The ecacy and safety of valganciclovir vs.oral ganciclovir in the prevention ofsymptomatic CMV infection in children aftersolid organ transplantation

Survival in pediatric SOT continues to improve asstrategies for immunosuppression and infectioncontrol progress (1). However, infections remaina leading cause of morbidity and mortality inpediatric transplant recipients (2). CMV has long

been recognized as a common viral opportunisticpathogen following SOT and it can lead tosignicant complications if not treated promptly(1). Its incidence in transplant recipients variesfrom 5% to 60% with the highest rate in thepediatric population, as a considerable propor-tion of them are CMV-seronegative and receivesorgans from CMV-seropositive donors (36).Eorts to prevent CMV infection and its

consequences in SOT recipients have entailedthe use of prophylactic treatment with antiviralagents. These agents reduce the risk for CMVinfection and associated mortality compared toplacebo (6, 7). IV ganciclovir is an eectiveprophylaxis and treatment for CMV disease inSOT, but its use requires central line placement

Lapidus-Krol E, Shapiro R, Amir J, Davidovits M, Steinberg R, MorE, Avitzur Y. The ecacy and safety of valganciclovir vs. oral ganci-clovir in the prevention of symptomatic CMV infection in children aftersolid organ transplantation.PediatrTransplantation2010:14:753760.2010JohnWiley&SonsA/S.

Abstract: Routine prophylaxis for CMV with valganciclovir is commonin adult recipients but data to support its use in children are scarce. Theaim of this study was to compare the ecacy and safety of valganci-clovir vs. ganciclovir in a pediatric cohort. We performed a retrospec-tive analysis of 92 children after KTx and/or LTx. All children havereceived IV ganciclovir for two wk, and then oral ganciclovir (TID;n = 41) before 2004, or valganciclovir (OD; n = 51) thereafter.Treatment was given for three months in R+/D+ or R+/D) recipi-ents and for six months in R)/D+. Patients were followed for one yrpost transplant. Both groups were comparable in their demographicand transplant-related history. Symptomatic CMV infection/diseasedeveloped in 13.7% vs. 19.5% of valganciclovir and ganciclovir groups,respectively (P-NS). Time-to-onset of CMV infection was comparablein both groups (P-NS); rates of acute allograft rejection were similar inboth groups (3.9% vs. 9.8%). Risk factors for CMV infection includedyoung age, serostatus of R)/D+, and allograft from cadaver donor.No signicant side eects were noted in both groups. As in adults,valganciclovir appears to be as ecacious and safe as oral ganciclovir.Valganciclovir should be considered as a possible prophylactic treat-ment for CMV in pediatric recipients of KTx or LTx.

E. Lapidus-Krol1*, R. Shapiro2,J. Amir1, M. Davidovits3, R. Steinberg4,E. Mor5 and Y. Avitzur21Department of Pediatrics C, 2Institute ofGastroenterology, Nutrition and Liver Diseases,3Institute of Nephrology and 4Department of GeneralSurgery, Schneider Childrens Medical Center ofIsrael, and 5Department of Organ Transplantation,Rabin Medical Center, Petah-Tikva, Sackler School ofMedicine, Tel Aviv University, Tel Aviv, Israel

Key words: cytomegalovirus infections/disease antiviral prophylaxis ganciclovir/valganciclovir children risk factors kidney/liver transplantation

Yaron Avitzur MD, Division of Gastroenterology,Hepatology and Nutrition, The Hospital for SickChildren, 555 University Ave., Toronto, ON, CanadaM5G 1X8Tel.: 416 813 7733Fax: 416 813 4972E-mail: yaron.avitzur@sickkids.ca

*This work was conducted as a partial fulfillment ofthe requirements for Master of Science degree inEpidemiology and Preventive Medicine at theGraduate School of Sackler Faculty of Medicine, TelAviv University, Tel Aviv, Israel.

