ORIGINAL ARTICLE. Received August 2, 2011; accepted November 9, 2011.

Transcription

1 LIVER TRANSPLANTATION 18: , 2012 ORIGINAL ARTICLE Retrospective Review of the Incidence of Cytomegalovirus Infection and Disease After Liver Transplantation in Pediatric Patients: Comparison of Prophylactic Oral Ganciclovir and Oral Valganciclovir Ashley N. Bedel, Pharm.D., Trina S. Hemmelgarn, Pharm.D., and Rohit Kohli, MBBS., MS. Pediatric Liver Care Center, Cincinnati Children s Hospital Medical Center, Cincinnati, OH Cytomegalovirus (CMV) is the most common viral infection after solid organ transplantation (SOT). Safe and effective prophylactic regimens that decrease its incidence after SOT are essential for long-term graft survival. Although valganciclovir is not Food and Drug Administration approved for CMV prophylaxis in liver transplant recipients, postmarketing studies have shown valganciclovir to be as effective as ganciclovir in high-risk adult patients undergoing SOT. Currently, data are lacking for pediatric liver transplantation. The purpose of this study was to compare the efficacy and safety of valganciclovir and ganciclovir for CMV infection prophylaxis in pediatric liver transplant recipients. This was a retrospective study of 56 pediatric liver transplant recipients who were prescribed either oral ganciclovir (n ¼ 37) or valganciclovir (n ¼ 19). Patients were followed until 200 days after transplantation or death. The primary outcome measure compared the rates of early-onset CMV infection and CMV disease in the 2 medication groups. Secondary outcome measures identified patient-specific factors that contributed to CMV acquisition and the incidence of late-onset CMV infection or disease. The rates of adverse drug effects and discontinuation were also evaluated. Early-onset CMV disease was documented in 0% of valganciclovir patients and in 5.4% of ganciclovir patients (P ¼ 0.54). There were no statistically significant differences in the secondary outcomes. An increased incidence of late-onset CMV disease was seen in the valganciclovir group versus the ganciclovir group (22.2% versus 8.1%, P ¼ 0.23). No differences in adverse events were reported. In conclusion, no statistically significant differences were found in the incidence of CMV infection or disease between patients receiving oral valganciclovir and patients receiving oral ganciclovir. Liver Transpl 18: , VC 2012 AASLD. Received August 2, 2011; accepted November 9, Cytomegalovirus (CMV) is the most common viral infection documented after solid organ transplantation (SOT). 1 CMV infection in immunocompromised transplant patients is associated with enhanced immunosuppression, which leads to opportunistic infections, an increased risk of graft loss, and significant morbidity and mortality. Strategies used to decrease the rate of infection include preemptive and prophylactic antiviral regimens. Cincinnati Children s Hospital Medical Center (CCHMC) follows evidencebased care guidelines for CMV prophylaxis after SOT 2 and uses a primary regimen of induction intravenous ganciclovir for 14 days, which is followed by maintenance oral ganciclovir (or valganciclovir as an Additional Supporting Information may be found in the online version of this article. Abbreviations: CCHMC, Cincinnati Children s Hospital Medical Center; CMV, cytomegalovirus; CrCl, creatinine clearance; FDA, Food and Drug Administration; PCR, polymerase chain reaction; SOT, solid organ transplantation. This work was supported by a grant from the National Institutes of Health (DK to Rohit Kohli). Address reprint requests to Ashley N. Bedel, Pharm.D., Pediatric Liver Care Center, Cincinnati Children s Hospital Medical Center, 3333 Burnet Avenue, MLC 15010, Cincinnati, OH Telephone: ; FAX: ; ashley.bedel@cchmc.org DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2012 American Association for the Study of Liver Diseases.

