Mar 5, 1997 - Clinical. Practice. Guidelines: Prevention of Cytomegalovirus. Disease. After Renal ..... a process dependent on the presence of thymidine kinase within the virus (30-32). Human. CMV lacks ..... in chemical nature to acycbovir.
J Am
Clinical Disease
Practice Guidelines: Prevention After Renal Transplantation
Soc Nephroi
9: 1697-1708.
1998
of Cytomegalovirus
SARBJIT VANITA JASSAL,* JANET MARY ROSCOE,* JEFFREY STEVEN ZALTZMAN,t TONY MAZZULLI, MEL KRAJDEN, MARYANN GADAWSKI,’ DANIEL CHEYNE CATTRAN,1 CARL JOSEPH CARDELLA,# SHELLEY ELIZABETH ALBERT,’11 and EDWARD HERMAN COLE’ *Djt,jsio,,
of Nephrologv,
Hospital;
Departineit
()f ‘Microbiologv, The
evidence-based to
having
prevent
sign
of
donor
viremia.
comes:
virus
The
control over
Evidence:
of
groups
disease
were
evaluated
the
and
6 mo
compiled
features
to
1 yr
using
after
conference
abstracts,
evidence-based
Force
on the
value
was
design
Periodic
placed
and
classified
on
blinded as poor
with
regard
20%
of patients
This
article
for
renal
period. based
and
scientific All
of
Examinations
studies
with
outcome
lost
presents
field.
Values:
Canadian
were
observers.
guidelines
for
the
evidence
available
and
Working
guidelines
(1,2).
Group
It
strict
evidence-based
rigor
was
applied were
from evaluation
made,
by
more
donor with
the
I 046-6673/0909Journal
Copyright
of the
L69
3GA.
United
consensus,
of the
evidence which
Society
U 1998 by the American
antiviral
ther-
immunosuppres-
recipient;
regimen.
No
(grade
seronegati
ye
prophyiaxis
with
recommendation).
D/E
(5)
or seronegative;
Prophylaxis
Newer
Sero-
immunosuppression
recommended
Seronegative
unproven,
antivirai (2)
(3) Seronegative
therapy
in charge
left
(grade
con-
to the
discrim-
C recommendation).
methodologies
are discussed
and briefly
treatments,
as future
direc-
tions.
National
Health
Materials
literature
were of the
used
and
Task
literature.
based
on
the
and
Evidence
Force
dations,
Methods
is presented
on the
using
Periodic
depending
on
A through
the
Building.
Clin-
Daulby
negated
by
high
studies.
Grade
quality
of Nephrobogy
concerns
principles
adopted
Examination
strength
support of the preventative the intervention) are given University
the
Health
E. The
of
the
strongest
usually
usually
were
given
the
from
evidence,
are
type
graded
is
weight
as type
A, in
the use of
supported
by
or
controlled
when
or other
using
(grade
I randomized
are given cohort
Canadian
recommen-
E. against
II evidence). Data from to be susceptible to bias same
The
recommendations
B and D recommendations evidence,
by the
(3).
intervention, or grade only if the intervention
studies,
controlled studies (type trolled studies believed
of Nephrology
Society
with
with
conventional
physician
or re-
immunosuppres-
Prophylaxis
donor seropositive
available.
remain
of insufficient
donor;
immunosuppression.
ination
not
respectively;
recommendation).
(grade
the
evidence,
( 1 ) Seropositive
donor;
required
recipient;
of
intervention
because
antiviral
(4)
therapy
ventional
the
evidence,
A recommendation)
with
Use
quality
Prophylaxis
A
products. (grade
were
B:
seronegative;
immunosuppressive
Seropositive
fair
of
made or
seropositive
antiviral
Use quality
seropositive
Prophylaxis
convincing
Kingdom.
1697$03.OO/O American
E:
or
products.
antilymphoeyte
donor; any
high
fair
(grade
recommended
B recommendation).
A and
Recommendations:
recipient;
High
to
and or
seropositive
sion.
than
D high
recommended
recipient;
caring
previous
Received January 20. 1998. Accepted March 4, 1998. Correspondence to Dr. Sarhjit V. Jassal, Geriatric Medicine. ical Department. University of Liverpool. The Duncan Liverpool
of Nephrolagv,
Recommendations
on
antilymphocyte
negative with
was
based
evidence).
categories
Street,
‘s
Departtnents
recommendations
approaches
in the
Division
(grades
C: No recommendation
The
intention
clinicians
the and
differs
in that
recommendations
on
grade
apy
(especially
when
St. Michael
Hospital;
performed.
system
on
Task
quality
when
and
#Head
not
grades based
and
controlled
present
regimens), to follow-up,
practical
used.