Accepted for publication 22 January 2010

Abbreviations: ALT, alanine aminotransferase; AST,aspartate aminotransferase; BID, two times a day; CBC,complete blood count; CI, condence intervals; CMV,cytomegalovirus; FDA, Food and Drug Administration;GI, gastrointestinal; IS, immunosuppression; IV, intrave-nous; KLTx, combined kidney and liver transplantation;KTx, kidney transplantation; LTx, liver transplantation;MMF, mycophenolate mofetil; P-NS; PTLD, post-trans-plant lymphoproliferative disease; SOT, solid organ trans-plantation; TID, three times a day.

Pediatr Transplantation 2010: 14: 753760 2010 John Wiley & Sons A/S.

Pediatric TransplantationDOI: 10.1111/j.1399-3046.2010.01330.x

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that frequently leads to inconvenience, expen-sive hospitalizations, frequent home health vis-its, and risk of line-related infection (810).Thus, the use of oral prophylaxis has thepotential to be safer and more convenient withlower overall cost. Oral ganciclovir prophylaxishas decreased the incidence and severity ofCMV infection and disease in adults after SOT,including high-risk patients (R)/D+) (11).However, oral ganciclovir is given three timesa day and has a low bioavailability with poorabsorption. Valganciclovir, the valine ester pro-drug of ganciclovir, has been observed todisplay up to a 10-fold higher level of bioavail-ability (60% vs. 610% when compared withoral ganciclovir) with a better compliancebecause of the fact that it is given in a once-daily dose (12). The ecacy of valganciclovir inadult recipients of SOT is well known (6, 13);however, data to support its use in children arescarce. A recently published study of 63 pedi-atric SOT recipients at risk for CMV disease hasfound that valganciclovir given at a dosingalgorithm adjusted for body surface area andrenal function provides ganciclovir exposuressimilar to those established as safe and eectivein adults (14). In addition, a retrospective caseseries of 10 pediatric liver transplant recipientsdemonstrated that valganciclovir (1518 mg/kg/day) given at the time of transplantationappears to be safe and eective in the prophy-laxis against CMV infection in low-risk patients(R+/D), R+/D+, R)/D)) (15). Pediatricstudies comparing ganciclovir to valganciclovirhave not been published yet.Thus, the aim of this study was to compare the

ecacy and safety of antiviral prophylaxis withvalganciclovir vs. oral ganciclovir in the preven-tion of symptomatic CMV infection or disease inkidney and liver transplant pediatric recipients.

Materials and methods

Patients and study design

A retrospective evaluation of all children who underwentKTx and/or LTx at Schneider Childrens Medical Center ofIsrael between the years 2000 and 2007 was conducted.Exclusion criteria included: recipients with R)/D) sero-status; graft loss or death within six months post trans-plantation for reasons other than CMV infection;combined treatment with acyclovir; or lost to follow-up.This study was designed to follow patients for one yr aftertransplantation for early and late CMV infection andpossible side eects. For this reason, patients who diedprior to completion of the follow-up period were excluded.To prevent any theoretical or actual bias in the results, wealso excluded any patient who have received acyclovir andrestricted the analysis to patients on one antiviral medica-tion. Eligible patients were divided into two groups

according to their CMV prophylactic treatment with eithervalganciclovir or ganciclovir. Patients were followed forone yr after transplantation. The ecacy and safety of thetwo treatment regimens were compared. The study wasapproved by the Helsinki Research Institutional EthicsCommittee.

Data collection

Demographic features, medical history, transplant relatedhistory, CMV serostatus and prophylaxis, and laboratoryparameters of all patients were reviewed by medical chartsand computer-assisted charts through the Schneider Chil-drens Medical Center Archive, the Electronic Data Inter-face (OFEK, CLIX), and the transplantation databases ofSchneider Childrens Medical Center and the NationalInstitute for Transplantation in Israel.

Immunosuppression

Immunosuppressive regimens included antibody inductionprotocol therapy with thymoglobulin or daclizumab since2005 with triple immunosuppressants: tacrolimus, MMF,and corticosteroids.

