1080
Ganciclovir Treatment of Symptomatic Congenital Cytomegalovirus Infection:
Results of a Phase II Study
Richard J. Whitley, Gretchen Cloud,
William Gruber, Gregory A. Storch, Gail J. Demmler,
Richard F. Jacobs, Wayne Dankner, Stephen A. Spector,
Stuart Starr, Robert F. Pass, Sergio Stagno,
William J. Britt, Charles Alford, Jr., Seng-jaw Soong,
Xiao-Jian Zhou, Lanette Sherrill, Jan M. FitzGerald,
Jean-Pierre Sommadossi, and the National Institute of
Allergy and Infectious Diseases Collaborative Antiviral
Study Group
Departments of Pediatrics, Microbiology, Medicine, and Pharmacology
and the Cancer Center Biostatistics Unit, University of Alabama at
Birmingham, Birmingham, Alabama; Vanderbilt University, Nashville,
Tennessee; Washington University, St. Louis, Missouri; Baylor College
of Medicine, Houston, Texas; University of Arkansas, Little Rock,
Arkansas; University of California at San Diego, La Jolla, California;
Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
Congenital cytomegalovirus (CMV) infection occurs in Ç1% of newborns in the United States.
A phase II evaluation was done of ganciclovir for the treatment of symptomatic congenital CMV
infection. Daily doses of 8 or 12 mg/kg were administered in divided doses at 12-h intervals for 6
weeks. Clinical and laboratory evaluations sought evidence of toxicity, quantitative virologic responses in urine, plasma drug concentrations, and clinical outcome. A total of 14 and 28 babies
received 8 and 12 mg/kg/day, respectively. Five additional babies received ganciclovir on a compassionate plea basis. Significant laboratory abnormalities included thrombocytopenia (£50,000/mm3)
in 37 babies and absolute neutropenia (£500 mm3) in 29 babies. Quantitative excretion of CMV in
the urine decreased; however, after cessation of therapy, viruria returned to near pretreatment
levels. Hearing improvement or stabilization occurred in 5 (16%) of 30 babies at 6 months or later,
indicating efficacy.
In the United States, Ç40,000 infants are born annually with
congenital cytomegalovirus (CMV) infection [1 – 4]. While
most children with congenital infection have subclinical,
chronic infection, 5% will have generalized cytomegalic inclusion disease (CID). CID of the newborn is characterized by
disease of the central nervous system (CNS), including intracranial calcifications, ventriculomegaly, and microcephaly,
with or without ophthalmic and auditory damage [5 – 9]. In
addition, these children can have petechiae, hepatosplenomegaly, jaundice, microcephaly, and retinitis [7]. Elevations in serum glutamic aspartic acid, thrombocytopenia, and conjugated
hyperbilirubinemia occur in 50% – 90% of cases, and mortality
in babies with CID is as high as 30%. With CID, the prospects
for normal development are poor: ú90% of surviving infants
develop significant CNS or perceptual defects (or both) within
the first 2 years of life [6 – 9]. Microcephaly and intracranial
calcifications are associated with severe intellectual impairment
in §80% of cases.
Received 22 August 1996; revised 11 December 1996.
Informed consent was obtained from the parents or guardians of study participants.
Financial support: NIH (AI-15113, AI-62554, AI-12667, and RR-032); the
state of Alabama.
Reprints or correspondence: Dr. Richard J. Whitley, University of Alabama
at Birmingham, Depts. of Pediatrics, Microbiology, and Medicine, 616 Children’s Hospital, 1600 7th Ave. S., Birmingham, AL 35233.
The Journal of Infectious Diseases 1997;175:1080–6
䉷 1997 by The University of Chicago. All rights reserved.
0022–1899/97/7505–0007$01.00
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Because of the severity of symptomatic congenital CMV
infection, the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group (CASG)
undertook a phase II pharmacokinetic, pharmacodynamic, and
safety evaluation of ganciclovir for the treatment of symptomatic CID. We have previously reported the results of the pharmacokinetic evaluations [10] and the population pharmacokinetic analysis [11] in children who participated in this study.
However, because of the requirement for long-term follow-up
in order to document perceptual impairment, we delayed the
reporting of clinical and laboratory responses.
