2010 John Wiley & Sons A/S.

Pediatr Transplantation 2010: 14: 753760

Pediatric Transplantation
DOI: 10.1111/j.1399-3046.2010.01330.x

The ecacy and safety of valganciclovir vs.

oral ganciclovir in the prevention of
symptomatic CMV infection in children after
solid organ transplantation
Lapidus-Krol E, Shapiro R, Amir J, Davidovits M, Steinberg R, Mor
E, Avitzur Y. The ecacy and safety of valganciclovir vs. oral ganciclovir in the prevention of symptomatic CMV infection in children after
solid organ transplantation.
Pediatr Transplantation 2010: 14: 753760.  2010 John Wiley & Sons A/S.
Abstract: Routine prophylaxis for CMV with valganciclovir is common
in adult recipients but data to support its use in children are scarce. The
aim of this study was to compare the ecacy and safety of valganciclovir vs. ganciclovir in a pediatric cohort. We performed a retrospective analysis of 92 children after KTx and/or LTx. All children have
received 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) recipients and for six months in R)/D+. Patients were followed for one yr
post transplant. Both groups were comparable in their demographic
and transplant-related history. Symptomatic CMV infection/disease
developed in 13.7% vs. 19.5% of valganciclovir and ganciclovir groups,
respectively (P-NS). Time-to-onset of CMV infection was comparable
in both groups (P-NS); rates of acute allograft rejection were similar in
both groups (3.9% vs. 9.8%). Risk factors for CMV infection included
young 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 treatment for CMV in pediatric recipients of KTx or LTx.

E. Lapidus-Krol1*, R. Shapiro2,
J. Amir1, M. Davidovits3, R. Steinberg4,
E. Mor5 and Y. Avitzur2
1

Department of Pediatrics C, 2Institute of

Gastroenterology, Nutrition and Liver Diseases,
3
Institute of Nephrology and 4Department of General
Surgery, Schneider Childrens Medical Center of
Israel, and 5Department of Organ Transplantation,
Rabin Medical Center, Petah-Tikva, Sackler School of
Medicine, 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 Sick
Children, 555 University Ave., Toronto, ON, Canada
M5G 1X8
Tel.: 416 813 7733
Fax: 416 813 4972
E-mail: yaron.avitzur@sickkids.ca
*This work was conducted as a partial fulfillment of
the requirements for Master of Science degree in
Epidemiology and Preventive Medicine at the
Graduate School of Sackler Faculty of Medicine, Tel
Aviv University, Tel Aviv, Israel.
Accepted for publication 22 January 2010

Survival in pediatric SOT continues to improve as

strategies for immunosuppression and infection
control progress (1). However, infections remain
a leading cause of morbidity and mortality in
pediatric transplant recipients (2). CMV has long

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, intravenous; KLTx, combined kidney and liver transplantation;
KTx, kidney transplantation; LTx, liver transplantation;
MMF, mycophenolate mofetil; P-NS; PTLD, post-transplant lymphoproliferative disease; SOT, solid organ transplantation; TID, three times a day.

been recognized as a common viral opportunistic

pathogen following SOT and it can lead to
signicant complications if not treated promptly
(1). Its incidence in transplant recipients varies
from 5% to 60% with the highest rate in the
pediatric population, as a considerable proportion of them are CMV-seronegative and receives
organs from CMV-seropositive donors (36).
Eorts to prevent CMV infection and its
consequences in SOT recipients have entailed
the use of prophylactic treatment with antiviral
agents. These agents reduce the risk for CMV
infection and associated mortality compared to
placebo (6, 7). IV ganciclovir is an eective
prophylaxis and treatment for CMV disease in
SOT, but its use requires central line placement
753

Lapidus-Krol et al.