LTxTacrolimus was given orally with target trough whole bloodlevels of 1015 ng/mL in the rst three months, 810 ng/mLat 36 months, 68 ng/mL at 612 months, and 35 ng/mLthereafter. MMF (600 mg/m2) was administered routinelyprior to 2006 and thereafter to cases with chronic renalfailure, tacrolimus toxicity, or recurrent graft rejection.Corticosteroids were gradually tapered from 10 to 0.1 mg/kg in the rst six months and then discontinued. Cyclo-sporine was given only to patients with tacrolimus neuro-toxicity. Subsequent immunosuppressive adjustments weremade based on the individuals clinical course consideringthe presence of rejection, drug toxicity, or infection.

KTxTacrolimus was given orally with target trough whole bloodlevels of 1015 ng/mL during the rst month, 812 ng/mLin the second and third month, 510 ng/mL in the 46 month, and 36 ng/mL thereafter. MMF was adminis-tered orally at a dosage of 600 mg/m2 BID during the rsttwo wks and 300 mg/m2 BID thereafter. Corticosteroidswere gradually tapered from 40 to 5 mg/m2/day during therst six months (minimal dose 2.5 mg/day). Treatment withcyclosporine and individual changes in IS were givenaccording to the same indications as in LTx.

CMV prophylaxis

IVGanciclovir (5 mg/kgBID)was given to all children for therst two wk post-transplant followed by oral ganciclovir(TID) before 2004 or valganciclovir (OD) thereafter. Treat-ment was given for three months in R+/D+ or R+/D) recipients and for six months in R)/D+. Ganciclovirdose was 30 mg/kg/dose up to 1 g/dose TID (16). Valganci-clovir was given once daily (oral solution or tablets up to amaximum of 900 mg). Valganciclovir oral solution was pro-vided by the hospital pharmacy by using 20 crushed tablets ofValcyte (450 mg 20 = 9000 mg) for reconstitution with20 mL of puried water, 1 mL of hydrochloric acid 10% (forpH adjustment to 3.2), and 100 mL of sucrose syrup to a nalvolume of 225 mL (valganciclovir concentration, 90 mg/

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mL). The suspension was chemically stable in temperature of28 C for up to 35 days (17, 18). The daily dose of val-ganciclovir in mg was determined by the following equation,which was provided by Roche Pharmaceutical (Kiryat Ma-talon Petach Tikva, Israel): 7 body surface area creati-nine clearance (according to the Schwartzs equation withcorrection to the child pubertal status and sex) (14).

CMV infection and disease definition, diagnosis, andtreatment

Symptomatic CMV infection was dened as isolation ofCMV or detection of viral nucleic acid in any body uid ortissue specimen with the clinical symptoms of fever 38 C,myalgia, new or increased malaise, and at least one of thefollowing: leukopenia (WBC 4000/mm3), thrombocyto-penia (Platelets 100 000/mm3), or increased liver func-tion tests (AST, ALT twice the upper limit of normal innon-liver transplant recipients) without another explanationor evidence of tissue invasion.Tissue-invasive CMV disease was diagnosed histopatho-

logically by the presence of CMV typical viral inclusionbodies or positive immunohistochemistry in the involvedorgan, with or without evidence of CMV in blood, and inassociation with apparent symptoms or signs of pneumonia,gastrointestinal disease, hepatitis, or other tissue-invasivedisease (19, 20).All patients with CMV infection or disease were initially

hospitalized and treated for at least 14 days with IVganciclovir followed by a 3- to 6-month course of oralganciclovir or valganciclovir.The denition of CMV infection does not include

asymptomatic infection. A screening protocol for asymp-tomatic CMV viremia was not an integral part of our rou-tine post-transplant follow-up.