2 348 BEDEL ET AL. LIVER TRANSPLANTATION, March 2012 alternative regimen). In liver transplant patients, this is continued until 120 days after transplantation. Valganciclovir is Food and Drug Administration (FDA) approved for prophylactic use after heart, kidney, and pancreas transplantation, 3 but it is currently not FDA-approved for use after liver transplantation because of data from the Valganciclovir Solid Organ Transplant Study Group. 1 This group found higher rates of CMV infection and CMV tissue-invasive disease in a subgroup analysis of adult liver transplant patients using valganciclovir. Subsequent studies have found valganciclovir to be a safe and efficacious alternative to ganciclovir. 4,5 The international consensus guidelines on the management of CMV in SOT patients recommend oral ganciclovir or valganciclovir for liver transplant recipients. 6 Because of the contradictory data on valganciclovir, our institution had been using ganciclovir in liver transplant recipients until a national shortage of the oral formulation of ganciclovir resulted in valganciclovir becoming the regimen of choice at CCHMC (July 2009). Ganciclovir is an antiviral agent classified as a nucleoside analogue. It inhibits viral DNA replication by interfering with DNA elongation. 7 When it is administered orally, ganciclovir has a low bioavailability of 5% to 9%, and dosing every 8 hours is required. 7-9 Valganciclovir is the L-valyl ester prodrug of ganciclovir. Valganciclovir has an oral bioavailability of approximately 60% 8,10 and has been shown to provide systemic exposure comparable to that of ganciclovir with equivalent dosing. 8,10,11 Because of the once daily dosing regimen, the current unavailability of oral ganciclovir capsules, and the proven comparable effectiveness, valganciclovir is now used in the majority of all SOT recipients. Even though it is not an FDA-approved therapy for liver transplant recipients, valganciclovir is used by 73% of responding liver transplant centers throughout the United States and Canada. 12 Multiple studies have demonstrated the effectiveness of prophylactic antiviral medications in reducing the incidence and severity of CMV disease in adult transplant recipients. 1,4,5,13 We found, however, no studies specifically looking at its incidence in pediatric liver transplant patients, so the impact and effectiveness of CMV prophylaxis in this population remain relatively unknown. Although previous studies have provided preliminary information on the safety and efficacy of valganciclovir, their results cannot adequately be extrapolated to the pediatric liver transplant population. It is very well understood that in comparison with the adult transplant population, pediatric transplant recipients are at increased risk of acquiring CMV infections because they are more often CMV-naive at the time of transplantation. 5,14 Children usually receive organs from adults, whose serology status is more likely positive because of their age and increased time of exposure to CMV. Therefore, pediatric transplant recipients are most often considered to be at high risk for acquiring CMV infections, and this is attributed to their age and decreased exposure to CMV before transplantation. There is a paucity of data on the incidence of CMV infection and subsequent disease in the pediatric liver transplant population. Symptomatic infections occur within the first 30 to 90 days after transplantation 4 in 22% to 60% of liver transplant recipients who are not treated with a CMV prophylaxis regimen. 13,15 When CMV prophylaxis is used to treat intermediate- and high-risk patients, infection and disease can be delayed until prophylaxis is discontinued. Despite effective prophylaxis, it has been documented that 10% to 20% of transplant recipients will present with evidence of CMV replication with or without end organ disease within 2 years of transplantation. 6 Therefore, we felt that it was important to determine whether the pediatric population has outcomes differing from those observed in the adult population. The purpose of this retrospective study was to determine the post liver transplant incidence of CMV disease in pediatric patients treated with 1 of 2 oral antiviral regimens for CMV prophylaxis: ganciclovir (Cytovene) or valganciclovir (Valcyte). Our hypothesis was that prophylactic oral valganciclovir would be associated with fewer occurrences of early-onset CMV infection and disease in comparison with oral ganciclovir in a pediatric liver transplant population. PATIENTS AND METHODS Our population consisted of pediatric liver transplant recipients at CCHMC who received oral ganciclovir or valganciclovir after transplantation between January 2006 and March Institutional review board approval was obtained before the start of data collection. Patients were identified through the use of electronic databases and electronic medical records (ChartMaxx, Epic, Integrated Clinical Information System, and Liver Group Portal). A retrospective chart review was performed. Patients were eligible for inclusion if they met the following criteria: they were followed up at CCHMC for 200 days after transplantation or until death, the donor/recipient CMV serology status was documented before transplantation, they were prescribed oral ganciclovir or valganciclovir after transplantation, and they were 21 years old or younger at the time of liver transplantation. Patients were excluded if they met the following criteria: they had received a multivisceral organ transplant, they were positive for human immunodeficiency virus (which confers an increased risk of adverse effects and infection in this population), they were not treated because of their donor-negative/recipientnegative CMV serology status in accordance with CCHMC protocol, they underwent transplantation before 2006 (the hospital protocol changed from acyclovir to ganciclovir), they had received acyclovir, or they had switched treatments during the study period (from ganciclovir to valganciclovir).