Methods
Study population. Enrollment criteria were isolation of CMV
from the urine, clinical evidence of CNS disease (as manifested
by intracranial calcifications, cortical atrophy, or retinitis), and age
õ1 month. Virus was quantitated at baseline and serially, as defined below. Premature and full-term infants were eligible for enrollment if the child’s weight at the time of entry was ú1200 g.
Girls and boys were equally recruited into the protocol.
Exclusion criteria for this study included imminent demise; receipt of other antiviral therapeutics, including CMV immunoglobulin, symptomatic disease not involving the CNS, asymptomatic
congenital CMV infection, or a serum creatinine level ú2.0 mg/
dL.
Clinical trial design. The study was designed as a phase II
trial to determine the safety, tolerance, and efficacious dosage of
ganciclovir for administration to babies with symptomatic congenital CMV infection involving the CNS. The primary response crite-
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JID 1997;175 (May)
Ganciclovir Treatment of CMV Infections
ria were tolerance of study medication as indicated by completion
of treatment and neurologic evaluation. Plasma and urine specimens were obtained to assess drug pharmacokinetics, which were
then correlated with clinical outcome events (pharmacodynamics).
Babies were enrolled into 1 of 2 cohorts, which were sequentially studied. The first cohort received 8 mg/kg/day in divided
doses at 12-h intervals. When safety was ascertained, the second
cohort was started. The second cohort received 12 mg/kg/day in
divided doses at 12-h intervals. Medication was reconstituted in
50 mL of intravenous fluid and administered over 1 h. Medication
was administered for 6 weeks unless protocol-specified toxicity
occurred. Serial plasma samples of 250 mL were obtained following administration of the initial dose at time 0 and subsequently
at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24, and 48 h after administration. Drug
was administered through a peripheral or central venous catheter.
Plasma samples were also obtained weekly (days 7, 14, 21, 28,
35, and 42) to determine peak and trough plasma concentrations.
The study drug was provided by Syntex (Palo Alto, CA; currently,
Roche Pharmaceuticals, Nutley, NJ).
At enrollment, a baseline history was obtained and physical
examination performed. The history included the mother’s pregnancy course, including fever, lymphadenopathy, development of
a mononucleosis syndrome, hepatitis, or rash, and documentation
of maternal CMV infection (primary or recurrent, if known). The
duration of labor, type of delivery, and complications were noted.
The history of the newborn included Apgar scores, associated
diseases, medications administered, method of feeding (i.e., breast
or bottle), appearance of general anomalies, lethargy, anorexia,
suck, Moro’s reflex, seizures, pneumonia, and disseminated intravascular coagulopathy. The weight, length, and head circumference were documented at the time of admission.
The children were evaluated daily during the course of drug
administration. Serial assessments included weight, length, level
of consciousness, seizures, status of skin changes (purpura, ecchymoses), bleeding, episodes of respiratory distress (including pneumonia), apnea, cyanosis, and the requirement for ventilatory support. Serial evaluations of the eye were done for retinitis, and serial
measurements were taken of liver and spleen. Spleen and liver
enlargement was defined as ú4 cm below the costal margins in
the absence of respiratory distress. A computed tomography scan
of the brain was done at enrollment and repeated at 42 days and
6 months of age. Laboratory evaluation at the time of admission
included a complete blood cell count, reticulocyte and platelet
counts, clinical chemistries, and urinalysis. The clinical chemistries
included evaluations of liver and renal function, including serum
glutamic aspartic transaminase, serum glutamic pyruvic transaminase, glutamyl glutamate transaminase, bilirubin (total and direct),
uric acid, creatinine, and blood urea nitrogen. All laboratory safety
evaluations were repeated on days 3, 5, 7, 10, 14, 17, 21, 28, 35,
42, and 49.
Cerebrospinal fluid was examined at days 0 and, if abnormal,
on days 21 and 42. The examination included cell enumeration,
protein and glucose content, and CMV antibody determinations
by ELISA.