Statistical analysis

All demographic data were analyzed using descriptive sta-tistics. All continuous data were compared between groupsusing Student t test if normal distribution assumed; MannWhitney or KruskalWallis test if normal distributionwithin a number of groups were not assumed. Dierencebetween laboratory tests was analyzed using repeated mea-sures if normal distribution assumed, if normal distributioncould not be assumed, these variables were analyzed aftertransformation with logarithm. Univariate association ofeach categorical variable with CMV infection was analyzedby the chi-square test or Fishers exact test. The dierencesin proportions ganciclovir valganciclovir were calculatedwith 95% CI.Time-to-event data were graphically displayed using a

KaplanMeier analysis and log-rank test comparing theCMV infection/disease-free survival rates between the twogroups.Multiple logistic regression analysis was performed to

determine if any variable had an independent inuence onthe development of CMV infection/disease while potentialconfounders were stratied.A p-value

(p = 0.460). Eleven cases of CMV episodeoccurred within the rst six months post-trans-plant with nine (60%) of those emerging whilereceiving CMV prophylaxis. All nine casesbelonged to the high-risk R)/D+ group, fourpatients from ganciclovir group, and ve fromvalganciclovir.

Because of the potential role of CMV ininduction of acute rejection or PTLD, the ratesof these pathologies were compared between thegroups. The rate of acute allograft rejection wassimilar between the study groups (25% valganci-clovir vs. 34% ganciclovir, P-NS) and betweenpatients with CMV infection compared to non-infected patients (40% vs. 27.3%, respectively, P-NS).Five patients in the ganciclovir group and one

patient in the valganciclovir group developedchronic graft rejection. No case of PTLD wasobserved.

Risk factors

Table 2 displays risk factors for CMV infectionfor the overall population with respect topotential confounders according to increasingorder. The risk factors identied for acquisitionof CMV infection included donor/recipient CMVserologic status and age of transplant recipient.R)/D+ was associated with the highest inci-dence of CMV infection (30%), while R+/D+and R+/D) were the lowest risk group (6.9%),OR = 0.17 (95% CI, 0.04; 0.59). Young age oftransplant recipient was also associated withhigher incidence of CMV infection (p = 0.005)with a mean age of 5.7 in recipients whodeveloped CMV infection compared to 10.5 yrin the CMV-negative group. Of 15 patients whodeveloped CMV illness, 10 belonged to the high-risk R)/D+ group, of which ve patients were inthe oral ganciclovir group and ve patients in thevalganciclovir group. Other possible risk factorsas shown in Table 2 did not reach statisticalsignicance.Inmultivariate analysis, young age (p =0.012),

R)/D+ CMV serostatus (p = 0.011), and cad-averic allograft (p = 0.026) were found asindependent risk factors for the development ofCMV infection.

Safety

The safety prole of valganciclovir was similar tothat of oral ganciclovir. No severe side eectswere noticed in all patients. CBC, renal, and liverfunction tests at one and a half, three, andsix months post-transplantation were compara-ble in both groups (Table 3). The overall inci-dence of adverse events was low (n = 3). Onepatient on oral ganciclovir withdrew because ofrash that was considered to be related to theganciclovir. One patient in the valganciclovirgroup experienced nephrotoxicity and one pa-tient had mild thrombocytopenia (Platelets =88 000/mm3). Other episodes of leukopenia and

Table 1. Baseline demographic and transplant data of the ganciclovir andvalganciclovir groups, no. (%)

CharacteristicOral ganciclovir(n = 41)

Valganciclovir(n = 51) p-Value

Age (years)Mean s.d. 9.608 5.17 9.912 5.64 0.727Range 0.817 0.618.3GenderMale 29 (70.7%) 32 (62.7%) 0.508Female 12 (29.3%) 19 (37.3%)Transplantation typesKidney 25 (61%) 38 (74.5%) 0.183Liver 16 (39%) 13 (25.5%)Donation typeLiving-related 15 (36.6%) 12 (23.5%) 0.249Cadaver 26 (63.4%) 39 (76.5%)CMV serostatusR)/D+ 15 (37.5%) 18 (35.3%) 0.641R+/D) 3 (7.5%) 7 (13.7%)R+/D+ 22 (55%) 26 (51%)Pretransplant diagnosis

LTxBilliary atresia 4 (25%) 6 (46.2%) 0.192Metabolic 8 (50%) 2 (15.4%)Acute liver failure 2 (12.5%) 1 (7.7%)Other 2 (12.5%) 4 (30.8%)