3 LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 BEDEL ET AL. 349 Because of a national shortage of the raw materials necessary to manufacture oral ganciclovir, valganciclovir became the prophylactic agent of choice in 2009 per the transplant protocol. At CCHMC, prophylactic antiviral regimens using either ganciclovir or valganciclovir for 120 days after transplantation are the standard of care. Ganciclovir was initiated at a dosage of 30 to 40 mg/kg/day and was given every 8 hours up to the maximum adult dose of 1000 mg every 8 hours. 9 The dosage was adjusted as recommended for renal impairment [creatinine clearance (CrCl) < 70 ml/minute/1.73 m 2 ] on a patient-specific basis. Valganciclovir was dosed with the following validated dosing equation 16 : Dose ¼ 7 Body surface area CrCl CrCl was calculated with the measured cystatin C value (if available) or with the modified Schwartz equation; the maximum CrCl value was 150 ml/ minute/1.73 m 2. However, dose adjustments were not collected as a part of this chart review. Quantitative polymerase chain reaction (PCR) for CMV was performed per protocol for all patients every 2 weeks for the first 3 months after transplantation and monthly thereafter until 1 year after transplantation. Outcomes The purpose of this study was to determine the incidence of CMV infection and disease in pediatric liver transplant recipients in order to validate the use of valganciclovir. The primary outcome was the incidence of CMV infection and disease within 120 days of liver transplantation (early onset) in patients given oral ganciclovir or valganciclovir as antiviral prophylaxis. CMV infection was defined as evidence of CMV replication in a clinical specimen without associated symptoms. CMV disease was defined as the presence of a CMV infection in addition to tissue biopsy confirmed tissue-invasive disease or a clinical diagnosis of CMV syndrome made by the liver transplant team because of the presence of symptoms including (but not limited to) fever, muscle pain, leukopenia, and/or thrombocytopenia. These definitions were obtained from the CCHMC evidence-based care guidelines for CMV prophylaxis after SOT. 2 Secondary outcomes were the rates of infection and disease in the ganciclovir and valganciclovir groups, which were compared by age, risk stratification based on the pretransplant serology status, the incidence of acute graft rejection, the incidence of sepsis (defined as documentation in the electronic medical record or an equivalent record of a diagnosis of sepsis with subsequent antibiotic treatment for longer than 48 hours) and the duration of antibiotic therapy, the length of intravenous ganciclovir therapy, the incidence of CMV infection and disease from days 120 to 200 (defined as late-onset CMV infection/disease), and the incidence of opportunistic infections. Epstein-Barr virus, herpes simplex virus, and adenoviruses were counted as opportunistic infections if there was documented viremia via PCR. Quantitative PCR monitoring for Epstein-Barr virus was performed in all patients every 2 weeks for the first 3 months after transplantation and monthly thereafter for the first year. Risk stratification based on the CMV serology was defined as follows: high risk (donor-positive/recipient-negative) or intermediate risk (donor-positive/recipient-negative or donor-negative/recipient-positive). Tertiary outcomes included the incidence of adverse events (neutropenia, leukopenia, thrombocytopenia, and anemia) in the comparison groups and the rates of discontinuation due to adverse effects. Neutropenia was defined as an absolute neutrophil count < 1000 cells/ll. Leukopenia was defined as a white blood count less than the age-specific laboratory value ranges from CCHMC s central laboratory reference ranges (see the supporting information). Thrombocytopenia was defined as a platelet count < 100,000/lL. Anemia was defined as a value less than the age-specific laboratory values from the CCHMC s central laboratory reference ranges (see the supporting information). Data Collection The data collection process was performed with a standard form for all patients. The following data were collected: date of birth; sex; race; ethnicity; primary liver disease; age at transplantation; CMV serology; human immunodeficiency virus status; date of transplantation; date of initiation of prophylactic antiviral therapy; results of