 19) or cadaveric (n = 12) liver transplantation received IL-2Rab, basiliximab 20 mg intravenously within 6 hours of graft reperfusion and on postoperative day 4 (IL-2ab group). Two doses of steroid injection were given intraoperatively and on postoperative day 1. Postoperative immunosuppression was maintained with oral tacrolimus and mycophenolate mofetil without the use of steroids. The operative outcomes were compared with those of 49 patients who received standard immunosuppressive regimen consisting of tacrolimus and corticosteroid (steroid group). The overall postoperative morbidity and hospital stay were comparable between the 2 groups. There were significantly lower incidences of postoperative new-onset diabetes (0% vs 28%, P = .011), acute cellular rejection (6% vs 27%, P = .038), and cytomegalovirus (CMV) antigenemia (0% vs 18%, P = .011) in the IL-2Rab group compared with the steroid group. The blood cholesterol level at 6 months after transplantation was significantly lower in the IL-2Rab group (median, 4.0 vs 4.4 mmol/L, P = .007). On follow-up, none of the patients in the IL-2Rab group had hepatitis B viral breakthrough or hepatocellular carcinoma (HCC) recurrence, whereas 1 and 3 patients in the steroid group developed these complications, respectively. In conclusion, treatment of liver transplant recipients with IL-2Rab with early withdrawal of steroids and reduction of tacrolimus dosage is associated with lower incidences of postoperative new-onset diabetes, acute cellular rejection, and CMV antigenemia, as well as a lower serum cholesterol level. Further studies and long-term follow-up are required to document their potential benefits on hepatitis B and HCC recurrences. (Liver Transpl 2004;10:728–733.)
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Corticosteroids have long been a cornerstone of immunosuppression for liver transplant recipients. However, there are well-known side effects that result in significant morbidities, including hypertension, obesity, diabetes, hyperlipidemia, and infectious complications. Previous reports have shown that early reduction or elimination of corticosteroids could significantly reduce the incidence of many of these complications in liver transplant recipients.1–3 However, there is a significant risk of increased incidence of acute rejection associated with early steroid withdrawal that may require treatment with high doses of pulse steroids. With the advent of newer immunosuppressive agents, including tacrolimus, mycophenolate, interleukin-2 receptor antibody (IL-2Rab), or sirolimus, early steroid reduction or withdrawal in liver transplant recipients appears to be practical.
The liver is generally considered immunologically privileged, with low incidences of graft loss related to acute or chronic rejection. In addition, acute and chronic rejections have been reported to occur less frequently in hepatitis B–positive recipients.4 However, recurrent hepatitis is frequently a major concern in liver transplant recipients with chronic hepatitis B infection. Corticosteroids are frequently implicated in the acceleration of a viral replication and recurrence after liver transplantation.5, 6 Despite the theoretical implication of upregulation of viral activity with corticosteroids, little has been published with regard to steroid avoidance in hepatitis B hepatic allograft recipients. Previous studies have documented the efficacy of IL-2Rab for induction therapy in liver transplant recipients in combination with a calcineurin inhibitor.7 We hypothesized that the use of IL-2Rab in combination with tacrolimus and mycophenolate mofetil would allow a safe early elimination of steroids. A study was performed to evaluate whether the use of IL-2Rab in the induction therapy with early elimination of steroids and low-dose tacrolimus would be beneficial in a cohort of liver transplant recipients, among whom the majority had chronic hepatitis B infection and underwent right-lobe live donor liver transplantation (RLDLT).
Patients and Methods
We evaluated the potential beneficial effects of IL-2Rab and early steroid withdrawal in patients undergoing liver transplantation in a prospective open-label nonrandomized study. Thirty-one adult patients, among whom 29 (94%) were chronic hepatitis B carriers, who underwent liver transplantation at the University of Hong Kong Medical Centre, Queen Mary Hospital from March 2002 to May 2003 received IL-2Rab for immunosuppressive induction therapy (IL-2Rab group). Nineteen underwent RLDLT, and 12 received cadaveric liver transplantation. Seven (22%) patients had coexisting hepatocellular carcinoma (HCC). IL-2Rab, basiliximab (Novartis Pharma AG, Basle, Switzerland) 20 mg, was given intravenously within 6 hours of graft reperfusion and on postoperative day 4. Steroid injection was given intraoperatively (hydrocortisone 1g) and on postoperative day 1 (methylprednisolone 500 mg). Postoperative immunosuppression was maintained with oral tacrolimus (0.15mg/kg/day), which was given within 12 hours after transplantation, and the dose was titrated to achieve a trough level of 5–10 ng/mL. Mycophenolate mofetil (1.5 g/day) was started within the first 48 hours after transplantation and was gradually tapered off at 3 months. A maintenance dose of steroids was not given.