KTxHereditary and congenitaldiseases of the kidney

13 (52%) 26 (68.4%) 0.632

Primary glomerular diseases 2 (8%) 2 (5.3%)Hemolytic-uremic syndrome 1 (4%) 1 (2.6%)Other 9 (36%) 9 (23.7%)

Transplant numberFirst 34 (82.9%) 42 (82.4%) 0.094Retransplant 7 (17.1%) 9 (17.6%)Immunosuppressive treatment

Induction therapyATG/ThyGB 17 (41.5%) 22 (43.1%) 0.003*Daclizumab 11 (21.6%)None 24 (58.5%) 18 (35.3%)

Maintenance regimenFK + Pred 4 (9.8%) 4 (7.8%) 0.787FK + MMF 1 (2%)Fk + MMF + Pred 36 (87.8%) 44 (86.3%)CsA + MMF + Pred 1 (2.4%) 2 (3.9%)

Acute rejection 14 (34.1%) 13 (25.5%) 0.49Chronic rejection 5 (12.2%) 1 (2%) 0.085ATN 9 (22%) 10 (19.6%) 0.801Other opportunistic infectionsViral 7 (17.1%) 6 (11.8%) 0.563Bacterial 21 (51.2%) 37 (72.5%) 0.050*Fungal 9 (22%) 11 (21.6%) 1Postoperative complications 26 (63.4%) 31 (60.8%) 0.832Known incompliance 3 (7.3%) 2 (3.9%) 0.653

ATN, acute tubular necrosis.*Statistically significant.

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elevated creatinine were considered by the treat-ing physicians as unrelated to the prophylaxistreatment, but rather to immunosuppressiveagents or kidney-related etiologies and usuallyresolved after treating those etiologies without achange in the antiviral medications dose.

Discussion

The ecacy and safety of valganciclovir in adultSOT recipients is well known, but only fewpediatric studies have assessed its ecacy in theprevention of CMV episode (6, 14, 15). Thecurrent study is the rst to compare the ecacyand safety of valganciclovir vs. oral gancicloviramong pediatric recipients after KTx and/orLTx.The overall incidence of CMV episode in our

study was 16% (15/92 patients). This rateresembles rates reported in earlier studies, inwhich the incidence of CMV episode in post-transplantation patients with prophylactic treat-ment ranged from 5% to 40% (2024). As inadults, valganciclovir appears to be as ecaciousas oral ganciclovir in the prevention of CMVepisode in children after liver or kidney trans-plantation (incidence of 13.7% vs. 19.5%, respec-tively, p = 0.573). Paya et al. (13) showed inmulticenter randomized prospective trial that by12 months, a once-daily dose of 900-mg ofvalganciclovir was as eective and safe as a 1 gTID of oral ganciclovir (infection rate of 17.2%vs. 18.4%, respectively) for the prevention ofCMV disease in high-risk CMV R)/D+ SOTrecipients. Similarly, a retrospective analysisfound that in kidney and/or pancreas transplantrecipients, three months of prophylaxis withvalganciclovir (450 mg/day) was as eective asoral ganciclovir (1 g TID) for preventionof CMV infection (15% vs. 17%, respectively)at one-yr follow-up (25). A recent systematicreview of randomized controlled trials of CMV

Table 2. Risk factors for CMV infection/disease for the overall study popu-lation

Risk factorCMV infection/disease(n = 15)

Free of CMV(n = 77) p-Value

CMV serostatusR)/D+ 10 (71.4%) 23 (29.9%) 0.005*R+/D) 2 (14.3%) 8 (10.4%)R+/D+ 2 (l4.3%) 46 (59.7%)Age (years)Mean s.d. 5.678 5.096 10.575 5.135 0.002*Transplantation typesLiver 8 (53.3%) 21 (27.3%) 0.068Kidney 7 (46.7%) 56 (72.6%)Donor typeLiving related 2 (13.3%) 25 (32.5%) 0.215Cadaver 13 (86.7%) 52 (67.5%)Acute rejectionNo 9 (60%) 56 (72.7%) 0.360Yes 6 (40%) 21 (27.3%)Chronic rejectionNo 14 (93.3%) 72 (93.5%) 1.000Yes 1 (6.7%) 5 (6.5%)Induction therapyNo 8 (53.3%) 34 (44.2%) 0.578Yes 7 (46.7%) 43 (55.8%)GenderMale 8 (53.3%) 53 (68.8%) 0.251Female 7 (46.7%) 24 (31.2%)

Fig. 1. KaplanMeier curve forCMV episode free survivalbetween the two prophylaxisgroups.