that frequently leads to inconvenience, expensive hospitalizations, frequent home health visits, and risk of line-related infection (810).
Thus, the use of oral prophylaxis has the
potential to be safer and more convenient with
lower overall cost. Oral ganciclovir prophylaxis
has decreased the incidence and severity of
CMV infection and disease in adults after SOT,
including high-risk patients (R)/D+) (11).
However, oral ganciclovir is given three times
a day and has a low bioavailability with poor
absorption. Valganciclovir, the valine ester prodrug of ganciclovir, has been observed to
display up to a 10-fold higher level of bioavailability (60% vs. 610% when compared with
oral ganciclovir) with a better compliance
because of the fact that it is given in a oncedaily dose (12). The ecacy of valganciclovir in
adult recipients of SOT is well known (6, 13);
however, data to support its use in children are
scarce. A recently published study of 63 pediatric SOT recipients at risk for CMV disease has
found that valganciclovir given at a dosing
algorithm adjusted for body surface area and
renal function provides ganciclovir exposures
similar to those established as safe and eective
in adults (14). In addition, a retrospective case
series of 10 pediatric liver transplant recipients
demonstrated that valganciclovir (1518 mg/kg/
day) given at the time of transplantation
appears to be safe and eective in the prophylaxis against CMV infection in low-risk patients
(R+/D), R+/D+, R)/D)) (15). Pediatric
studies comparing ganciclovir to valganciclovir
have not been published yet.
Thus, the aim of this study was to compare the
ecacy and safety of antiviral prophylaxis with
valganciclovir vs. oral ganciclovir in the prevention of symptomatic CMV infection or disease in
kidney and liver transplant pediatric recipients.
Materials and methods
Patients and study design
A retrospective evaluation of all children who underwent
KTx and/or LTx at Schneider Childrens Medical Center of
Israel between the years 2000 and 2007 was conducted.
Exclusion criteria included: recipients with R)/D) serostatus; graft loss or death within six months post transplantation 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 after
transplantation for early and late CMV infection and
possible side eects. For this reason, patients who died
prior to completion of the follow-up period were excluded.
To prevent any theoretical or actual bias in the results, we
also excluded any patient who have received acyclovir and
restricted the analysis to patients on one antiviral medication. Eligible patients were divided into two groups

754

according to their CMV prophylactic treatment with either

valganciclovir or ganciclovir. Patients were followed for
one yr after transplantation. The ecacy and safety of the
two treatment regimens were compared. The study was
approved by the Helsinki Research Institutional Ethics
Committee.

Data collection
Demographic features, medical history, transplant related
history, CMV serostatus and prophylaxis, and laboratory
parameters of all patients were reviewed by medical charts
and computer-assisted charts through the Schneider Childrens Medical Center Archive, the Electronic Data Interface (OFEK, CLIX), and the transplantation databases of
Schneider Childrens Medical Center and the National
Institute for Transplantation in Israel.

Immunosuppression
Immunosuppressive regimens included antibody induction
protocol therapy with thymoglobulin or daclizumab since
2005 with triple immunosuppressants: tacrolimus, MMF,
and corticosteroids.
LTx

Tacrolimus was given orally with target trough whole blood

levels of 1015 ng/mL in the rst three months, 810 ng/mL
at 36 months, 68 ng/mL at 612 months, and 35 ng/mL
thereafter. MMF (600 mg/m2) was administered routinely
prior to 2006 and thereafter to cases with chronic renal
failure, 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. Cyclosporine was given only to patients with tacrolimus neurotoxicity. Subsequent immunosuppressive adjustments were
made based on the individuals clinical course considering
the presence of rejection, drug toxicity, or infection.
KTx

Tacrolimus was given orally with target trough whole blood

levels of 1015 ng/mL during the rst month, 812 ng/mL
in the second and third month, 510 ng/mL in the 4
6 month, and 36 ng/mL thereafter. MMF was administered orally at a dosage of 600 mg/m2 BID during the rst
two wks and 300 mg/m2 BID thereafter. Corticosteroids
were gradually tapered from 40 to 5 mg/m2/day during the
rst six months (minimal dose 2.5 mg/day). Treatment with
cyclosporine and individual changes in IS were given
according to the same indications as in LTx.