Study was
to immunosuppressive were
articles
the
respectively;
therapy
from Addi-
review
was
a graded
conflicting
of ne-
a randomized
cointervention
of the Evidence-Based reviews
in the
values
Health
when
and
transplant patients in the immediate posttransplant The goal is to help clinicians define treatment protocols
on
Institute
experts
and
Program,
Margaret
and
advised,
advised,
Out-
epidemiology.
from
methods
of
used.
search
recent
and
from
with
sion
tional
obtained
analysis
made
cipient;
a MEDLINE
Transplant Princess
Hospital;
treat
transplantation.
by representatives
was
Toronto
of cytomegabo-
1976 to July 1997, were reviewed phroiogy, microbiology, pharmacy. information
use earliest
patient
regimen
and
intervention
patients
at the by
induction
of symptoms
antiviral
The
or
Tue
stan-
of
Options: therapy
first
use
Renal
Hospital
(‘anada.
in aduit
induction
and
the
Articles,
the
Toronto;
Sinai
1Nephrologv,
Ontario,
disease
Treatments
serologic
for
transplantation.
time
Hospital
Mount
a set of comprehensive,
guidelines
renal
at the
Central
and
Toronto,
cytomegalovirus
undergone
medication,
Hospital,
To develop
Objective:
dardized, therapy
‘Pharmacy,
Toronto
Abstract.
Welleslev of Microbiology,
there
is less
nonrandomized randomized conor methodobogic
II studies.
Grade
C
1698
Journal
of the American
recommendations
indicate
evidence
either
situation,
the physician
on individualized
search
terms
insufficient
maker
J Am
or contradictory
intervention
in question.
should
base
their
articles
for
this
used:
antiviral
(therapeutic
use),
review
were
1976 to July agents.
a
The following
gancicbovir,
kidney
using
acycbovir,
transplant,
organ
a 2.5-fold
im-
and
transplant,
the definitions
infection. were limobtained
7%
had
from the pharmaceutical companies responsible for the distribution of anti-CMV therapies and from hand searches of the abstracts from the two most recent American Society of Nephroiogy meetings and the
this
represents
American
yr in association
ited
to studies
in humans.
Society
1996).
of
To ensure
Additional
data
Transplant
validity
references
Physicians
of the data,
(CMV) Articles
each
were
Abstracts
(CD-ROM
of the studies
reviewed
was
checked against six criteria. These criteria included blinded randomization, the use of a placebo or control limb, blinded outcome assessment using well defined criteria, the exclusion or boss to follow-up of less
than
20%
of randomized
patients,
drugs (or unclear
descriptions statistical testing.
appropriate assessment
by
outcomes
chosen
requiring
an
adjudication
were
no cointervention
with
other
of immunosuppression regimens), and In the absence of blinding, outcome committee
those
was
considered
accepted.
as serious
The
clinical
only
disease
hospitalization.
Results are reported as the relative risk (RR) of disease, the relative risk reduction (RRR) with therapy. and the number needed to treat (NNT) to prevent one case of disease (4,5). Most results included 95% confidence intervals (95% CI), and some included estimates of risk (or benefit) case
after
reconsideration
scenarios.
principles
All
taught
of the
epidemiologic by
the
data
using
principles
worst were
Evidence-Based
case
derived
Working
to participate.
from those in general and infectious disease
best the
Group
was
and
most
involved campus actively
representation
nephrobogy. specialties.
clinical epidemiology. pharmacy, Only one invited clinician chose to
sought
of
in most
Exposure
a lifelong
communities.
recipient
to the virus
often
CMV-specific
recipients
and
serology
results
antibody
cause
CMV
disease
lowest given
by the presence
always
virus
is char-
The
burden
report
summary that
had CMV
prevalence
is demonstrated
no study
increased
has confirmed
immunosuppression
tion
may
lead
and
effect
the
the
expenloss
Renal
Data
observations,
(14-17).