quantitative and qualitative CMV PCR; results of all tissue biopsy procedures; length of intravenous ganciclovir induction therapy; concurrent medications; incidence of sepsis and subsequent length of antibiotic therapy; incidence of acute cellular rejection and opportunistic infections; date of antiviral discontinuation; any adverse effects; and laboratory values pertaining to the adverse effects of neutropenia, thrombocytopenia, leukopenia, and anemia. Statistics Statistical comparisons of patient demographics were performed with Fisher s exact test and chi-square tests for categorical variables and with t tests for continuous variables. Primary and secondary outcome variables were analyzed with Fisher s exact test and chi-square tests. A logistic regression analysis was performed to analyze risk stratification associated with the following variables: age, incidence of sepsis, duration of antibiotic treatment, incidence of acute graft rejection, and duration of intravenous ganciclovir therapy. Analyses were performed with the Statistics Online Computational Resource. 17 A P value < 0.05 was considered statistically significant. RESULTS Patient Characteristics Between January 2006 and March 2011, 73 patients received a liver transplant at CCHMC; 22 received valganciclovir as prophylaxis against CMV, and 51

4 350 BEDEL ET AL. LIVER TRANSPLANTATION, March 2012 TABLE 1. Patient Demographics Valganciclovir (n ¼ 19) Ganciclovir (n ¼ 37) P Value Age (years)* 5.3 ( ) 2.3 ( ) 0.3 Sex [n (%)] 0.97 Male 7 (36.8) 17 (45.9) Female 12 (63.2) 20 (54.1) Race [n (%)] 0.05 White 12 (63.2) 20 (54.1) Black 3 (15.8) 5 (13.5) Other 4 (21.1) 12 (32.7) Primary liver disease (n) 0.07 Cholestatic 9 18 Metabolic 1 7 Acute liver failure 1 5 Cirrhosis Other 2 5 Donor/recipient CMV 0.13 serology status (n) Positive/negative Positive/positive 5 10 Negative/positive 1 7 Unknown 2 0 *The data are presented as medians and ranges. Cholestatic includes Alagille s syndrome, biliary atresia, idiopathic cholestasis, primary sclerosing cholangitis, and idiopathic cholestasis. Metabolic includes antitrypsin 1 deficiency, citrullinemia, glycogen storage deficiency, hemochromatosis, ornithine transcarbamylase deficiency, urea cycle disorders, and Wilson s disease. Acute liver failure includes liver failure due to viral, autoimmune, or indeterminate causes or drug toxicity. Cirrhosis includes autoimmune hepatitis, cryptogenic cirrhosis, and neonatal hepatitis. Other includes tumors (blastoma, carcinoma, and hemangioendothelioma) and cystic fibrosis. TABLE 2. Primary Outcomes Outcome Variable Valganciclovir (n ¼ 19) Ganciclovir (n ¼ 37) P Value CMV infection [n (%)] 0 0 >0.99 CMV disease [n (%)] 0 2 (5.4) 0.54 Outcome Variable Valganciclovir: High-Risk Ganciclovir: High-Risk P Value Patients (n ¼ 11)* Patients (n ¼ 20)* CMV infection [n (%)] 0 0 CMV disease [n (%)] 0 2 (10) 0.53 *Donor-positive/recipient-negative serology status. received ganciclovir. Three valganciclovir patients were excluded because they had previously used ganciclovir (n ¼ 2) or acyclovir (n ¼ 1) during the study period. Fourteen ganciclovir patients were excluded for one of the following reasons: they were not treated with ganciclovir or valganciclovir because their CMV serology status was donor-negative/recipient-negative (n ¼ 4), they had received a multivisceral transplant (n ¼ 4), or their therapy was switched during the study period (n ¼ 6). Therefore, 56 patients were included in the study: 19 in the valganciclovir group and 37 in the ganciclovir group. Patient Demographics The only statistical difference in the demographic variables between the treatment groups was the fact that the valganciclovir arm had more patients with cirrhosis as the underlying primary liver disease (P ¼ 0.02). The majority of the patients in both groups were placed in the high-risk CMV serology category (58% in the valganciclovir group and 54% in the ganciclovir group; Table 1). Notably, the ganciclovir group had a larger number of patients in the 0- to 2-year range (n ¼ 17) in comparison with the valganciclovir group (n ¼ 7); however, there was no statistical difference in the age distributions of the 2 groups. Primary Outcome The incidence of CMV infection within 120 days after transplantation was 0% in both groups. The incidence of CMV disease was 0% in the valganciclovir group and 5.4% in the ganciclovir group (n ¼ 2, P ¼ 0.54).