Adverse events. Adverse events were immediately reported to
the Central Unit of the NIAID CASG by both phone and fax. The
following events were recorded: serum creatinine ú2.0 mg/dL, an
absolute neutrophil count of £500 cells/mm3, a platelet count of
£50,000 cells/mm3, or a 50% reduction in either absolute neutro-
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1081
phil or platelet count from their baseline level. A 3-fold increase
in serum glutamic aspartic transaminase from baseline was considered significant. Any other adverse event, as perceived by the local
principal investigator, was reported to the Central Unit.
Modification of dose. For patients with absolute neutrophil
counts £500 cells/mm3 or platelet counts £50,000/mm3, the drug
dose was reduced by 50%. Of note, many patients had baseline
hematologic values reflecting substantial bone marrow suppression
secondary to CMV infection. If the adverse event did not resolve
within 1 week following the dose adjustment or if there was progressive deterioration in laboratory aberration(s), study medication
was discontinued until values returned to baseline. At the discretion
of the investigator, therapy could be reinstituted at the initial starting dose following resolution of the laboratory abnormality.
Follow-up clinical evaluations. Baseline hearing (brain stem–
evoked potential) and ophthalmologic examinations were done at
study entry, and the tests were repeated at 6 weeks and at 6,
12, 24, and 36 months. Neurologic evaluations were recorded at
identical time intervals. Children were evaluated as developing
either normally or with impairment. The degree of neurologic
impairment was documented by serial physical examinations.
Virologic evaluations. Isolation and quantitation of CMV from
urine and throat were done in human foreskin fibroblasts. Quantitative cultures of the urine were obtained at baseline and weeks 1,
2, 4, 6, 8, 10, 12, 24, and 52. Isolates were frozen at 070⬚C and
evaluated at the Central Unit of the NIAID CASG for sensitivity
testing (first and last or recurrent isolates). Throat cultures for
CMV were obtained on admission and, if positive, at 2 weeks after
onset of treatment and at completion of the study. Cultures of
white blood cells (WBCs) were obtained on admission and, if
positive, at 1 or 2 weeks after onset of therapy and at the end of
study.
Serum was obtained at admission, 6 weeks, and 6 and 12 months
for ELISA and immunoblot determinations.
Plasma and urine drug concentration determinations. Plasma
and urine concentrations of ganciclovir were determined by highperformance liquid chromatography, as previously reported [10,
12]. Peak and trough plasma concentrations and pharmacokinetic
parameters, including area under the curve (AUC), volume of distribution, and clearance, were assessed as previously described [10,
11] and were correlated with clinical and laboratory end points.
Data management and analysis. Information regarding the patient’s history, treatment, laboratory results, evaluation of response,
and follow-up status was recorded on case report forms designed
for easy computerization. All analyses were done using the SAS
(Cary, NC) statistical package. Since this is a phase II study,
only descriptive statistics are provided. No attempt was made to
compare the demographics and baseline patient characteristics of
the dose groups because the study was not designed to be comparative.
Pharmacokinetic and pharmacodynamic analyses. Population
pharmacokinetic analyses were done using the nonlinear mixedeffects modeling program (NONMEM, double precision, version
IV, level 1.2; Beal SL and Sheiner LB, NONMEM User’s Guide,
University of California at San Francisco) [11].
A one-compartment pharmacokinetic model with zero-order input and first-order elimination was used with clearance and volume
of distribution as basic parameters. Proportion error models were
used to describe intersubject variability in clearance and volume
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Whitley et al.
of distribution and residual intrasubject variability. The construction of the regression model for fixed effects consists of the following four steps: (1) fitting the basic model to data to estimate global
population mean values of clearance and volume of distribution
and to obtain a reference value of 02 log likelihood (LLD). The
difference between the 02 log LLD of reduced and full models
is asymptotically x2 distributed; (2) screening the influence of each
of the individual characteristics on clearance and NIAID CASG.
These characteristics included age, height and weight at enrollment, weight at birth, levels of bilirubin and blood urea nitrogen,
platelet and WBC counts, serum creatinine clearance, and, as categorical factors, gender and race; (3) constructing a full model
incorporating fixed effects that significantly improve the goodnessof-fit as evidenced by the drop in 02 log LLD value supplied by
NONMEM (P õ .001); and (4) refining the final model by removing covariates from the full model. The deleted factors are those
which, when set to their null value, fail to significantly increase
the 02 log LLD value (P ú .005).