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prophylaxis also supported the notion that val-ganciclovir is as eective as oral ganciclovir (7).Previous publications in SOT adult recipients

have not found a therapeutic disadvantage forvalganciclovir in liver transplant recipients (13,25, 26). However, Paya et al. (13) have sug-gested that in the liver transplant sub-popula-tion, there was a higher incidence of overallCMV disease in the valganciclovir arm (19% vs.12%) and an increase in the number of patientswith tissue-invasive CMV disease in the high-risk group R)/D+ (14% in the valganciclovirarm vs. 3% in ganciclovir). Based on theseresults, the FDA cautioned against the use ofvalganciclovir for the prevention of CMV dis-ease in the high-risk R)/D+ liver transplantrecipients. However, some experts still use andrecommend valganciclovir for this patient pop-ulation (27, 28), and in Canada, for example,valganciclovir is approved for all organ groups(20). In our study, we found that four childrendeveloped tissue-invasive CMV disease, two ofthem were liver transplant recipients, onekidney, and one combined kidney with liver(valganciclovir n = 3, ganciclovir n = 1). Nev-ertheless, because of the low number of events inour study it is impossible to draw a solidconclusion regarding this risk.The safety prole of valganciclovir was similar

to that of oral ganciclovir, as was previouslyfound in other studies (13, 25, 26). Both groupswere comparable regarding the incidence of renaltoxicity, leukopenia, or neutropenia, and onlyone patient in the ganciclovir group had to stopthe treatment because of rash. Moreover, most

cases of leukopenia were considered by thetreating physicians as unrelated to gancicloviror valganciclovir but rather to other factors post-transplant mainly other drugs such as MMF orinfections. Those episodes usually resolved with-out any change in the dose of the antiviralmedications. Nevertheless, considering the retro-spective nature of the study and its sample size,the true incidence of severe adverse events mightbe dierent.CMV serostatus is considered to be the most

important predictor for CMV infection aftertransplantation (21, 29, 30) and the incidence ofCMV disease in the high-risk group (R)/D+)varies from 40% to 73% without prophylaxis(10). Along those lines, our study demonstratedincidence of CMV infection of 30% in the high-risk group (R)/D+) versus 7% in the interme-diate risk group (R+/D+, R+/D)). Unlikeother publications (13, 14), four patients in theoral ganciclovir group and ve in the valganci-clovir group developed CMV episode whileunder active prophylaxis. All of them belongedto the high-risk category (R)/D+) that wastreated for six months. The reason for thedierence between our study and others isunknown. Whether prophylaxis with IV ganci-clovir will be more eective in children withR)/D+ than oral treatment remains an openquestion. Other risk factors for CMV infectionthat have been identied in the current studyincluded young age of recipient and cadavericgraft type. These observations are supported byother studies dealt with risk factors for CMVinfection (1, 6, 10, 25, 29, 31).

Table 3. Safety parameters during prophylaxis with ganciclovir and valganciclovir

Time

1.5 month 3 month 6 month

N Mean s.d. N Mean s.d. N Mean s.d.