CMV prophylaxis
IV Ganciclovir (5 mg/kg BID) was given to all children for the
rst two wk post-transplant followed by oral ganciclovir
(TID) before 2004 or valganciclovir (OD) thereafter. Treatment was given for three months in R+/D+ or R+
/D) recipients and for six months in R)/D+. Ganciclovir
dose was 30 mg/kg/dose up to 1 g/dose TID (16). Valganciclovir was given once daily (oral solution or tablets up to a
maximum of 900 mg). Valganciclovir oral solution was provided by the hospital pharmacy by using 20 crushed tablets of
Valcyte (450 mg 20 = 9000 mg) for reconstitution with
20 mL of puried water, 1 mL of hydrochloric acid 10% (for
pH adjustment to 3.2), and 100 mL of sucrose syrup to a nal
volume of 225 mL (valganciclovir concentration, 90 mg/

Valganciclovir vs. ganciclovir in pediatric recipients

mL). The suspension was chemically stable in temperature of
28 C for up to 35 days (17, 18). The daily dose of valganciclovir in mg was determined by the following equation,
which was provided by Roche Pharmaceutical (Kiryat Matalon Petach Tikva, Israel): 7 body surface area creatinine clearance (according to the Schwartzs equation with
correction to the child pubertal status and sex) (14).

CMV infection and disease definition, diagnosis, and

treatment
Symptomatic CMV infection was dened as isolation of
CMV or detection of viral nucleic acid in any body uid or
tissue specimen with the clinical symptoms of fever 38 C,
myalgia, new or increased malaise, and at least one of the
following: leukopenia (WBC 4000/mm3), thrombocytopenia (Platelets 100 000/mm3), or increased liver function tests (AST, ALT twice the upper limit of normal in
non-liver transplant recipients) without another explanation
or evidence of tissue invasion.
Tissue-invasive CMV disease was diagnosed histopathologically by the presence of CMV typical viral inclusion
bodies or positive immunohistochemistry in the involved
organ, with or without evidence of CMV in blood, and in
association with apparent symptoms or signs of pneumonia,
gastrointestinal disease, hepatitis, or other tissue-invasive
disease (19, 20).
All patients with CMV infection or disease were initially
hospitalized and treated for at least 14 days with IV
ganciclovir followed by a 3- to 6-month course of oral
ganciclovir or valganciclovir.
The denition of CMV infection does not include
asymptomatic infection. A screening protocol for asymptomatic CMV viremia was not an integral part of our routine post-transplant follow-up.

Statistical analysis
All demographic data were analyzed using descriptive statistics. All continuous data were compared between groups
using Student t test if normal distribution assumed; Mann
Whitney or KruskalWallis test if normal distribution
within a number of groups were not assumed. Dierence
between laboratory tests was analyzed using repeated measures if normal distribution assumed, if normal distribution
could not be assumed, these variables were analyzed after
transformation with logarithm. Univariate association of
each categorical variable with CMV infection was analyzed
by the chi-square test or Fishers exact test. The dierences
in proportions ganciclovir valganciclovir were calculated
with 95% CI.
Time-to-event data were graphically displayed using a
KaplanMeier analysis and log-rank test comparing the
CMV infection/disease-free survival rates between the two
groups.
Multiple logistic regression analysis was performed to
determine if any variable had an independent inuence on
the development of CMV infection/disease while potential
confounders were stratied.
A p-value <0.05 were considered as signicant. The statistical analysis was performed using spss for Windows
Version 16.0 (SPSS Inc., Chicago, IL, USA).
Because of the low incidence of overall symptomatic
CMV infection and tissue-invasive CMV disease, these two
types were combined into CMV episode for data analysis
in this study.

Results
Patient characteristics

Between January 1, 2001, and March 31, 2007,

153 children underwent KTx and/or LTx at
Schneider Childrens Medical Center. Of these,
61 patients (39%) were excluded from the study
because of: CMV serostatus R)/D) (n = 9);
graft loss or death within six months post transplantation (n = 11); combined treatment with
acyclovir (n = 13), and lost to follow-up because
of transfer of care to another hospital (n = 28).
None of the patients who were excluded from the
study had a CMV episode (data are missing for
patients who were lost to follow-up). Ninety-two
patients were included in the study (25 LTx, 63
KTx, and four combined KLTx). Of these, 41
patients received oral ganciclovir (12 LTx, 25
KTx, four KLTx) and 51 patients received oral
valganciclovir (13 LTx, 38 KTx) according to the
CMV prophylaxis protocol.
Table 1 displays the baseline patient demographics and post-transplant characteristics for
the oral ganciclovir and valganciclovir groups.
Both study groups were comparable in all
parameters except for a predicted dierence in
the type of induction therapy in view of the fact
that daclizumab was used in our center only in
the last few years. In addition, patients in the oral
ganciclovir group tended to have a higher incidence of bacterial opportunistic infections vs. the
valganciclovir group (72.5% vs. 51.2%,
p = 0.05).
Efficacy of treatment regimens