Individual posterior Bayesian estimates of clearance and volume
of distribution were obtained using the final population pharmacokinetic model of ganciclovir. These parameters were in turn used
to evaluate potential pharmacokinetic-pharmacodynamic relationships by using regression analyses implemented in the SAS program. Available pharmacodynamic events included neutropenia,
thrombocytopenia, death, quantitative urine virus levels, normal
development, and persistence of normal hearing.
Results
Study Population
Forty-two infants met eligibility requirements and were entered into the study. Five additional patients were enrolled
under the compassionate plea section of the protocol and were
evaluated for safety only. These 5 children, who were referred
to the CASG sites by Food and Drug Administration staff,
had rapidly progressive liver disease that was considered life
threatening. Demographic and clinical characteristics of the
study participants are shown in table 1 by dose of ganciclovir.
Fourteen babies received 8 mg/kg/day and 28 received 12 mg/
kg/day. Of the additional 5 babies, 2 received the lower dose
and 3 the higher dose. The median age at study entry was
similar for the 2 dose cohorts (11 and 18 days, respectively).
The study population was nearly equally divided between boys
and girls, and Ç70% was white. About one-third of the children
were born prematurely.
Overall, 60% of the babies (25) were microcephalic, and
74% (31) had intracranial calcifications. At study entry, onethird (14) of the 42 children had retinitis, and 20 had either
unilateral or bilateral (8 and 12 babies, respectively) hearing
loss. Most of the subjects had hepatosplenomegaly.
Safety and Tolerance Evaluations
Drug discontinuation and death. All 47 treated patients
were evaluated for safety, toxicity, and survival. Therapy
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JID 1997;175 (May)
was discontinued because of toxicity in 9 (19%) of 47 children. The dose was modified in 6 children, 3 in each dose
group. Of 16 children treated at 8 mg/kg/day, 3 (19%) had
therapy discontinued because of neutropenia, which occurred
on days 7, 8, or 27, respectively. Therapy was discontinued
prematurely in 6 (19%) of 31 children who received 12 mg/
kg/day: 3 had neutropenia (days 11, 23, or 25), 1 had bacterial
sepsis (Escherichia coli on day 8), 1 had a significant elevation of serum glutamic aspartic transaminase (day 26), and
1 died (day 9, secondary to congenital heart disease [translocation of the great vessels]). In addition, 3 other children
died of presumed overwhelming CMV infection on days 43
(necrotizing enterocolitis), 55 (CMV pneumonia), and 90
(multiple congenital infections, including human immunodeficiency virus, syphilis, and CMV). Thus, the overall mortality rate in this clinical trial using an intent-to-treat analysis
was 4 (9%) of 47 babies.
Reported adverse experiences. The most common adverse experience, absolute neutropenia (as shown in table 2),
was evident in 10 children (63%) who received 8 mg/kg/day
and 6 (19%) who received 12 mg/kg/day. In addition, other
adverse events attributed to study medication included necrotizing enterocolitis, diarrhea, elevated liver function test results, and anemia. With the exception of absolute neutropenia
(2 patients), these other events occurred in 1 patient each.
As noted below, neutropenia occurred in a higher percentage
of patients but was not attributed to ganciclovir therapy by
the investigator. No adverse events were attributed to the
infusion of medication.
Aberrant laboratory parameters. There were significant
aberrations in laboratory parameters for creatinine, serum
glutamic aspartic transaminase, serum glutamic pyruvic
transaminase, direct bilirubin, and absolute neutrophil and
platelet counts. These aberrations are also summarized in
table 2. Overall, a serum creatinine increase in excess of 2
mg/dL did not occur in any child; however, increases between 0.3 and 0.5 mg/dL developed in 3 children, irrespective of the dose of ganciclovir. Serum glutamic aspartic
transaminase ú250 IU/dL was documented at any point during the clinical study in 17 babies (36%). Increases of ú200 –
350 IU/dL (maximum) from baseline occurred in 6 babies
(13%), and 6 other babies had increases from baseline between 100 – 200 IU/dL. Elevations in serum glutamic pyruvic
transaminase ú150 IU/dL, which occurred at any point during the study, developed in 17 children (36% overall). No
significant change in serum glutamic pyruvic transaminase
was documented in 31 of the children (66%); however, 3
children had increases ú200 IU/dL (250, 414, and 520 IU/
dL). Significant elevations in bilirubin occurred in 3 children. An increase in direct hyperbilirubinemia during treatment was associated with levels between 8 and l2 mg/dL in
3 children (7%).