5 LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 BEDEL ET AL. 351 TABLE 3. Secondary Outcomes Outcome Variable Valganciclovir (n ¼ 19) Ganciclovir (n ¼ 37) P Value Acute graft rejection [n (%)] 9 (47.4) 16 (43.2) >0.99 Opportunistic infection [n (%)] 5 (26.3) 8 (21.6) >0.99 Documented sepsis [n (%)] 9 (47.4) 9 (24.3) 0.39 Mean duration of antibiotic therapy (days) Mean duration of intravenous ganciclovir (days) Late onset [n (%)] Infection 0/18 0/37 Disease 4/18 (22.2) 3/37 (8.1) 0.23 These data were also analyzed for the high-risk patient population. Eleven valganciclovir patients and 20 ganciclovir patients had a donor-positive/recipient-negative serology status. Zero of the 11 valganciclovir patients and 2 of the 20 ganciclovir patients (10%) had early-onset CMV disease (P ¼ 0.53). No statistically significant differences were identified. One of the 2 patients who had documented CMV disease had CMV colitis, and the other had CMV cystitis. Both patients had the high-risk CMV serology status (donor-positive/recipient-negative). These 2 ganciclovir patients did not have the same age range, sex, race, or primary liver disease (Table 2). Secondary Outcomes No statistically significant differences were identified for the following secondary outcome variables: acute graft rejection, opportunistic infections, documented sepsis, duration of antibiotic therapy, and length of intravenous ganciclovir induction therapy. The most common opportunistic infection was Epstein-Barr virus (11 documented cases). Epstein-Barr virus was documented for 6 ganciclovir patients and 5 valganciclovir patients. Two ganciclovir patients had documented adenovirus viremia. Eighteen patients in the valganciclovir group were followed until day 200; 1 patient died within the study period. All 37 ganciclovir patients were followed through day 200. The incidence of late-onset CMV infection (days ) was 0% in both treatment groups. The incidence of CMV disease was 22.2% (4/18) in the valganciclovir group and 8.1% (3/37) in the ganciclovir group (P ¼ 0.23; Table 3). Six of the 7 patients who acquired late-onset CMV disease were diagnosed within 60 days of the discontinuation of antiviral prophylaxis (range ¼ days). The 3 ganciclovir patients had CMV syndrome; 1 of the 4 valganciclovir patients had CMV colitis, and the other 3 patients had CMV syndrome. Three patients were in the high-risk serostatus category (donor-positive/recipient-negative), and the status for 4 patients was donor-positive/recipientpositive. A risk stratification analysis was performed with logistic regression to determine whether any patientspecific variables were associated with a higher risk of CMV acquisition. None of the following variables had a statistically significant confidence interval or increased odds ratio: age, sepsis, antibiotic duration, incidence of acute graft rejection, and duration of intravenous ganciclovir therapy. The small number of occurrences of CMV infection and disease and the study s population size limited the utility of this analysis. Tertiary Outcomes: Safety Documented adverse effects thought to be due to the study medication were validated via a laboratory result review. There were 3 patients in the valganciclovir group (15.8%) who had 1 or more adverse effects [thrombocytopenia (1), leukopenia (2), and neutropenia (2)] and 3 patients in the ganciclovir group (8.1%) who had an adverse effect [neutropenia (3), P ¼ 0.49]. The difference was not statistically significant. The 3 valganciclovir patients with an adverse drug effect discontinued their medication before day 120, and another patient discontinued therapy 9 days early. Ten ganciclovir patients discontinued therapy before day 120. The reasons for early discontinuation included the acquisition of CMV disease (n ¼ 2), an adverse drug effect (n ¼ 3), and unknown causes (n ¼ 5; Table 4). Because of the retrospective nature of this study, documented explanations for the early discontinuation of both valganciclovir and ganciclovir were not found. The duration of prophylactic therapy was not available for all patients because (1) the institutional review board gave approval for collecting data only until day 200 and (2) the data acquisition was retrospective. The median duration of antiviral prophylaxis was 117 days for the valganciclovir group (n ¼ 17) and 118 days for the ganciclovir group (n ¼ 34; Table 4). DISCUSSION Valganciclovir usage in adult SOT patients has been shown to be safe and efficacious in some studies and controversial in others. 18,19 It is widely used in pediatric SOT patients, although evidence specifically for pediatric liver transplant recipients is limited. Few trials