The operative outcomes of the IL-2Rab group were compared with those of a historic control consisting of 49 consecutive patients who underwent liver transplantation during a 14-month period immediately before the IL-2Rab group from January 2001 to February 2002. The preoperative morbid status and clinical parameters, graft weight, graft ischemic time, and blood and blood product requirement were comparable to those of the studied group. The control group received a standard immunosuppressive regimen consisting of tacrolimus and corticosteroids (steroid group). Among the steroid group, 41 (84%) patients had chronic hepatitis B infection, and 13 (27%) had concomitant HCC. Sixteen patients in the steroid group underwent cadaveric liver transplantation, whereas the remaining 33 underwent RLDLT. Steroid injection was given intraoperatively using 1 g of hydrocortisone, and a postoperative taper dose of methylprednisolone was given starting at 200 mg/day to 40 mg/day by 7 days after transplantation. Steroid treatment was then maintained with oral prednisolone at 20 mg/day and was gradually tapered off 6 months after transplantation. Oral tacrolimus was given at a daily dosage of 0.15mg/kg within 12 hours after transplantation, and the dose was titrated to achieve a trough level of 10–15 ng/mL.
Prophylaxis against hepatitis B using lamivudine (Glaxo Wellcome, Middlesex, UK) 100 mg daily was given orally to all patients with chronic hepatitis B infection before transplantation and was continued indefinitely afterward.8 Hepatitis B immunoglobulin was not used in any of the patients. All patients in both groups received the same concomitant therapy, which included antiulcer therapy, trimethoprim-sulfamethoxazole for Pneumocystis carinii, fluconazole, and acyclovir 1200 mg/day for 3 months. The serum lipid profile of all patients was routinely monitored every 3 months. Bone density of the patients was not assessed after transplantation.
The clinical and demographic parameters and operative outcomes of both groups of patients were compared. Clinical data of all patients, including all postoperative complications, were prospectively recorded in a computerized database by a single research assistant. Postoperative new-onset hypertension was defined as sitting systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg on 3 separate occasions. Postoperative diabetes was diagnosed when fasting plasma glucose was greater than or equal to 7.0 mmol/L. Significant cytomegalovirus (CMV) pp65 antigenemia was defined as more than 10 positive cells per 100,000 white blood cells on 2 separate occasions. Statistical analysis was performed by chi-squared test or Fisher's exact test to compare discrete variables. Continuous variables were expressed as median (range) and compared using the Mann-Whitney U test. Statistical analyses were performed by SPSS for Windows computer software (SPSS Inc., Chicago, Ill). P < .05 was considered to indicate statistical significance.