The most significant abnormalities involved quantitative
enumeration of neutrophils and platelets. Absolute neutropenia
UC: J Infect
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Ganciclovir Treatment of CMV Infections
1083
Table 1. Baseline demographic and clinical characteristics of infants in a phase I/II clinical trial of ganciclovir for the treatment of CMV
infections.
Ganciclovir
Characteristic
8 mg/kg
No. of patients
Age (days), median (range)
Sex
Boys
Girls
Race
White
Black
Other
Gestational age (weeks), mean { SE (range)
No. of premature (õ37 weeks) infants
Weight (kg), mean { SE
Median (range)
CNS abnormality
Microcephaly
Hydro- or hydranencephaly
Intracranial calcifications
Eyes
Retinitis
Hearing
Bilateral loss
Unilateral loss
Abdomen
Hepatomegaly
Splenomegaly
12 mg/kg
14
17.5 (2 – 29)
Total
28
11.0 (2 – 30)
42
13 (2 – 30)
16 (57)
12 (43)
24 (57)
18 (43)
19 (68)
7 (25)
2 (7)
37.3 { 0.4 (32 – 41)
12 (44)
2.4 { 0.1
2.2 (1.8 – 4.4)
29 (69)
10 (24)
3 (7)
37.5 { 0.4 (32 – 41)
16 (38)
2.5 { 0.1
2.4 (1.5 – 4.4)
6 (46)
1 (7)
9 (6)
19 (68)
4 (14)
22 (78)
25 (60)
5 (12)
31 (74)
2 (14)
12 (43)
14 (33)
3 (21)
4 (29)
9 (32)
4 (14)
12 (29)
8 (19)
13 (93)
12 (86)
23 (82)
20 (71)
36 (86)
32 (76)
8 (57)
6 (43)
10 (71)
3 (21)
1 (8)
37.9 { 0.7 (32 – 41)
4 (29)
2.8 { 0.2
2.8 (1.5 – 3.8)
NOTE. Data are no. (%) unless otherwise specified. Data for ‘‘compassionate plea’’ – treated babies are not included. CNS Å central nervous system.
(£500 polymorphonuclear leukocytes) occurred in 14 of the
children (30%). A maximum decrease from baseline §1000
WBCs/mm3 occurred in 21 (45%). Platelet counts £50,000/
mm3 were documented in 17 infants (38%; 5 in the 8-mg/
kg group and 12 in the 12-mg/kg group), and platelet counts
£20,000/mm3 occurred after the first week of therapy in 4
babies (9%). Neutrophil and platelet changes were transient
and varied significantly with the administration of drug,
prompting the investigators to maintain the therapeutic regimen
in the absence of persistent declines in cell counts and platelet
levels as delineated above.
Clinical Outcome
Audiologic. Audiologic follow-up was available for 30 of
42 children at 6 months or later. Status of hearing did not
differ by treatment group. Hearing remained normal in 2 of
the children who had normal baseline hearing. Three children
with abnormal hearing at baseline had normal hearing on follow-up, and normal hearing evaluations became abnormal for
11 babies. Fourteen children had abnormal hearing at baseline
and at follow-up.
Ophthalmologic evaluation. Fourteen children had retinitis
at baseline and were checked at 6 months for ophthalmologic
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evidence of disease. Of 13 children with retinitis, 8 had complete normalization of the retina and 5 developed retinal detachment (3 patients) or optic atrophy (2 patients). Of note, during
therapy, 1 child with a normal baseline ophthalmologic examination developed a retinal hemorrhage, which led to retinal
scarring. Of the children with normal ophthalmologic examinations, 3 originally assessed as normal developed evidence of
retinal scarring, which was attributed to CMV.