Because
of acute
of CMV
differentiated.
at 3
(I 3). The
U.S.
study
treatment
incidence
be easily
If accurate,
status
causation for
to an increased
cannot
from
rejec-
disease,
The
1.
renal
care
in graft
donor
by other
all
an additional
health
increase CMV
in data
of
disease. of
a fourfold
seropositive
in Table
I I%
and that
invasive
component
suggest with
is given
8 to
syndrome
of serious
a significant
but to date
data
cause
do
suggest
a higher rate of graft boss in patients transplanted from a seropositive donor but do not demonstrate
with a kidney a higher rate
of graft
transplant
loss
cipients.
in recipient-positive/donor-negative
If
true,
an
association
increased
graft boss would recommendations.
these
Possible
different
drug
passive
acyclovir, were
between
change
CMV
re-
disease
the clinical
and
significance
of
Interventions
Three
therapies
were
immunization
and
with
ganciclovir.
considered
All
collectively
A summary macologic intervention view of each intervention of this article. A summary
considered.
human
These
pharmacologic
for
the
in-
immunoglobulin, interventions
purposes
of the
recom-
of the evidence supporting each pharis covered. However, an in-depth rewas deemed to be beyond the scope of most
studies
reviewed
is given
in
2.
of viral
symptoms
patients). and
(8,9).
and
viral
infection,
in the blood, hence
and
the
does
spectrum
and dose
from
globulin is
as the cost
immunoglob-
nonspecific blood
globulin
globulin,
donors,
(HCMVIg),
and in
a
which
from selected donors with high CMV antibody titers to produce a single plasma pool with a CMV antititer greater than 1 in 7000. Both preparations are admin-
pooled
body istered
intravenously
ication
at set
flushing, with
as
as
remains
Although
and
intervals,
using
divided
usually
Complications nausea,
diphenhydramine,
well
ferences with either
of human
volunteer
hyperimmune
to fever,
to medical resources or the impact on the patient. In terms of hospital care, a retrospective case-control study has shown prolonged hospitalization (from a mean hospital stay of 22 to
form
preparations:
healthy
not
of Suffering be considered
many
16 wk posttranspbantation.
of
in the
in two
CMV-specific
roids,
can
immunization,
is available
de-
is wide.
of suffering
Immunization
derived In
to donor
to the type
Active
particles
of disease
ulin,
of clinical disease is rehighest in bone marrow
in renal
Passive
opinion
The Burden
in patients
as the reported
System database and is supported
Passive
in the production
(seroconversion).
pretranspiantation,
of immunosuppression fined
The
to remain latent in the body and to cause periods of immune stress or immunosup-
transplant recipients, the prevalence bated to the organ transplanted (being transplant
costs
1998
Information
is prevalent
acterized by its ability active disease during pression.
A brief
recipients
association
Table CMV
used.
mendations.
In addition,
not participate.
Background
in institutional
series
manifestations
diture (I 1,12). Recent reports
the
with were
recent
transplant
eluded
Canadian Task Force for Periodic Health (6,7). To ensure unbiased representation. all clinicians renal transplantation within the University of Toronto invited
and from
9: 1697-1708,
of symptomatic disease in the literature. A number of observational studies were examined, but each differed in the study population reviewed, the methodology used to detect disease, The
heart transplant, liver transplant, cytomegalovirus herpesviridae infection. prevalence, and incidence.
increase
Soc Nephrol
with CMV disease ( I 0). Patient impact may be measured
treatment
identified
1997.
d) and
59
In this
criteria.
for the period
were
munogiobulin
of Nephrobogy
is
the
or decision
and
search
there
or for
clinical
Publications
MEDLINE
that
against
Society
and
over
appear
can
infusion
on whether
10 to
by premed-
(pethidine), rates
there
first
to be limited
be reduced
meperidine slow
the
(18,19).
or
ste-
Expert
are
significant
dif-
HCMVIg or nonspecific globulin many observational or ease-control
therapy. studies
have
been published (14,19-26), the only blinded randomized controbled trial, in seronegative renal patients at risk of primary disease, compared the efficacy of hyperimmune globulin
J Am Soc Nephrol
Table
9: 1697-1708,
1. Studies
Practice
1998
showing
effect
of pretransplant
serology
on clinical
CMV
Guidelines
for the Prevention
of CMV
1699
diseas&’ Serology
±ALG
Study
R-/D+
R-/D-
Tricontinental
Weir
study
1987
Weir
Some
(11)
1988
Mancilla
(1 2)
1996
No
(74)
Some
1992
8%
tissue
invasive
1 1 .7%
CMV
syndrome
3 of 142
11 of2O
0 of 36
disease
overall
overall 3 of 142 (includes
1992
(76)
Yes
0 of 37
7 of
Peterson
1997
(77)
No
0 of S
4 of 12
4 of 16
No
0 of 7
6 of 12
9 of 54
Rubin
1989 1977
Grundy
( 17)
(78)’
1988
0 of 8
1989
(25)
Yes
Chatterjee
1986
(79)
No
1975
(80)
Cuhadaroglu
1992
Conlon
1992
(81)
(82)
ysis.