The overall incidence of CMV episode was 16%

(n = 15) with slightly lower incidence in the
valganciclovir group (13.7%, n = 7) compared
to the ganciclovir group (19.5%, n = 8;
p = 0.573). The dierence in proportions between treatment groups was 0.058 (95% CI,
)0.108; 0.233).
Of the 15 patients who developed CMV
episode, 11 patients developed symptomatic
infection and four had invasive disease. In the
patients with invasive disease, the GI tract or
liver were involved in all cases (gastritis; n = 1,
diarrhea; n = 1, hepatitis; n = 2). All patients
with CMV infection or invasive disease responded to IV ganciclovir that was given for a
mean duration of 14 days. There were no deaths
in the study groups.
Figure 1 depicts the actuarial CMV diseasefree survival rates between the two groups. The
overall time to CMV infection was not signicantly dierent for the two study groups
755

Lapidus-Krol et al.
Table 1. Baseline demographic and transplant data of the ganciclovir and
valganciclovir groups, no. (%)

Characteristic
Age (years)
Mean s.d.
Range
Gender
Male
Female
Transplantation types
Kidney
Liver
Donation type
Living-related
Cadaver
CMV serostatus
R)/D+
R+/D)
R+/D+
Pretransplant diagnosis
LTx
Billiary atresia
Metabolic
Acute liver failure
Other
KTx
Hereditary and congenital
diseases of the kidney
Primary glomerular diseases
Hemolytic-uremic syndrome
Other
Transplant number
First
Retransplant
Immunosuppressive treatment
Induction therapy
ATG/ThyGB
Daclizumab
None
Maintenance regimen
FK + Pred
FK + MMF
Fk + MMF + Pred
CsA + MMF + Pred
Acute rejection
Chronic rejection
ATN
Other opportunistic infections
Viral
Bacterial
Fungal
Postoperative complications
Known incompliance

Oral ganciclovir Valganciclovir

(n = 41)
(n = 51)
p-Value

9.608 5.17
0.817

9.912 5.64
0.618.3

0.727

29 (70.7%)
12 (29.3%)

32 (62.7%)
19 (37.3%)

0.508

25 (61%)
16 (39%)

38 (74.5%)
13 (25.5%)

0.183

15 (36.6%)
26 (63.4%)

12 (23.5%)
39 (76.5%)

0.249

15 (37.5%)
3 (7.5%)
22 (55%)

18 (35.3%)
7 (13.7%)
26 (51%)

0.641

4
8
2
2

6
2
1
4

(46.2%)
(15.4%)
(7.7%)
(30.8%)

0.192

13 (52%)

26 (68.4%)

0.632

2 (8%)
1 (4%)
9 (36%)

2 (5.3%)
1 (2.6%)
9 (23.7%)

34 (82.9%)
7 (17.1%)

42 (82.4%)
9 (17.6%)

0.094

17 (41.5%)

24 (58.5%)

22 (43.1%)
11 (21.6%)
18 (35.3%)

0.003*

4 (9.8%)

36 (87.8%)
1 (2.4%)
14 (34.1%)
5 (12.2%)
9 (22%)

4 (7.8%)
1 (2%)
44 (86.3%)
2 (3.9%)
13 (25.5%)
1 (2%)
10 (19.6%)

0.787

0.49
0.085
0.801

7 (17.1%)
21 (51.2%)
9 (22%)
26 (63.4%)
3 (7.3%)

6 (11.8%)
37 (72.5%)
11 (21.6%)
31 (60.8%)
2 (3.9%)

0.563
0.050*
1
0.832
0.653

(25%)
(50%)
(12.5%)
(12.5%)

Risk factors

ATN, acute tubular necrosis.

*Statistically significant.

