EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: This study sought to evaluate in pediatric liver transplant recipients the effects of hybrid antiviral therapy on the rate of posttransplant lymphoproliferative disorder.

Materials and Methods: All pediatric patients (87 cases) who had undergone a liver transplant between April 2011 and March 2012 took part in the study and received hybrid antiviral treatment (case group). Epstein-Barr virus polymerase chain reaction was monitored intermittently. The results were compared to those of a historical control group including 117 pediatric patients who received a liver transplant between April 2009 and March 2011. Follow-up was 27 to 47 months in the control group and 12 to 26 months in the case group.

Results: Posttransplant lymphoproliferative disorder occurred in 12 patients in control group (10.2%) and 5 patients in case group (5.7%) (P = .249). Of 12 cases of posttransplant lymphoproliferative disorder, death occurred in 5 cases in the control group (41.7%), while no posttransplant lymphoproliferative disorder-associated death was seen in the case group (P = .086).

Conclusions: Although hybrid antiviral treatment did not result in a statistically significant decrease in posttransplant lymphoproliferative disorder and posttransplant lymphoproliferative disorder-associated mortality rates, considering the limited number of posttransplant lymphoproliferative disorder cases in this study, this decrease may be interpreted as noticeable, and we advise using this strategy for pediatric patients undergoing a liver transplant.

Key words : Posttransplant lymphoproliferative disorder, Epstein-Barr virus, Liver transplant, Pediatric, Ganciclovir

Posttransplant lymphoproliferative disorder (PTLD) is potentially fatal complication after an orthotopic liver transplant.^1,2 In addition to the mortality and morbidity rates associated with PTLD,^2,3 this disease imposes significant costs.

The frequency of PTLD is higher in pediatric patients because of their naïve immunity and the greater prevalence of Epstein-Barr virus (EBV) infection.⁴ The reported incidence of PTLD varies from 0.9% to 20%.^5,6

Posttransplant lymphoproliferative disorder usually is related to potent immunosuppression and secondary EBV infection. Main immunosuppressive drugs including tacrolimus and cyclosporine inhibit cytotoxic T-cell responses, and immunosuppressed patients are predisposed to develop EBV infection.⁷ Epstein-Barr virus infection plays a central role in developing PTLD after a solid-organ transplant.⁸ It has been estimated that approximately 80% to 95% of PTLDs are associated with EBV infection.^1,9

In this study, a hybrid strategy (combination of prophylactic and preemptive treatments) was used to reduce the incidence of PTLD in pediatric patients using intravenous ganciclovir and oral valganciclovir.

Materials and Methods

Patients were divided into 2 groups: all pediatric patients (aged < 18 y) who had undergone a transplant between April 2011 and March 2012 took part in the study and received hybrid preventive treatment (case group). The historical control group was composed of consecutive children who had undergone a liver transplant between April 2009 and March 2011 and received no preventive therapy. The incidence and outcomes of PTLD between the groups were compared. The study was approved by the Ethical Review Committee of the institute. All protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from all subjects.

Prednisolone and tacrolimus were used as the primary immunosuppressive protocol for all patients. From the first postoperative day, tacrolimus was begun at 0.1 to 0.15 mg/kg/day orally, and the dosage was titrated to maintain levels of between 15 to 20 ng/mL for the first 3 months after an orthotopic liver transplant, 12 to 15 ng/mL during the second trimester, 7 to 12 ng/mL from 6 months to 1 year after the transplant, and from 5 to 7 ng/mL thereafter. Most patients were weaned off prednisolone in 6 months, except patients with autoimmune hepatitis and patients with severe or multiple rejection episodes (more than 1). Mycophenolate mofetil was combined with other agents if more immunosuppression was required.

All case group patients received intravenous ganciclovir at 10 mg/kg/day in 2 divided dosages during hospitalization. After discharge, oral valganciclovir ([7 × body surface area × creatinine clearance]/d) was begun and continued until the end of the first month after transplant. Since that time, EBV was checked by qualitative polymerase chain reaction weekly during the second month and every 2 weeks thereafter. (We considered a peripheral blood EBV viral load of more than 2000 copies/mL at our hospital to be a positive polymerase chain reaction according to a general population-based study). The oral valganciclovir was continued for 2 weeks after a negative result. Ganciclovir and valganciclovir were reduced for renal impairment. In the control group, serologic tests were performed to determine the risk of EBV infection before transplant and during follow-up. Symptomatic patients with positive test results received ganciclovir or valganciclovir. Posttransplant lymphoproliferative disorder was diagnosed based on clinical findings and was confirmed by tissue biopsy results, histopathologic evaluation, and immunohisto-chemical staining.