randomized
associated CMV yses. data that (95%
uses
study
No
4 of
12
5 of
No
0 of 9
but
subsequently
reported
a
(from
on the 59 patients the effective RRR
excluded
significant
from
similar results principles,
followed remains
to study significant
CI, 0.09 to 0.86; NNT, 3.0 an intention to treat analysis
the
reduction
60 to 2 1 %) in patients
immune globulin, with Using strict epidemiologic
in
analCMV-
treated
in subgroup reanalysis
with analof the
completion but falls
showed to 0.27
patients). Similarly, and recalculates
if one the risk
of 146
with
the
open label studies HCMVIg may confer
disease
(level
2 of 4
1 of S
II evidence);
treatment
group
(5
of
24
however,
all have
(27,28) against significant
or do not feature renal patients as the main Supportive evidence, not specific to renal
patients
randomized
Acyclovir Acyclovir activity
is a potent
and
has
been
ment of infections in the management the
were
followed
compound, thymidine kinase
drug
for 0.56;
therapeutic intravenous some (34-37),
of
to be
must
first
viral
I yr. Rates 95%
kinase,
rendering
of
CI, 0.28
to
is higher
than
administration but
not
of
be phosphorylated
all
on the Human
the CMV
that
have required achieved
acyclovir
(21,38-45),
polymerase
in the
manage-
viruses. However, its role has been cabled into doubt
vitro. Cole and Balfour inhibitory concentration
effect
DNA
efficacious
a process dependent within the virus (30-32).
this virus-specific in mean
inhibitor
shown
caused by herpes of CMV disease
active
active
relative and meta-analyses significant benefit
patients, of a trend to benefit is available from a study in liver transplant patients. In this series, 141
.
acyclovir
group compared 12 of 35).
design flaws population.
-
-
CMV disease fell from 31 to 19% (RR, 1 I 8; not statistically significant) (29).
control
study study
18
transplant subsequent
because
CMV
10
in article.
syndromes
Subsequent indicate that
8 of
6 of 7
reduction and NNT using a worst case and best case scenario, the RR ranges from I .75 (suggesting harm from HCMVIg) to 0.10; (NNT, -4 to 1.8). In addition, the results are confounded by a higher frequency of use of antibymphocyte products in the versus
10 of 26
6 of 23
10 of 12
no therapy (19). Although well designed, interpretation study results is limited by the high number of patients The
0 of 15
7 of 9
10
Not
initially
14
3 of
C
against of the
10 of
No
CMV, cytomegabovirus; ALG. antilymphoeyte globulin. Cointervention with acyclovir and ALG in some patients. all data given
12 of 45
12 of 33
b
a
16 of 45
26 of 68
No
Metselaar
Ho
12
?
(73)
group)
9 of 123
Hibberd
Metselaar
R-/D--
1 of 72
6 of 33
Some
(75)h
R+/D+
R+/D-
virus
into
an
presence of CMV lacks resistant
to
shown that the for an effective by either
oral
or
(33). Nevertheless, in vivo studies have
shown a benefit in patients treated with high doses of oral or intravenous acycbovir. Balfour et al. demonstrated that regard-
Journal
I700
of the American
Society
of Nephrology
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I 702
Journal
less
of the American
of pretransplant
serologic
risk
of disease (RRR, when oral acycbovir transplant and
patients
were
effect
(37).
case
(NNT.
as an
Although
the
published
by Dunn
only
be
transplant
course
of oral acyclovir and immunoglobulin. given
of treatment
to
with
Skepticism
concerning
plantation
are discussed
treatment
with
acycbovir, in liver with intravenous
in
the
section,
and
intravenous
transplant ganciclovir.
“Direct
of viremia,
and
1995
(11.,
et al., in
1997
both
by
is infestudies
onset
is phosphorylated
by
phate.
that
a compound
Although
first
management
of disease
is
now
standard with
(47-49)
infections,
treatment
intravenous
for and
It (46).
for
were
with
CI,
and
liver
although the 95%
and
groups
(54)
were
and
Conti
studied
(R-/
Both
lacked
significant
power
a benefit. to either
with
both
been
randomized
to 0.86),
smaller
et al. , I 993
refute
prophylaxis in renal i mmunosuppression has
0.12
et
Brennan
statistical significance but both rates of disease and delayed
treatment.
Prophylaxis
by Conti
and
wider.
is available
however,
in symptomatic
to 0.96)
were
of
treated steroid-
transplants
and
the
role
transplant patients treated (i. e. , no antilymphocyte oral
shown
and
intravenous
be
of
to
controlled
or support
trials
in
ganci-
benefit
patients
conventional
in
well
receiving
immunosuppres-
be less.
prevalence Serious
An
attempt
at predicting
the
NNT
for
rates of disease was made and is shown side effects of gancicbovir are infrequent
different
in Table 3. and include
intravenous
symptomatic
oral
the
95%
trans-
in the onset
sion (in which the prevalence of CMV disease is much higher) (40,56-58). From this evidence one may propose that a treatment effect would be seen, although the magnitude of effect may
activity
studies CMV
to
CMV.