Hepatosplenomegaly. Resolution of hepatosplenomegaly
from the onset of therapy to the completion of treatment occurred in 3 of all treated children (7%). Eleven children (26%)
never had evidence of hepatosplenomegaly and did not subsequently develop it; however, 27 babies (64%) had persistent
evidence of hepatosplenomegaly without significant resolution
during treatment.
Three babies with splenomegaly and 13 without it at the
outset of treatment had no splenomegaly at 6 weeks. Similarly,
25 babies (60%) had evidence of splenomegaly that did not
resolve.
Neurologic status. Functional status in children who participated in this clinical trial was defined over time. Children
identified as normal met all developmental milestones and had
no detectable evidence of neurologic impairment. Neurologic
status did not differ by medication dose. Results of follow-up
UC: J Infect
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Whitley et al.
JID 1997;175 (May)
Table 2. Adverse events or aberrant laboratory results during phase I/II clinical trial of ganciclovir for the treatment of CMV infections.
Ganciclovir
Adverse event*
Neutropenia
Absolute neutrophil count
decreased
Vomiting
Necrotizing enterocolitis
Decreased hemoglobin
Diarrhea
Elevated liver enzyme
Hematocrit
Laboratory results
Creatinine (%)
ú2.0 mg/dL
Maximum increase from
baseline
None
0.1
0.2
0.3
0.4
0.5
Aspartate aminotransferase
ú250 IU/dL
Maximum increase from
baseline
None
1 – 50
51 – 100
101 – 150
151 – 200
201 – 250
251 – 300
ú300
Alanine aminotransferase
ú150 IU/dL
Maximum increase from
baseline
None
1 – 50
51 – 100
101 – 150
151 – 200
ú200
Ganciclovir
8 mg/kg
(n Å 16)
12 mg/kg
(n Å 31)
Total
(n Å 47)
10 (63)
6 (19)
16 (34)
2 (13)
1 (6)
1 (6)
0
0
0
0
0
0
0
1
1
1
1
0
0
11
1
3
0
1
0
(69)
(6)
(19)
(6)
6 (38)
5
4
4
1
1
0
1
0
(31)
(25)
(25)
(6)
(6)
(6)
21
7
1
0
1
1
(3)
(3)
(3)
(3)
(4)
(2)
(2)
(2)
(2)
(2)
(2)
0
(68)
(23)
(3)
(3)
(3)
11 (35)
7
11
4
3
1
0
3
2
2
1
1
1
1
1
1
(23)
(35)
(13)
(10)
(3)
(10)
(6)
32
8
4
0
2
1
(68)
(17)
(9)
(4)
(2)
17 (36)
12
15
8
4
2
0
4
2
(25)
(32)
(17)
(8)
(4)
(9)
(4)
5 (31)
12 (39)
17 (36)
5
8
1
1
2
0
3
15
4
5
1
3
8
23
5
6
3
3
(31)
(50)
(6)
(6)
(13)
(10)
(48)
(13)
(16)
(3)
(10)
Bilirubin
Maximum increase from
baseline
None
0.1 – 1.9
2.0 – 3.9
4.0 – 5.9
6.0 – 7.9
8.0 – 9.9
ú10
Neutrophils
ú1000
500 – 1000 (cells/mm3)
õ500 (cells/mm3)
No data available
Maximum decrease from
baseline
None
1 – 999
1000 – 1999
2000 – 2999
§3000
Platelets
§50,000 (cells/mm3)
20,000 – 50,000 (cells/mm3)
õ20,000 (cells/mm3)
No data
Maximum decrease from
baseline
None
1000 – 25,000
25,001 – 50,000
51,001 – 100,000
ú100,000
8 mg/kg
(n Å 16)
12 mg/kg
(n Å 31)
Direct only
12 (75)
3 (19)
0
0
0
1 (6)
0
19 (62)
8 (26)
2
0
0
0
2 (6)
31
11
2
0
0
1
2
4 (28)
5 (36)
5 (36)
2 (—)
8 (29)
13 (42)
9 (29)
1 (—)
12 (26)
18 (39)
14 (30)
3 (—)
4
3
2
4
3
11
8
5
3
4
15
11
7
7
7
(25)
(19)
(12)
(25)
(19)
10 (67)
3 (20)
2 (13)
1 (—)
6
4
3
1
2
(38)
(25)
(18)
(6)
(13)
(35)
(26)
(16)
(10)
(13)
Total
(n Å 47)
(66)
(23)
(4)
(3)
(4)
(32)
(23)
(15)
(15)
(15)
18 (60)
10 (33)
2 (7)
1 (—)
28 (62)
13 (29)
4 (9)
2 (—)
18
7
1
3
2
24
11
4
4
4
(58)
(23)
(3)
(10)
(6)
(51)
(22)
(9)
(9)
(9)
(17)
(49)
(11)
(13)
(6)
(6)
NOTE. Data are no. (%) of subjects.