In PTLD patients, mycophenolate mofetil was discontinued, tacrolimus and prednisolone were decreased, and sirolimus was begun. Qualitative EBV DNA polymerase chain reaction testing was requested, and patients were empirically treated with intravenous ganciclovir. All PTLD cases received a sequence of 4 courses of rituximab, while chemo-therapy was given to patients who had histologically documented lymphoma.

Between group differences were assessed by the chi-square or the Mann-Whitney U test, with statistical significance indicated by P values < .05. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, NY, USA).

From April 2009 to March 2012, two hundred four consecutive pediatric patients (mean age at the time of transplant, 7.6 ± 5.3 y) who underwent an orthotopic liver transplant at the Shiraz Transplant Center in Shiraz, Iran, were enrolled in 2 groups: a case group (received ganciclovir; n = 87), and a historical control group (received no hybrid antiviral treatment; n = 117). Mean follow-up was 34 ± 12 months in control group and 20 ± 5.6 months in the case group. Patient demographics are shown in Table 1.

The most common indications for an orthotopic liver transplant were biliary atresia (n = 26), progressive familial intrahepatic cholestasis (n = 26), tyrosinemia (n = 26), Crigler–Najjar syndrome (n = 25), cryptogenic cirrhosis (n = 22), and Wilson disease (n = 21). Eighty-one patients received living-donor liver transplants, while 59 patients received grafts recovered from a deceased donor (41 whole organs and 18 cases of split-liver). There were no significant between group differences regarding age, sex, primary disease, transplant type (deceased-donor, living-related, split-liver), and Model for End-Stage Liver Disease or Pediatric End-Stage Liver Disease scores (Table 1).

Seventeen patients (8.3%) developed PTLD including 12 patients in the control group (10.2%) and 5 patients in case group (5.7%) (P = .249). Of those, 5 patients in control group died of PTLD (41.6%) but all patients in the case group survived; this difference was not statistically significant (P = .086). The interval between orthotopic liver transplant and development of PTLD was 7.2 ± 6.2 and 7.2 ± 3.6 months in control and case groups (P = .908). The last blood trough level of tacrolimus before a diagnosis of PTLD was 20.34 ± 8.66 ng/mL in the control group and 18.65 ± 8.89 ng/mL in the case group; this difference was not statistically significant (P = .806). The main characteristics of PTLD patients are summarized in Table 2.

Among 87 patients in the case group who received ganciclovir and valganciclovir, 10 patients (11.4%) and 3 patients (3.4%) developed bone marrow suppression and an increase in creatinine levels. All cases were managed with a dosage reduction, and no break in treatment was necessary.

Posttransplant lymphoproliferative disorder ranks as the second most common malignancy after undergoing a transplant and is a major cause for morbidity and death in pediatric liver transplant recipients. Primary EBV infection is a known risk factor for PTLD^10,11 and after initial EBV infection, there is considerable risk of developing PTLD.⁸

Different strategies decrease the incidence of PTLD including antiviral treatment, reduction of immunosuppression, and EBV monitoring.^12-14 Lowering the immunosuppression dosage combined with preemptive treatment and early diagnosis of EBV infection (with serial monitoring of EBV viral load) can decrease the incidence of PTLD after undergoing a liver transplant.

There is no consensus regarding EBV prevention after a liver transplant. Two major strategies are commonly used by transplant centers: prophylactic treatment (consisting of routine administration of an antiviral agent for a defined time after transplant) and preemptive therapy (which relies on strict monitoring and early detection of EBV infection to prevent a progression to symptomatic EBV disease). This hybrid strategy has been introduced recently, using a combination of these strategies. However, there is no large study that compares these approaches and supports the superiority of one approach over the other.

Although our hybrid strategy reduced the rate of PTLD from 10.2% to 5.7%, it was not statistically significant. This may have been due to a small sample size, and larger multicenter studies are required to confirm the effectiveness of this protocol. There is a paucity of studies addressing preventive antiviral therapy, and reduced incidents of PTLD in children. Most studies demonstrate no benefit of preventive treatment,^15-17 while others show that their preventive strategy lowers the rate of PTLD in pediatric patients who undergo a liver transplant.¹²

In this study, the incidence of PTLD-induced mortality decreased from 41.7% in the control group to 0 in the case group. We observed milder and more treatable episodes of PTLD in the case group. However, because of the limited number of PTLD patients, this was not statistically significant (P = .086). To best of our knowledge, no other study supports this finding.

There are 2 limitations in this study. The first concerns the lack of a randomized control group. The other limitation was a relatively short follow-up in the case group.

In conclusion, the incidence of PTLD and PTLD-induced death was lowered in this study. We advise using this hybrid antiviral strategy for pediatric patients undergoing a liver transplant.

Volume: 13 Issue: 5 October 2015

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