DHPG-triphos-
polymerase
in uncontrolled
Prophylaxis,
to
between
demonstrated
CI, 0.35
numbers
demonstrate
evidence
products).
nature
against
cells
DNA
systemic
in chemical activity
infected
inhibits
of severe
gancicbovir tients.
used
virally
similar
95%
study achieved toward reduced
to conclusively
heart
vitro
were
0.65;
study
intervals
of gancicbovir with conventional
or
0.84;
(RRR,
the
showed
In two other studies, by Rondeau et a!., 1994 (55), different serologic
No
guanine.
(52)
cases
D+). Neither showed trends
et a!.
also reductions
(RRR,
(51)
confidence
Gancielovir
in
time
a delay
a decrease
designed
DHPG) is a guanosine analogue acycbovir. which has excellent
and
risk
Between
.3-dihydroxy-2-propoxymethyl
in the
increase
viremia,
rejection
cbovir,
(9-I
an
detectable
treat14.3).
trends from suba decrease in the
acute
Interventions.”
Gancicbovir
the results showed consistent with the intervention causing
Similar
acyclovir
Comparisons
was
gancicbovir,
resistant
immu-
patients. These
1998
disease
intravenous
disease.
ganciwas seen to 0.99);
Martin
invasive
with
any
is supported
et al. (40)
Tissue
treated
was
of the longer duration acyebovir therapy was
of acycbovir
to 0.64).
analysis of patients ALG therapy for
1 2-wk
and
0.12 in those
9: 1697-1708,
CMV disease. In addition, subgroup with intravenous ganciclovir during
is im-
a
of gancicbovir
the use
that
followed by oral nor to treatment Available
Furthermore, group analysis, occurrence
with
either
CI,
Soc Nephrol
but because of a lower prevalence 15 patients required ment for every case prevented (odds ratio, 0.53; NNT,
both
results
patients to
was because or because
by Winston
show
study,
(95%
less common
and 0.83
study
or a 7-d course of intravenous A lower risk of disease (RR, 0.65; 95% CI, 0.42
if this acycbovir
published
Both
).
using
to 0.21 also
randomtreatment
0.33
these
randomized
indeed superior to the combination nogbohulin therapy.
(4 1
in
randomized
Balfour’s
confirm
In this
were
acycbovir
it is unclear
the results
was
recalculated,
from
able
et al. (35).
organ
those
study
to lie between
benefit
study
solid
in
can
scenarios,
treatment
the
however.
reduction
I I .8).
pressive.
clovir
an overall
1 18 patients initially analysis. Thus, the
the
RRR)
J Am
0.25 to 0.91) was seen over 12 wk to renal
the
ofthe
from
and best case
3. 1 to
status,
Although 14
excluded
(measured
worst
of Nephrology
0.74; 95% CI. was administered
placebo-controlled,
ized
Society
pa-
ganciclovir,
has
Table
3.
Usefulness
shown to be of benefit in three randomized controlled studies (50-52) (and in a subsequent study as yet reported only
of therapya
been
in abstract
form
1531)
I evidence). Most with antilymphocyte trial
was
was
limited
in the renal
transplant
population
patients studied were simultaneously products. The largest and most
published
in 1995
to patients
by Hibberd
who
were
et a!. (50).
seropositive
clovir
for
mized
Risk of CMV Infection
Recruitment
a median therapy
was
present
in nine
with
acycbovir,
the
by randomization.
The
results
regimens
patients
globulin (either for rejection).
effects
showed
because of this
and other
relevant
were
a reduction
0.27 to I .00) of CMV disease NNT, 4.5). After adjustment
of ALG
of simul-
factors,
mini-
in RR
(odds ratio for different the RR fell
Effectiveness Treatment
of Equal
to 10% (low effectiveness)
5%
before
Effectiveness
of
Effectiveness
Treatment Equal to 30%
Treatment to 60%
(moderate effeeti
200
a
33
67
25%
40
35%
-‘9
10
5
45%
22
7
4
55%
18
6
3
This
table
gives
the number
needed
of Equal (high
effectiveness)
veness)
I
13
but unblinded study, I 13 patients were either intravenous infusions of ganciof 9 d or no prophylactic therapy. Although
by 0.54 (95% CI, 0.33 with treatment; dosing
Baseline
designed, to receive
cointervention taneous
treated supportive
for CMV
transplantation and who received antilymphocyte (ALG) during the early course of transplantation induction or for treatment of steroid-resistant acute In this well randomized
(level
to treat,
i.e.