Indications for liver transplantation in the IL-2Rab group of patients included chronic hepatitis B liver cirrhosis (n = 16), acute-on-chronic hepatitis B liver failure (n = 12), fulminant hepatic failure related to hepatitis B infection (n = 1), and chronic hepatitis C liver cirrhosis (n = 2). Indications for liver transplantation in the steroid group of patients included chronic hepatitis B liver cirrhosis (n = 23); acute-on-chronic hepatitis B liver failure (n = 18); primary biliary cirrhosis (n = 1); cryptogenic liver cirrhosis (n = 1); chronic hepatitis C liver cirrhosis (n = 1); Wilson's disease (n = 1); and fulminant hepatic failure related to hepatitis E infection (n = 1), drug (n = 1), and idiopathic cause (n = 2). Patients' demographics are outlined in Table 1 and were similar between the IL-2Rab and the steroid groups. The median preoperative model for end-stage liver disease (MELD) scores7, 9 were 24 and 19 in the IL-2Rab group and the steroid group, respectively (P = .39). Tumor staging of the 20 patients with coexisting HCC is listed in Table 2. Intraoperative data, including the operative time, graft weight, and transfusion requirements, were also similar in both groups (Table 1). The median blood tacrolimus trough level on postoperative day 7 was 10.0 ng/mL (range, 3.1–19.0 ng/mL) in the IL-2Rab group and 13.5 ng/mL (range, 5.3–49.0 ng/mL) in the steroid group, respectively (P =.005). There was no significant difference in the median blood tacrolimus trough levels on postoperative day 30, which were 8.3 ng/mL in the IL-2Rab group and 8.7 ng/mL in the steroid group, respectively (P = .108). The postoperative liver function and renal function were similar in both groups, except that serum alanine aminotransferase level was significantly higher in the steroid group (median, 181 U/L; range 51–2140 U/L) compared with the IL-2ab group (median, 114 U/L; range 26–328 U/L) on postoperative day 7 (P = .013). The difference could be related to higher incidence of histology-proven acute cellular rejection in the steroid group. The postoperative hospital stay was comparable in the IL-2Rab and steroid groups (median, 19 days vs 21 days, P = .217). The median postoperative follow-up duration was 10.8 months (range, 1.6–16.6 months) in the IL-2Rab group and was significantly shorter than that of 21.6 months (range, 3.9–30.6 months) in the steroid group (P < .001). The actuarial patient and graft survival rates were 94% and 94% in the IL-2Rab group and 96% and 94% in the steroid group, respectively, on follow-up.
Table 1. Clinical Parameters of Patients in the IL-2Rab Group and Steroid Group
|Male : Female||28 : 3||35 : 14|
|Age* (yrs)||48 (29–60)||46 (18–66)|
|Chronic hepatitis B infection||29 (94%)||41 (84%)|
|Coexisting hepatocellular carcinoma||7 (23%)||13 (27%)|
|Cadaveric liver transplantation||12 (39%)||16 (33%)|
|Right lobe live-donor liver transplantation||19 (61%)||33 (67%)|
|Preoperative MELD scores*||24 (7–49)||19 (7–48)|
|Preoperative serum total bilirubin* (μmol/L)||299 (14–879)||139 (13–930)|
|Preoperative AST* (U/L)||73 (41–5590)||74 (26–8600)|
|Preoperative blood ammonia* (μmol/L)||74 (21–275)||52 (4–244)|
|Preoperative prothrombin time* (seconds)||24 (12–59)||20 (12–60)|
|Preoperative urea* (mmol/L)||5.6 (1.7–28.8)||4.1 (0.4–33.3)|
|Preoperative creatinine* (μmol/L)||93 (66–515)||91 (49–564)|
|Graft weight* (g)||695 (485–1650)||692 (415–1620)|
|Graft weight/recipient ESLW* (%)||61 (39–134)||56 (32–132)|
|Operating time* (minutes)||610 (322–975)||690 (389–1180)|
|Intraoperative blood product transfusion* (unit)|| || |
| Red blood cell||6 (0–33)||4 (0–32)|
| Fresh frozen plasma||10 (0–33)||9 (0–24)|
| Platelet concentrate||10 (0–38)||8 (0–42)|
Table 2. Tumor Staging of Patients in the IL-2Rab Group and in the Steroid Group
A total of 19 postoperative complications occurred in 12 recipients in the IL-2Rab group, resulting in an overall operative morbidity rate of 39%. The overall operative morbidity rate was not different from that of the patients in the steroid group (51%, P = .282, Table 3). Two (6%) patients in the IL-2Rab group had acute cellular rejection, which was proven on histology and required steroid treatment. The incidence was significantly higher in the steroid group, in which 13 (27%) patients had the complication (P = .038). Among them, none of the patients in the IL-2Rab group developed early acute cellular rejection within 30 days of liver transplantation, whereas 9 patients in the steroid group had early acute cellular rejection (0% vs 18%, P = .011). In the steroid group, 11 (28%) of the 40 patients without diabetes before liver transplantation developed new-onset diabetes and required oral hypoglycemic drugs (6 patients) or insulin injections (5 patients), whereas none of the patients in the IL-2Rab group developed new-onset diabetes (0%, P = .011). There was no significant difference in the incidence of new-onset hypertension in the IL-2Rab and the steroid groups (7% vs 10%, P = .704). The incidence of postoperative CMV antigenemia was significantly higher in the steroid group. Nine (18%) patients in the steroid group developed CMV pp65- antigenemia and required treatment with intravenous ganciclovir. None of the 31 patients in the IL-2Rab group had the complication (P = .011).