* As reported on case report form as attributable to drug or as unknown cause event.
†
Event for each patient is measured as occurring §1 times.
neurologic examination at §2 years of age were available for
33 children; 8 (24%) were developing normally.
Virologic Laboratory Evaluations
Quantitative virology. Figure 1 shows that a more pronounced
antiviral effect was detected in the urine of children in the 12-mg/
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03-24-97 09:33:17
jinfa
kg dose group compared with that of children in the 8-mg/kg
group. Of note, however, all children who excreted virus in the
urine had a subsequent return of virus in urine following discontinuation of antiviral therapy, albeit at levels somewhat lower than
those at the initiation of treatment. Of 7 babies, 3 were positive
for CMV by WBC cultures; however, after 2 weeks of therapy,
none was culture positive for CMV in the blood.
UC: J Infect
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Ganciclovir Treatment of CMV Infections
Figure 1. Comparison of CMV quantities in urine of children who
received 8 vs. 12 mg/kg/day of ganciclovir.
At study entrance, 14 of 20 babies were CMV positive by
throat-wash culture. On subsequent evaluation, 3 of 5 babies
and 0 of 4 babies were culture positive at 2 and 6 weeks,
respectively.
A total of 40 isolates were obtained before and after therapy
and were evaluated for viral sensitivity to ganciclovir. Of these
isolates, none changed sensitivity during or after drug therapy.
All isolates maintained a sensitivity of £2.0 mg/mL to ganciclovir.
Pharmacokinetic and pharmacodynamic evaluations. Population pharmacokinetic analyses revealed a direct relationship
between plasma drug clearance and renal functions and a dependence of the volume of distribution with body weight.
Plasma concentrations of ganciclovir were correlated with evidence of toxicity and clinical response. Parameters selected
for evaluation in the pharmacodynamic model were absolute
neutropenia, thrombocytopenia (platelet counts of £20,000
cells/mm3), death, quantitative urine virus levels, normal development, and persistence of normal hearing.
The clearance of virus in urine correlated with normal neurologic examinations at 1 year (r Å .63, P Å .036). Normal
audiometric examination correlated with a low AUC/dose ratio
(r Å .54, P Å .057), increased total clearance (r Å .707, P Å
.07), and a high volume of distribution (r Å 0.65, P Å .057).
Only increased platelets were positively correlated with the
volume of distribution (r Å .480, P Å .11). For unexplained
reasons, the deaths were negatively correlated with total clearance (r Å .526, P Å .005). No other efficacy or toxicity parameters were correlated with pharmacokinetic parameters.
Discussion
This phase II safety, tolerance, and pharmacodynamic study
was done to determine a potentially efficacious dosage of gan-
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ciclovir for the treatment of symptomatic congenital CMV infection. Before interpreting the clinical results, a few comments
are in order. First, and most important, symptomatic congenital
CMV infection is a significant cause of morbidity in the United
States. It has been estimated that the direct and indirect costs
for treating babies with congenital CMV infection approaches
$1 billion per year [13], a figure greater than that associated
with Haemophilus influenzae meningitis. As a consequence,
prevention of this disease has become a target for vaccine
development, particularly for administration to seronegative
susceptible women of child-bearing age [14, 15]. Second, the
morbidity and mortality attributed to CID cannot be underestimated. Overall, mortality in several prospective studies of
symptomatic congenital CMV infection ranged from 10% to
30%, with ú90% of survivors having evidence of significant
neurologic impairment [16]. The morbidity, including the requirement for serial assessments of vision, hearing, and abnormal laboratory parameters, remains tremendous. Third, while
many experimental therapeutics have been evaluated for the
treatment of CMV infections in general, none have been vigorously evaluated for the treatment of congenital CMV even in
phase I or II studies.