(p = 0.460). Eleven cases of CMV episode

occurred within the rst six months post-transplant with nine (60%) of those emerging while
receiving CMV prophylaxis. All nine cases
belonged to the high-risk R)/D+ group, four
patients from ganciclovir group, and ve from
valganciclovir.
756

Because of the potential role of CMV in

induction of acute rejection or PTLD, the rates
of these pathologies were compared between the
groups. The rate of acute allograft rejection was
similar between the study groups (25% valganciclovir vs. 34% ganciclovir, P-NS) and between
patients with CMV infection compared to noninfected patients (40% vs. 27.3%, respectively, PNS).
Five patients in the ganciclovir group and one
patient in the valganciclovir group developed
chronic graft rejection. No case of PTLD was
observed.

Table 2 displays risk factors for CMV infection

for the overall population with respect to
potential confounders according to increasing
order. The risk factors identied for acquisition
of CMV infection included donor/recipient CMV
serologic status and age of transplant recipient.
R)/D+ was associated with the highest incidence 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 of
transplant recipient was also associated with
higher incidence of CMV infection (p = 0.005)
with a mean age of 5.7 in recipients who
developed CMV infection compared to 10.5 yr
in the CMV-negative group. Of 15 patients who
developed CMV illness, 10 belonged to the highrisk R)/D+ group, of which ve patients were in
the oral ganciclovir group and ve patients in the
valganciclovir group. Other possible risk factors
as shown in Table 2 did not reach statistical
signicance.
In multivariate analysis, young age (p = 0.012),
R)/D+ CMV serostatus (p = 0.011), and cadaveric allograft (p = 0.026) were found as
independent risk factors for the development of
CMV infection.
Safety

The safety prole of valganciclovir was similar to

that of oral ganciclovir. No severe side eects
were noticed in all patients. CBC, renal, and liver
function tests at one and a half, three, and
six months post-transplantation were comparable in both groups (Table 3). The overall incidence of adverse events was low (n = 3). One
patient on oral ganciclovir withdrew because of
rash that was considered to be related to the
ganciclovir. One patient in the valganciclovir
group experienced nephrotoxicity and one patient had mild thrombocytopenia (Platelets =
88 000/mm3). Other episodes of leukopenia and

Valganciclovir vs. ganciclovir in pediatric recipients

Fig. 1. KaplanMeier curve for

CMV episode free survival
between the two prophylaxis
groups.

elevated creatinine were considered by the treating physicians as unrelated to the prophylaxis
treatment, but rather to immunosuppressive
agents or kidney-related etiologies and usually
resolved after treating those etiologies without a
change in the antiviral medications dose.

Table 2. Risk factors for CMV infection/disease for the overall study population

Risk factor

CMV infection/disease
(n = 15)

CMV serostatus
R)/D+
10 (71.4%)
R+/D)
2 (14.3%)
R+/D+
2 (l4.3%)
Age (years)
Mean s.d.
5.678 5.096
Transplantation types
Liver
8 (53.3%)
Kidney
7 (46.7%)
Donor type
Living related
2 (13.3%)
Cadaver
13 (86.7%)
Acute rejection
No
9 (60%)
Yes
6 (40%)
Chronic rejection
No
14 (93.3%)
Yes
1 (6.7%)
Induction therapy
No
8 (53.3%)
Yes
7 (46.7%)
Gender
Male
8 (53.3%)
Female
7 (46.7%)

Free of CMV
(n = 77)

p-Value

23 (29.9%)
8 (10.4%)
46 (59.7%)

0.005*

10.575 5.135

0.002*

21 (27.3%)
56 (72.6%)

0.068

25 (32.5%)
52 (67.5%)

0.215

56 (72.7%)
21 (27.3%)

0.360

72 (93.5%)
5 (6.5%)

1.000

34 (44.2%)
43 (55.8%)

0.578

53 (68.8%)
24 (31.2%)