,
the estimated
number of patients who will require treatment (unnecessarily) for each case of infection that is prevented. Assuming that the increase in cost for each case of CMV is $25,302 ( I 0) and the cost of 2 wk of prophylaxis with gancicbovir is $1966.12. 12 patients can be
treated represented
with prophylaxis by the area
without below
additional the heavy
expense. line.
This
is
J
Soc Nephrol
Am
bone
9:
marrow
high
are
deterioration
given,
or
serious
intervention
can
be
Practice
1998
suppression,
doses
long-term
1708,
1697-
and,
on
side
effect
of
occasion, has
considered
renal
function
allergic been
reported,
In a study
if
reactions. and
No
(64)
the
therapy
unable
Other Drugs Valaciclovir in
Current/v Available and famciclovir are newer
chemical
structure
L-valyl
ester
clovir,
after
times
greater
dosing
to
prodrug than
with
To
to prevent
bioavailability
date,
viral
vabaciclovir
zoster
adults.
achieved
and
replication.
oral
herpes
with CMV requires than for other herpes
However,
randomized
placebo-controlled
(published of valacielovir
in abstract form only), the administration of prophylaxis was shown to reduce the risk
of laboratory-confirmed 95%
CI,
similar
0.042
CMV
to 0.854)
results
with
disease
(60-62).
few
side
from
transplant
5 to 1% (RR.
Subgroup
analyses
with
those
clinical
symptoms
0.19;
despite
previous
2 1 patients
Although
small,
the
Comparisons
Between
Few
of
have
actually
different treatment seen with acycbovir studies used
regimens and
treatment
criteria
for
in liver
transplant
high
quality)
IgG
or
compare
alone.
studies (40,41,63), better
0.99)
discrepancy therapy but
to be more
effect than
However,
(42)
(RR
although
that
with
acyclovir
with
intravenous
a
by
the
consensus
a treatment one
that of either group,
effect
was
methodologically
duction
or at the
method, often viral replication closely
may
with
chosen
this
was
or gancicbovir. as the
based
consistently sound
Duration, Route, of Prophylaxis Prophybaxis
acycbovir
was
treatment
solely
the 10 to
on the fact
demonstrated
in more
To
be
patient days
or
of Administration
weeks,
is the
most
and
ganeiclovir
acyclovir
Recent
(52,66,67).
data
first
therapy with
at
during
the
course
of
therapy.
convenient
for
preferably
the
for a few
regimen.
Both
in oral
and
intravenous
has
shown
that
1 evidence renal
show
products.
a 1 2-wk
treatment
that 4 mo
even
(i.e.,
be
available
In contrast,
the
prophylaxis
taken
practical
in both
a longer
gancicbovir
must
be
show
of immunogbobulin
therapy,
level
is effective
for
products),
are
may examined
to give
gancicbovir
prophybaxis oral
been
antilymphocyte
course
Thus,
and
liver
immunoglobulin
oral
transplant therapy
pamust
be
given intravenously.
Combination
administered
sign
either
of active
at the
viremia.
time
The
of
in-
latter
termed preemptive therapy, assumes that active is easily and quickly detectable and correlates syniptomatic
a l6-wk
effective,
to take.
therapy
not
the
reconimend
or
CoIn-
transplant
of
disease
with
group
organ
studies
wk)
(2
of antilymphocyte
Therapy
Although
earliest
in
theit l)Ieof pre-
study.
and Timing be
regimen
sense
however,
given
oral
acyclovir,
has
of CMV
14 d of intravenous
gancicbovir
than
a subse
of debate.
duration it makes
administration
tients
not
at the
confirmed effectiveness
in solid
premise
short-term
consensus
formulations.
that
was
was
gancicbovir
a preemptive
epidemiologic
risk
when
least
of choice
study
In
oral
of either
administered
the subject
In practice,
with
Thus,
Although
this
because
(9,50,51,53,65)
the
that in
the
method.
studies
Theoretically,
transplantation.