Thus, ganciclovir was selected for utilization in this protocol
because of its significant antiviral activity [17]. However, due
to ganciclovir’s known toxicity, particularly bone marrow suppression and gonadal toxicity, only children at exceedingly high
risk for death or severe neurologic impairment were selected for
entry into this protocol. It was determined at the outset that
the risk-benefit ratio for such patients outweighs the potential
harm that could be attributed to the administration of ganciclovir, particularly for treatment as long as 6 weeks. All
children enrolled in this trial had evidence of severe disease,
likely the consequence of fetal infection early in gestation [18].
Because disease was chronic, any therapeutic effect (e.g., stabilized or improved hearing) should be considered significant.
From this clinical trial, we learned that ganciclovir at 12
mg/kg/day in two divided doses led to a significant reduction
in the overall quantity of virus in the urine and other sites.
Neutropenia, thrombocytopenia, and elevated results of liver
function studies were encountered in a significant number of
children in this study, requiring dosage modification. Nevertheless, most (81%) of the children completed a 6-week treatment
course with ganciclovir. Because the study was not controlled,
the potential adverse harm of administration of ganciclovir
versus no therapy whatsoever cannot be accurately assessed.
The mortality rate directly attributed to CMV in this study
is as low, if not lower, than that in historical, retrospective
studies done in patient populations significantly less ill than
the one reported here. In addition, the percentage of study
children who appear to be developing normally 2 years after
the onset of therapy (24%) is in excess of the percentage that
we anticipated from the literature.
These findings provided the impetus for the NIAID CASG
to initiate a phase III controlled clinical trial of ganciclovir for
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Whitley et al.
the treatment of symptomatic congenital CMV infection with
CNS involvement. The phase III clinical trial randomizes children to receive or not receive treatment for 6 weeks. A dosage
of 12 mg/kg/day is administered in two divided doses. To date,
70 children have been enrolled, with a required sample size of
90 analyzable children. We strongly emphasize that the current
data do not provide adequate evidence of efficacy of ganciclovir
for the treatment of symptomatic congenital CMV infection to
warrant routine use. As a consequence, we would strongly
encourage investigators to consider referring children to this
comparative clinical trial in order to establish or refute the
potential efficacy of this compound.
Ganciclovir has been studied in 12 children with symptomatic infection [19]. While the results are encouraging, the number of children evaluated is too few to reach conclusions regarding treatment efficacy. Nevertheless, toxicity did not create
problems in this study.
Pharmacodynamic evaluations, which compare peak plasma
and trough levels, AUC, and volume of distribution with targeted outcome events from a toxicity and an efficacy standpoint, indicated several positive correlations. First, elimination
of virus in the urine during therapy correlated positively with
normal neurologic development. Thus, as would intuitively be
the case, a goal for future studies is the elimination of CMV
from the urine. Second, the pharmacokinetics of ganciclovir
correlated with either stabilized or improved hearing as reflected by a high volume of distribution and increased clearance. Third, while few in number, death correlated with poor
clearance, as might be anticipated. In contrast, abnormal laboratory parameters did not correlate with AUC, peak or trough
plasma concentrations, clearance, or volume of distribution.
In conclusion, for this study, we selected children with the
most severe CID. Such children, as evidenced by other studies,
presumably would be at the greatest risk for mortality and
neurologic impairment. Evidence of stabilization or improvement warrants further evaluation in a controlled clinical trial.
In addition, we administered treatment for 6 weeks and had to
make dose changes during that time. We believe that treatment
of congenital CMV will require long periods of drug administration, perhaps even as long as 1 year. Thus, the importance of
developing a safe antiviral medication that can be administered
orally rather than intravenously, is essential. While we are
completing our controlled clinical trial of CID, we look to the
future when other orally bioavailable medications with improved safety and efficacy profiles become available for the
treatment of this devastating infection. The promise of a vaccine for the prevention of congenital CMV infection by immunization of women at risk for primary infection during gestation
becomes increasingly important and a target for the future.
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