0.251

Discussion

The ecacy and safety of valganciclovir in adult

SOT recipients is well known, but only few
pediatric studies have assessed its ecacy in the
prevention of CMV episode (6, 14, 15). The
current study is the rst to compare the ecacy
and safety of valganciclovir vs. oral ganciclovir
among pediatric recipients after KTx and/or
LTx.
The overall incidence of CMV episode in our
study was 16% (15/92 patients). This rate
resembles rates reported in earlier studies, in
which the incidence of CMV episode in posttransplantation patients with prophylactic treatment ranged from 5% to 40% (2024). As in
adults, valganciclovir appears to be as ecacious
as oral ganciclovir in the prevention of CMV
episode in children after liver or kidney transplantation (incidence of 13.7% vs. 19.5%, respectively, p = 0.573). Paya et al. (13) showed in
multicenter randomized prospective trial that by
12 months, a once-daily dose of 900-mg of
valganciclovir was as eective and safe as a 1 g
TID of oral ganciclovir (infection rate of 17.2%
vs. 18.4%, respectively) for the prevention of
CMV disease in high-risk CMV R)/D+ SOT
recipients. Similarly, a retrospective analysis
found that in kidney and/or pancreas transplant
recipients, three months of prophylaxis with
valganciclovir (450 mg/day) was as eective as
oral ganciclovir (1 g TID) for prevention
of CMV infection (15% vs. 17%, respectively)
at one-yr follow-up (25). A recent systematic
review of randomized controlled trials of CMV
757

Lapidus-Krol et al.
Table 3. Safety parameters during prophylaxis with ganciclovir and valganciclovir
Time
1.5 month

White Blood Cell (K/lL)

Hemoglobin (g/dL)
Platelets (K/lL)
Creatinine (mg/dL)
Urea (mg/dL)
AST (U/L)
ALT (U/L)
GGT (U/L)

Ganciclovir
Valganciclovir
Ganciclovir
Valganciclovir
Ganciclovir
Valganciclovir
Ganciclovir
Valganciclovir
Ganciclovir
Valganciclovir
Ganciclovir
Valganciclovir
Ganciclovir
Valganciclovir
Ganciclovir
Valganciclovir

3 month

Mean s.d.

Mean s.d.

Mean s.d.

40
51
40
51
40
51
41
51
41
51
40
51
41
51
40
51

9.2
8.2
11.4
10.8
279
296.8
1.28
0.98
48.5
44.7
28.7
31.4
36
26
112.3
49.3

40
51
40
51
40
51
40
40
40
51
40
50
40
50
40
51

7.5
6.1
11.7
11.3
274.2
283.6
1.18
1.18
49.3
41.8
28.4
27.6
27.8
27.2
94.1
39.8

39
50
39
50
39
50
39
50
39
50
39
49
39
49
39
50

7.4
6.5
11.6
13.4
276.6
268
1.32
1.03
49.1
41.3
34.4
28.6
46
29
86.1
45.7

prophylaxis also supported the notion that valganciclovir is as eective as oral ganciclovir (7).
Previous publications in SOT adult recipients
have not found a therapeutic disadvantage for
valganciclovir in liver transplant recipients (13,
25, 26). However, Paya et al. (13) have suggested that in the liver transplant sub-population, there was a higher incidence of overall
CMV disease in the valganciclovir arm (19% vs.
12%) and an increase in the number of patients
with tissue-invasive CMV disease in the highrisk group R)/D+ (14% in the valganciclovir
arm vs. 3% in ganciclovir). Based on these
results, the FDA cautioned against the use of
valganciclovir for the prevention of CMV disease in the high-risk R)/D+ liver transplant
recipients. However, some experts still use and
recommend valganciclovir for this patient population (27, 28), and in Canada, for example,
valganciclovir is approved for all organ groups
(20). In our study, we found that four children
developed tissue-invasive CMV disease, two of
them were liver transplant recipients, one
kidney, and one combined kidney with liver
(valganciclovir n = 3, ganciclovir n = 1). Nevertheless, because of the low number of events in
our study it is impossible to draw a solid
conclusion regarding this risk.
The safety prole of valganciclovir was similar
to that of oral ganciclovir, as was previously
found in other studies (13, 25, 26). Both groups
were comparable regarding the incidence of renal
toxicity, leukopenia, or neutropenia, and only
one patient in the ganciclovir group had to stop
the treatment because of rash. Moreover, most
758