CI,
is also a longer
at maximal
for
the type of By extrap-
in
of
compared
with
died
duration
therapy
preferred
(52)
different that
study. are
after
size
the
patients
and
preemptive
period
however,
of therapy,
95%
reason
these four studies, one may expect therapy will be superior to acyclovir
ganciclovir
course
benefits
has
the renal population; however, this remains unproven. The efficacy of immunogbobulin therapy alone has not been directly compared
suggests
patients
four
In
significant
No
number
trial. The results against the cost
across
effective;
in a formal
are of
acyclovir
acyclovir;
possible
the
of therapy
of data
more
with
than
duration
recipients
randomized
of the
is that the latter study varied not only the duration over which it was given.
obation of the data from intravenous ganciebovir
the
clinically
therapy).
therapy
et a!.
in the
1 5 cases
became
clinically
sample
that
a 1 2-wk
of
when
strategies.
The parison
and
of which
Three effective
One
RRR
in combination
shows
0.65
ganciclovir.
The
four
(three
either
of
populations
(40-42,63).
the fourth
prophylactic
similar,
patients
acycbovir,
ganeicbovir whereas
to
disease.
to gancicbovir
show
0.42
seem
in different
different
effectiveness
population.
ganciclovir
performed
studies
the
in the renal
were
control
over
six
only
hospitalization
and
remains
Brennan
a randomized controlled vious recommendations
Available
compared
power
group
manifestation.
ganciclovir.
in the
prophylactic
induction study,
with
seen
concluded Thus,
emptive
studies
the
respec-
preemptive
non-CMV-rebated
authors
culture, preemptive
treated
developed
therapy
was
or
group.
quent
Interventions
infection
1 3 of
time
effects.
In
CMV
(four
required
were
PCR. levels
clinical
evident.
group,
group,
prophylaxis
Direct
became
difference
any
and
sensitivity
and
in the
group
control
and
vial,
before
evident
no
shell
were
pretransplant
culture, with
viremia
control
treated
cost-effective.
showed
PCR,
patients
using
conventional
et a!.
preemptive
study.
ofpatients,
gancicbovir
in the
CMV-related
patients
for
with
infection
detectable
I 703
Brennan
savings
In this
CMV
in 94%
47%
of (‘MV
therapy,
cost
technique.
with
whereas
and
tered 8 g/d
in renal
and
treated
disease
in a multi-cen-
trial
vial
preemptively
only
genital
for
detected
Patients
were
3 to 5
is approved
reculTent
Infection of acyebovir
the
after
44,
lively.
of aey-
is almost
concentrations
of herpes
in immunocompetent higher oral concentrations
The
is
91,
of
similar
Valaciclovir
of valaciclovir,
serum
acycbovir.
formulations.
(59).
of acycbovir.
the administration
for the treatment
viruses
acycbovir
shell was
any
population.
screened
Viremia
gancicbovir
to show
in a high-risk
serology,
kr the Prevention
of preemptive
were
intensively
safe.
Guidelines
infection.
support
the
transplant
course
by some
simultaneous
use
population,
therapy tory:
advocated
with the of
first
use
two
acycbovir
studies
of a single
study
shows than
(68),
of two
there
is little
evidence
or more
drugs.
In the
have
compared
agent.
The
better
prophylaxis
a 7-d
course
results
to liver
combination are
contradic-
s ith
of gaitcicbovir
a 3 mo and
hy
Journal
1704
perimmune
of the American
globulin
proved
results
(42),
with
Society
and
the
ganciclovir
with
course
J Am
study
shows
im-
with
acy-
in combination
a 2-wk acycbovir
of oral acyclovir. transplant patients,
a 2-wk
second
used
clovir (4 1). In the latter study, supplemented by 10 wk of oral 12-wk period study in renal
of Nephrobogy
course of ganciclovir was compared with
of gancielovir,
followed
was included, dence). Other
few conclusions can be retrospective nonrandomized
(34)
shown
a trend
of drugs,
but
also
combinations
is the
a
In a subsequent observational Martin et al. treated patients by a 10-wk
drawn
to low disease none
(type or cohort
rates
confirms
with
area.
III evistudies
cols
In 1995,
of CMV centers
benefit
to
using
the different
made
of
published
studies
were
3).
not
in this in the field
the therapeutic
were
principles;
management
has
published
transplants
was
review
line
(Table
proto-
in their
own
the
quality
of
last
year
by Dick-
assessed
and
however,
the
inter-
guidelines
drafted.
Implications
Cost
efficacy
studies
calculated
CMV
disease
$17,309,
P
in
1997
than
for
0.001).