6 352 BEDEL ET AL. LIVER TRANSPLANTATION, March 2012 TABLE 4. Tertiary Outcomes Outcome Variable Valganciclovir (n ¼ 19) Ganciclovir (n ¼ 37) P Value Patients with medication-related adverse 3 (15.8) 3 (8.1) 0.49 drug events [n (%)] Medication-related adverse drug events (n) Anemia 0 0 Thrombocytopenia 1 0 Leukopenia 2 0 Neutropenia 2 3 Discontinuation before day 120 [n (%)] 4 (21.1) 10 (27.0) >0.99 Duration of prophylaxis (days)* 117 (92-138) 118 (32-194) >0.99 *The data are presented as medians and ranges and were collected for 17 of the 19 valganciclovir patients and for 34 of the 37 ganciclovir patients. are available that include pediatric patients, and fewer still include only liver transplant patients. The current study included patients who were 21 years old or younger and underwent liver transplantation at CCHMC. No trends were found for the primary liver disease, the incidence of CMV infection or disease, or any other demographic variable. The percentage of patients in the 0- to 2-year age range was higher in the ganciclovir group versus the valganciclovir group. Because of the increased risk of CMV acquisition in younger patients, this difference could have skewed the results in the ganciclovir group and could be a source of bias. No statistically significant differences were found in the numbers of patients in each age range. Fifty-six patients were evaluated in all: 0 of the 19 valganciclovir patients and 2 of the 37 ganciclovir patients had documented early-onset CMV disease. The late-onset rates of infection and disease were also evaluated because of information alluding to the idea that antiviral prophylaxis may only delay the onset of CMV Four of the 18 valganciclovir patients and 3 of the 37 ganciclovir patients had documented lateonset CMV disease. This difference was not statistically significant. Because of the small sample size and the discrepancy in the numbers of patients in each group, it is difficult to draw clinical significance from this result. Six of the 7 cases of late-onset disease occurred within 60 days of the discontinuation of antiviral therapy. Three of the 9 cases of CMV disease were considered to be tissue-invasive, and 6 were defined as CMV syndrome. Overall, the incidence of CMV disease in the studied population was 16%, which is similar to that reported in previous studies. 1,6,15 There were no documented recurrences of CMV infection or disease in any patient within 200 days of transplantation. We found no statistically significant differences when we compared the incidence of early- and lateonset CMV infection and disease in patients treated with oral ganciclovir and patients treated with valganciclovir, although the study was not adequately powered for this. The original hypothesis that the incidence of early-onset CMV infection would be lower in the valganciclovir group versus the ganciclovir group could not be accepted or rejected because of the small population size; no difference was found between the groups. The rates of discontinuation of antiviral therapy and the incidence of bone marrow toxicity, which was defined as anemia, thrombocytopenia, neutropenia, or leukopenia, were similar for the 2 groups. This study s limitations include its design (a retrospective chart review); in rare instances, the definitions dictated by the CCHMC evidence-based care guidelines were not followed with respect to chart documentation and diagnosis codes by physicians. Furthermore, some patients were on sulfamethoxazole/trimethoprim therapy, which can also cause bone marrow suppression. A limitation of this study method was the interpretation of chart documentation for determining the true cause of bone marrow suppression. Many more patients exhibited signs of anemia, thrombocytopenia, leukopenia, and/or neutropenia; however, only sulfamethoxazole/trimethoprim was discontinued as the probable offending agent. The practice of discontinuing sulfamethoxazole/ trimethoprim alone instead of sulfamethoxazole/ trimethoprim and the antiviral agent appeared to be physician-specific. Some patients received other immunosuppressant agents, including azathioprine (1 patient on valganciclovir), mycophenolate mofetil (7 patients on valganciclovir and 7 patients on ganciclovir), sirolimus (2 patients on valganciclovir and 2 