White Blood Cell (K/lL) Ganciclovir 40 9.2 3.4 40 7.5 2.6 39 7.4 2.2Valganciclovir 51 8.2 4.5 51 6.1 2.8 50 6.5 2.9

Hemoglobin (g/dL) Ganciclovir 40 11.4 1.7 40 11.7 2.1 39 11.6 1.7Valganciclovir 51 10.8 1.54 51 11.3 1.7 50 13.4 1.7

Platelets (K/lL) Ganciclovir 40 279 137.1 40 274.2 109.6 39 276.6 105Valganciclovir 51 296.8 130.4 51 283.6 89.3 50 268 99.5

Creatinine (mg/dL) Ganciclovir 41 1.28 1.84 40 1.18 1.44 39 1.32 1.8Valganciclovir 51 0.98 1.23 40 1.18 1.44 50 1.03 1.3

Urea (mg/dL) Ganciclovir 41 48.5 39.6 40 49.3 40.3 39 49.1 31Valganciclovir 51 44.7 19.2 51 41.8 18 50 41.3 16.5

AST (U/L) Ganciclovir 40 28.7 27.4 40 28.4 22 39 34.4 31.05Valganciclovir 51 31.4 48.5 50 27.6 25.6 49 28.6 21.2

ALT (U/L) Ganciclovir 41 36 45 40 27.8 29.8 39 46 66.5Valganciclovir 51 26 27.8 50 27.2 36.2 49 29 55.6

GGT (U/L) Ganciclovir 40 112.3 186 40 94.1 180.6 39 86.1 147.8Valganciclovir 51 49.3 80.3 51 39.8 77 50 45.7 100.6

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Previous reports on medication compliancehave conrmed the inverse relationship betweennumber of daily doses and rate of compliance(32, 33). A systematic review of the associationbetween dose regimens and medication compli-ance found that compliance was signicantlyhigher for once-daily (79%) versus three-times-daily (65%) regimens (p = 0.008) (32). In chil-dren after SOT, compliance is a major challengeand determinant of graft and patient outcome.One of the strategies to improve compliance inpediatrics is a reduction in the number of dailydoses of any medication, if possible. The fact thatvalganciclovir is given once daily (12 pills/day)compared to three times a day with oral ganci-clovir (612 capsules/day) can improve signi-cantly the compliance in the pediatric age group.Unfortunately, we could not assess a day to daycompliance to either valganciclovir or ganciclovirin this retrospective study as these data are notroutinely recorded in our medical records.The current study has a few shortcomings that

deserve to be acknowledged. The relatively smallsample size of 92 patients undoubtedly couldhave decreased the power and ability to detectsignicant dierences in the ecacy and thesafety of the treatment regimens. To nd a 10%dierence between treatment groups with a deltaof 5% and power of 80%, a sample size of atleast 198 individuals would be needed in eachgroup. In addition, the retrospective nature ofthe study could have lead to loss of importantdata and misclassication bias. This was largelyovercome by using our computerized and pro-spectively collected databases. A selection bias asa result of biased sampling is unlikely as ourinstitute performs the vast majority of pediatrickidney and liver transplants in Israel. In addi-tion, although 28 children were lost to follow-upbecause of transfer of care to other hospitals, aselection bias is unlikely considering the randomtransfer of these patients, according to theirresidence. Other possible confounders include theuse of mixed population of kidney and livertransplant recipients and comparison of dierenteras of immunosuppression. However, the distri-bution of the dierent organs was equal betweenthe groups, and the same method have been usedrepeatedly in adult studies to increase their powerwithout an eect on the results (13). The onlysignicant dierence in the immunosuppressiveregimen was related to the use of inductiontherapy. Forty percents of the patients in bothgroups have received thymoglobulin, while 21%of the patients in the valganciclovir group weretreated with IL-2 blockers compared to none inthe ganciclovir group. Although it is impossible

to control for the eect of this change, it isprobably minor or at the most should haveincreased the number of CMV infections in thevalganciclovir group. These limitations call for alarge multicenter prospective randomized pedi-atric study to further evaluate the role ofvalganciclovir in pediatric recipients. Until then,an alternative strategy for treatment decisionmaking can be reliance on adult studies and onretrospective pediatric studies such as this one.In summary, we have demonstrated that as in

adults, valganciclovir appears to be as safe and asclinically eective as ganciclovir in the prophy-laxis against CMV infection in pediatric patientsfollowing kidney, liver, and combined liverkidney transplantation. A multicenter, prospec-tive randomized controlled study comparingvalganciclovir to either oral or IV ganciclovir iswarranted to further evaluate the role of val-ganciclovir in pediatric recipients.

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