=
attributable 0.001),
in this
area
are
greatly
case-controlled study, the cost The study showed higher mean
costs,
to
Canadian The
inpatient
laboratory
differences ($7001
($4916
P
Conti
et
report
nous ganciclovir than include only pharmacy mate
the
cost
costs
medical care. In a cost decision using
lower
with (travel,
effectiveness
analysis
costs
with
date,
P
the
lost work
therapy.
time),
Tsevat
to evaluate
(US) per life saved, whereas recipient receiving an organ
or other
et al.
the
They
of the
cost
costs
(69)
used
of saving
demonstrate
of a
a life
an
mere-
that from
of a CMV a seropositive
seronegative donor
is
supplies). Assuming that hospital average $25,302 (CAN) (12), cost
would be achieved if 12.9 patients were given for each case of CMV prevented. Table 3 shows for different
prevalence
rates
of CMV
disease
and for
efficacy levels for treatment. For example, in a popsimilar to that of Hibberd et al. (50), treated with a course of intravenous ganciclovir of 50%, only three patients would one
case
to interpret
from
the
the
of combination
most
the
clarification.
use
optimal
duration
of
remain
unanswered,
protocols.
and
only
To
this
field
will
provide
the
continued
long-term
solutions
needed.
(Grade based (two
of CMV
disease.
This
with a treatment effineed to be treated to value
is well
below
Recipient; Donor linmunosuppression Products with
A
the
Antiviral
on strong evidence high quality, one
This
(40,42,56-58).
drug
also solid
of choice
studies
in renal
or
Recommended recommendation
from three type of low quality)
evidence in other
The
Seropositive with Therapy
Recommendation).
patients. Supportive ized clinical trials
1 studies in renal
comes organ
from five transplant
remains
is
(37,50,51) transplant randompatients
unknown,
transplant
because
patients
have
been
done; however, based on the quality of the studies and supportive evidence from liver and heart transplant patients, prophylaxis with oral or intravenous ganeiclovir for a minimum 14-d
and $600 for administration costs for one case of CMV
different ulation
benefit
include
and
questions in
no comparative
current estimate of the cost of a 2-wk course of intraganciclovir is $1966. 12 (CAN) ($1 366. 12 for the drug
the NNT
these
research
Prophylaxis
drug,
(US).
equivalency prophylaxis
therapy
(1) Seropositive Seronegative; Antilymphocyte
of intrave-
however, they is made to esti-
administration
study,
model
immunoglobulin
The venous
issues
it difficult
would
after
diagnostic
be
mental cost of therapy as the risk of infection falls. For exampie, the cost of administering therapy to a CMV seronegative recipient of a seronegative donor is estimated at $ 1 .68 million
$29,800
that
of CMV and
=
would
the use
with immunoglobulin; costs, and no attempt
associated
patient-incurred
but effective
unresolved
made
have
areas
treatment
definitions
Recommendations
(55)
ti!
a cheap
studies
are
prophylactic
therapy
from
in the
Inconsistent
across
and
Other
potential
savings (Table 3).
is required
=
of intervention proposed that the
large
research
transplantation.
variability
$3198,
$1782,
Directions
results
in costs
versus
versus
renal
with
$7484,
Future Further
1 versus
were
versus
costs
expenses
In a
patients
($42,61
($ 19,988
radiology
pharmacy
for
subjects
main
care
and
0.01), and
dollars
control
needed.
of CMV disease total institutional
0.01). No attempt to calculate the effectiveness was made. Nevertheless, the consensus group
prevent
been
organ
evidence-based
provider
of researchers
published
solid
assessment
inson et a!. (72),
retrospective was reported.
2-wk cacy
No
all
to show
this
Bodies have
group
collectively for
is drawn below
the service
guidelines
In a systematic
for patient
=
and
line
value
of Other
used
literature.
black Any
a distinguished
(7 1 ).
preted
P
the patient
therapy
being
heavy
points.
evidence-based
No
monotherapy.
Cost
cutoff
for both
(calculated above as 12.9), and that prophylaxis with gancicbovir
The
choice.
Recommendations
rates group
different
additional
optimal
the cost-effective benefit
period
of oral acyclovir and hyperimmune globulin (68). Disease were encouragingly low, but because no comparative
have
cost effectiveness number therefore one would suggest
Soc Nephrol 9: 1697-1708, 1998
period
is recommended.
(2) Seronegative Immunosuppression Prophylaxis (Grade based
transplant
from
studies
plant both though
with
Seropositive
comes
patients
(37,54)
in R+/D± from
patients type
patients (40,42,56-58). oral acyclovir and no head-to-head
Donor;
with Antilymphocyte Antiviral Therapy
A Recommendation). on data from two randomized
renal evidence
Recipient;
oral
1 studies
Products Recommended
This recommendation clinical trials in R-ID+ and
on
(50,51).
results
Studies demonstrate and intravenous
comparison
trial
extrapolated
Further
in heart
is
and
supportive liver
benefit ganciclovir,
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