patients on ganciclovir), pentamidine (7 patients on valganciclovir and 11 patients on ganciclovir), and mercaptopurine (1 patient on valganciclovir). All patients in both treatment groups received tacrolimus during all or part of the study period. When these medications were taken into account, differences in cytopenia outcomes were not compared because of the small sample size. The true rate of adverse effects due to valganciclovir and ganciclovir may, therefore, be higher than reported. The indication of the antiviral agent as the primary cause of abnormal laboratory values for anemia, thrombocytopenia, leukopenia, and neutropenia was dependent on documentation by the physician. Another limitation was the ability to determine the reasoning for the early discontinuation of therapy. Besides documentation of adverse drug

7 LIVER TRANSPLANTATION, Vol. 18, No. 3, 2012 BEDEL ET AL. 353 events, the reasons for early discontinuation were unknown. Two patients were difficult to classify because they were treated as high-risk patients even though their CMV serology status was unknown at the time of transplantation. Only 56 patients were able to be included in this study; thus, this study was not powered to find a difference between the treatment groups because of the small number of patients meeting the inclusion criteria. Therefore, we are unable to make any concluding statements about the superiority or inferiority of one antiviral agent versus the other on the basis of this study s results. Although the total patient population is small, if we consider that this is a pediatric study evaluating a very specific population, the number is actually relatively large for a single-center pediatric liver transplant cohort. Our study emphasizes the need for future research to investigate the true incidence of late-onset disease and to determine whether there is an association between valganciclovir and an increased risk of lateonset disease. This study found an increased rate of CMV disease in the valganciclovir group versus the ganciclovir group (22.2% versus 8.1%). Although this difference was not statistically significant and the low number of occurrences limits our ability to determine true clinical significance, this finding is notable and warrants future research. This result is particularly alarming when we consider the results of the Valganciclovir Solid Organ Transplant Study Group, which was led by Paya et al. 1 The Valganciclovir Solid Organ Transplant Study Group compared the efficacy and safety of valganciclovir versus oral ganciclovir for the prevention of CMV disease in SOT. That study included patients older than 13 years who had received their first heart, liver, kidney, kidney-pancreas, kidney-heart, or kidney-liver transplant with a donor-positive/recipient-negative CMV serology status. One hundred eighty-five of 372 patients were liver transplant recipients. The incidence of CMV disease in the liver subgroup was 19% with valganciclovir and 12% with ganciclovir. The incidence of significant tissue-invasive CMV disease was also found to be approximately 4.5 times higher in the valganciclovir group (14% versus 3%) 6 months after transplantation. Because the incidence of CMV disease was increased in liver transplant patients on valganciclovir versus liver transplant patients on oral ganciclovir, valganciclovir did not receive FDA approval for CMV prophylaxis. Subsequent studies have shown no difference in the incidence of late-onset CMV disease 4,5 ; however, this study s results do mimic those reported by Paya et al. The reasons for this reported difference in the liver transplant population are not known. In conclusion, our results are inconclusive about whether a difference exists in the safety and efficacy outcomes of ganciclovir and valganciclovir as prophylaxis for early- and late-onset CMV infection and disease in pediatric liver transplant patients. The association of valganciclovir with late-onset CMV disease warrants further investigation. A larger multicenter prospective clinical trial in the pediatric liver transplant population may be warranted to address the important concerns raised by our single-center retrospective review. REFERENCES 1. Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, et al.; for Valganciclovir Solid Organ Transplant Study Group. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2004;4: Cincinnati Children s Hospital Medical Center. 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