Table 3. Postoperative Complications of Patients IL-2Rab Group and Steroid Group
|Portal vein thrombosis||1||0|
|Acute cellular rejection||2*||13*|
|Early rejection (<30 days)||0*||9*|
Among the 80 patients who had chronic hepatitis B, 7 (23%) patients in the IL-2Rab group and 5 (10%) patients in the steroid group remained positive for hepatitis B surface antigen serology after liver transplantation. Hepatitis B virus DNA levels remained low in all patients, except 1 (2%) patient in the steroid group who developed hepatitis B virus DNA breakthrough related to the emergence of YMDD variant after transplantation. He remained well after treatment with adefovir. None of the patients in the IL-2Rab group had the complication. Three (23%) of the 13 patients with HCC in the steroid group developed posttransplant tumor recurrence, whereas none of the 7 patients with HCC in the IL-2Rab group developed tumor recurrence on follow-up (P = .521). The serum lipid profile of all patients was routinely monitored every 3 months. At 6 months after liver transplantation, the median serum cholesterol level was 4.0 mmol/L (range, 2.2–5.1 mmol/L) in the IL-2Rab group, which was significantly lower than that of 4.4 mmol/L of the steroid group (range, 2.1–9.3 mmol/L, P = .007). The serum triglyceride levels in both groups were comparable at 6 months (medium, 1.4 mmol/L vs 1.2 mmol/L, P = .149).
Currently, classical induction therapy with long-term steroid therapy is inadvisable for low-risk liver transplantation recipients, given the efficacy of immunosuppressive regimens based on tacrolimus, mycophenolate or sirolimus, and the risk of infections and malignancies.1 With reduction of the incidence of early acute rejection and without any relevant associated toxicity, monoclonal antibodies against IL-2Rab receptor offer the possibility of a more selective immunosuppression.10–12 Although the efficacy of IL-2Rab in liver transplant recipient has previously been evaluated,10–12 the safety and benefits in patients with chronic hepatitis B infection or RLDLT recipients have not been reported.
The current study was performed primarily to look into the safety and benefits of early steroid withdrawal within 24 hours after liver transplantation, using induction therapy with IL-2Rab and maintenance therapy with low-dose tacrolimus and mycophenolate mofetil in a cohort of liver transplant recipients in whom the majority had chronic hepatitis B infection and underwent RLDLT. Triple therapy for solid organ transplantation was introduced in the 1980s. The dose of each drug was progressively reduced when stable graft function appeared. The implicit belief was that the combination of a number of agents would confer an additive graft protective effect, in which the agent-specific toxicities would be reduced. In this study, the trough tacrolimus level was maintained at a significantly lower level in the IL-2Rab group compared with that in the steroid group. Thus, there was a potential benefit of minimizing the tacrolimus-related morbidity, including diabetes, hypertension, and renal function impairment. No adverse events were associated with the administration of IL-2Rab, including the risk of opportunistic infection. Indeed, the current study showed that the incidence of significant CMV antigenemia that required treatment with ganciclovir was significantly lower with the use of IL-2Rab and early elimination of steroids. The incidence of biopsy-proven rejection in the IL-2Rab group was 6%, which was significantly lower than that of the steroid group (28%). In addition, none of the patients in the IL-2Rab group developed early rejection. The low rate of rejection in the IL-2Rab group may be a reflection of the characteristics of the patients with chronic hepatitis B infection4 and the addition of IL-2Rab to the combination immunosuppressive therapy of tacrolimus with mycophenolate mofetil in our regimen.