6 month

3.4
4.5
1.7
1.54
137.1
130.4
1.84
1.23
39.6
19.2
27.4
48.5
45
27.8
186
80.3

2.6
2.8
2.1
1.7
109.6
89.3
1.44
1.44
40.3
18
22
25.6
29.8
36.2
180.6
77

2.2
2.9
1.7
1.7
105
99.5
1.8
1.3
31
16.5
31.05
21.2
66.5
55.6
147.8
100.6

cases of leukopenia were considered by the

treating physicians as unrelated to ganciclovir
or valganciclovir but rather to other factors posttransplant mainly other drugs such as MMF or
infections. Those episodes usually resolved without any change in the dose of the antiviral
medications. Nevertheless, considering the retrospective nature of the study and its sample size,
the true incidence of severe adverse events might
be dierent.
CMV serostatus is considered to be the most
important predictor for CMV infection after
transplantation (21, 29, 30) and the incidence of
CMV disease in the high-risk group (R)/D+)
varies from 40% to 73% without prophylaxis
(10). Along those lines, our study demonstrated
incidence of CMV infection of 30% in the highrisk group (R)/D+) versus 7% in the intermediate risk group (R+/D+, R+/D)). Unlike
other publications (13, 14), four patients in the
oral ganciclovir group and ve in the valganciclovir group developed CMV episode while
under active prophylaxis. All of them belonged
to the high-risk category (R)/D+) that was
treated for six months. The reason for the
dierence between our study and others is
unknown. Whether prophylaxis with IV ganciclovir will be more eective in children with
R)/D+ than oral treatment remains an open
question. Other risk factors for CMV infection
that have been identied in the current study
included young age of recipient and cadaveric
graft type. These observations are supported by
other studies dealt with risk factors for CMV
infection (1, 6, 10, 25, 29, 31).

Valganciclovir vs. ganciclovir in pediatric recipients

Previous reports on medication compliance

have conrmed the inverse relationship between
number of daily doses and rate of compliance
(32, 33). A systematic review of the association
between dose regimens and medication compliance found that compliance was signicantly
higher for once-daily (79%) versus three-timesdaily (65%) regimens (p = 0.008) (32). In children after SOT, compliance is a major challenge
and determinant of graft and patient outcome.
One of the strategies to improve compliance in
pediatrics is a reduction in the number of daily
doses of any medication, if possible. The fact that
valganciclovir is given once daily (12 pills/day)
compared to three times a day with oral ganciclovir (612 capsules/day) can improve signicantly the compliance in the pediatric age group.
Unfortunately, we could not assess a day to day
compliance to either valganciclovir or ganciclovir
in this retrospective study as these data are not
routinely recorded in our medical records.
The current study has a few shortcomings that
deserve to be acknowledged. The relatively small
sample size of 92 patients undoubtedly could
have decreased the power and ability to detect
signicant dierences in the ecacy and the
safety of the treatment regimens. To nd a 10%
dierence between treatment groups with a delta
of 5% and power of 80%, a sample size of at
least 198 individuals would be needed in each
group. In addition, the retrospective nature of
the study could have lead to loss of important
data and misclassication bias. This was largely
overcome by using our computerized and prospectively collected databases. A selection bias as
a result of biased sampling is unlikely as our
institute performs the vast majority of pediatric
kidney and liver transplants in Israel. In addition, although 28 children were lost to follow-up
because of transfer of care to other hospitals, a
selection bias is unlikely considering the random
transfer of these patients, according to their
residence. Other possible confounders include the
use of mixed population of kidney and liver
transplant recipients and comparison of dierent
eras of immunosuppression. However, the distribution of the dierent organs was equal between
the groups, and the same method have been used
repeatedly in adult studies to increase their power
without an eect on the results (13). The only
signicant dierence in the immunosuppressive
regimen was related to the use of induction
therapy. Forty percents of the patients in both
groups have received thymoglobulin, while 21%
of the patients in the valganciclovir group were
treated with IL-2 blockers compared to none in
the ganciclovir group. Although it is impossible

to control for the eect of this change, it is

probably minor or at the most should have
increased the number of CMV infections in the
valganciclovir group. These limitations call for a
large multicenter prospective randomized pediatric study to further evaluate the role of
valganciclovir in pediatric recipients. Until then,
an alternative strategy for treatment decision
making can be reliance on adult studies and on
retrospective pediatric studies such as this one.
In summary, we have demonstrated that as in
adults, valganciclovir appears to be as safe and as
clinically eective as ganciclovir in the prophylaxis against CMV infection in pediatric patients
following kidney, liver, and combined liver
kidney transplantation. A multicenter, prospective randomized controlled study comparing
valganciclovir to either oral or IV ganciclovir is
warranted to further evaluate the role of valganciclovir in pediatric recipients.
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