Padbury et al.13 reported a lower prevalence of hypertension and diabetes in the steroid-free liver transplant recipients. Stegall et al.2 also showed a decreased incidence of hypertension in liver transplant recipients who had early steroid withdrawal and were maintained on tacrolimus and mycophenolate mofetil in comparison with historical controls who were maintained on cyclosporine and corticosteroids. A similar trend was observed in the current study toward a lower incidence of hypertension in the IL-2Rab group. The incidence of postoperative diabetes was significantly lower in the IL-2Rab group. The serum cholesterol level also was found to be significantly lower in the IL-2Rab group at 6 months after liver transplantation. Previous reports have indicated that tacrolimus has a less detrimental effect than cyclosporine on some cardiovascular risk factors,14 and tacrolimus also has been shown to have a more favorable effect on lipid profiles in comparison with a cyclosporine-based regimen.15 Together with a minimal use of steroids after transplantation, the incidences of postoperative hyperlipidemia and diabetes were significantly reduced. Hyperlipidemia and hypertension have been reported in liver transplant recipients, and they contribute to an increased risk of ischemic heart disease and cardiovascular deaths.16 The long-term cardiovascular complications of immunosuppressive treatment after liver transplantation can theoretically be reduced with the use of IL-2Rab and early withdrawal of steroids.
Liver transplantation in patients who are chronic carriers of hepatitis B surface antigen is associated with a high risk of graft reinfection that rapidly progresses to graft failure.17 An effective hepatitis B prophylaxis is crucial in the successful management of these patients. Polyclonal hepatitis B immunoglobulin is an effective form of prophylaxis that has been widely adopted.18, 19 More recently, the advent of nucleoside analog reverse transcriptase inhibitor, such as lamivudine which inhibits hepatitis B virus replication, has provided an alternative approach.20 Recent studies showed that a combination therapy using both hepatitis B immunoglobulin and Lamivudine is probably the most effective approach.21 In our initial experience with liver transplantation in patients with chronic hepatitis B, satisfactory outcomes have been observed using Lamivudine monoprophylaxis.8 We also have noticed the occurrence of antibody to hepatitis B surface antigen in some of the patients after transplantation, suggesting the possibility of adoptive immunity transfer through a liver graft.22
The benefits of early steroid abstinence on viral replication and the clinical outcome of liver transplant recipients with chronic hepatitis B infection have not been studied in clinical practice. Viral replication may accelerate in the presence of steroids.5, 23–25 In vitro experiments reported by McMillan et al.5 showed that steroids facilitated a 2-fold, and azathioprine a 4-fold, increase in hepatitis B virus replication. Cyclosporine alone did not influence replication, yet the 3 agents in combination stimulated an 8-fold increase in replication. Hepatitis C viremia posttransplantation also was reported to significantly increase after pulse steroid administration.23, 25 It is therefore possible that a steroid-free or early steroid withdrawal protocol might be beneficial to patients with chronic hepatitis B infection. In the current study, none of the patients in the IL-2Rab group had hepatitis B viral breakthrough, whereas 1 patient in the steroid group had the complication. However, it is obvious that the number of patients in each arm of the study was small, and the follow-up duration in the IL-2Rab group was too short for a valid conclusion. Long-term follow-up and further prospective studies with larger patient numbers are required to document the potential benefits of early steroid withdrawal or abstinence in this group of patients. Similarly, although none of the patients with HCC in the IL-2Rab group developed tumor recurrence after transplantation on follow-up, the difference in the follow-up duration of the 2 groups of patients may have affected the observation. The potential benefits of early steroid withdrawal on HCC recurrence need further evaluation.
The major drawbacks of the current study are the use of a historic control, the small number of patients in each group, and the relatively short follow-up in the IL-2Rab group. Because the 2 groups of patients were comparable in their demographic data and most of the complications related to immunosuppressive agents appeared early in the posttransplant course, we believe that the data presented in this study are convincingly valid for clinical practice.
In summary, with the use of IL-2Rab for immunosuppression induction therapy after liver transplantation, corticosteroids could be safely withdrawn 24 hours after operation while low-dose tacrolimus and mycophenolate mofetil were maintained. The regimen was associated with significantly lower incidences of postoperative new-onset diabetes, acute cellular rejection, and CMV antigenemia when compared with patients maintained on steroid therapy. Further prospective randomized studies are required to evaluate the potential benefits of early steroid withdrawal on hepatitis B viral replication and HCC recurrence after liver transplantation.