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British
Journal
of
Ophthalmology,
1980,
64,
763-765
A
comparison
of
acyclovir
and
idoxuridine
as
treatment
for
ulcerative
herpetic
keratitis
DOUGLAS
J.
COSTER,
K.
R.
WILHELMUS,
R.
MICHAUD,
AND
BARRIE
R.
JONES
From
the
Department
of
Clinical
Ophthalmology,
Institute
of
Ophthalmology,
Moorfields
Eye
Hospital,
City
Road,
London
SUMMARY
Sixty
patients
were
treated
with
either
acyclovir
3%
ointment
or
idoxuridine
1%
ointment
5
times
a
day
in
a
stratified
randomised
double-blind
clinical
trial.
The
2
antiviral
agents
were
equally
effective.
Acyclovir
(ACV,
previously
called
Wellcome
248U
and
acycloguanosine)
is
a
compound
active
in
herpes
simplex
virus
(HSV)
infections.
It
has
con-
siderable
clinical
potential
because
it
is
extremely
specific.
Only
cells
infected
with
virus,
and
therefore
with
virus-coded
thymidine
kinase,
phosphorylate
the
drug
to
a
form
capable
of
inhibiting
DNA-
polymerase.
Furthermore,
it
does
not
appear
to
be
metabolised
to
inactive
substances
by
human
cells.1
The
inhibition
of
viral
coded
DNA-polymerase
is
also
highly
specific.
The
potential
value
of
the
drug
is
related
to
its
high
specificity
and
low
toxicity.
Acyclovir
has
been
demonstrated
to
possess
potent
antiviral
activity
in
vitro
and
in
animal
models
of
herpetic
keratitis.2
Clinical
studies
have
confirmed
the
activity
of
the
drug
in
human
herpetic
disease.
The
first
of
these
studies
involved
debriding
epithelial
lesions
produced
by
HSV
and
comparing
the
ability
of
acyclovir
to
prevent
lesion
formation.3
When
dendritic
ulcers
are
treated
with
debridement
alone,
healing
is
rapid
and
patients
become
free
of
pain
within
24-48
hours.
However,
50%
of
patients
so
treated
develop
small
foci
of
viral
activity
in
the
epithelium
within
a
week
of
treatment
that
requires
further
debridement
or
antiviral
chemotherapy.4
Placebo-controlled
trials
designed
to
test
an
anti-
viral
agent's
ability
to
suppress
the
formation
of
these
microscopic
lesions
are
capable
of
demon-
strating
a
potentially
useful
biological
activity
while
subjecting
a
very
small
number
of
patients
to
a
small
amount
of
drug.
Correspondence
to
Professor
D.
J.
Coster,
Department
of
Clinical
Ophthalmology,
Moorfields
Eye
Hospital,
City
Road,
London
ECIV
2PD.
The
biological
activity
of
acyclovir
having
been
confirmed
in
human
viral
disease,
the
next
step
was
to
compare
the
drug
used
in
a
more
conventional
manner
to
established
antiviral
chemotherapy.
Here
we
report
the
results
of
a
trial
comparing
the
effects
of
acyclovir
and
idoxuridine
(IDU)
ointments
on
the
rate
of
healing
of
herpetic
corneal
ulcers.
Patients
and
methods
Sixty
consenting
patients
presenting
with
ulcerative
herpetic
keratitis
were
admitted
to
the
trial.
Patients
were
allocated
to
strata
on
the
basis
of
clinical
features
likely
to
be
significant
in
prognosis.
The
stratification
factors
were
the
type
of
ulcer,
that
is,
geographic
or
dendritic,
the
size
of
the
ulcer,
whether
the
patient
had
received
topical
cortico-
steroids
within
the
3
weeks
prior
to
presentation,
and
the
degree
of
inflammatory
reaction
in
the
cornea
and
anterior
chamber.
Within
these
strata
patients
were
randomly
allocated
to
1
of
2
treatment
groups.
One
group
received
IDU
1%
ointment
5
times
a
day
until
the
epithelial
defect
had
healed
and
then
3
times
aday
for
3
more
days.
The
other
group
received
acyclovir
3%
ointment
5
times
a
day
until
the
epithelial
defect
healed
and
then
3
times
a
day
for
a
further
3
days.
All
patients
received
a
drop
of
atropine
1%
each
day
until
healed.
Neither
the
patient
nor
the
ophthalmologist
knew
which
treatment
was
being
used,
so
that
the
trial
was
stratified,
randomised,
and
double-blind.
Having
begun
treatment,
patients
were
examined
at
the
slit-lamp
on
alternate
days.
The
point
of
healing
was
judged
to
have
occurred
when
no
epithelial
defect
was
demonstrable
with
rose
Bengal
and
fluorescein
staining.
763
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Douglas
J.
Coster,
K.
R.
Wilhelmus,
R.
Michaud,
and
Barrie
R.
Jones
Results
Sixty
patients
were
admitted
to
the
trial.
Fifty-four
had
dendritic
and
6
had
geographic
(amoeboid)
ulcers.
Thirty
received
IDU
and
30
received
acyclo-
vir.
The
distribution
of
patients
is
set
out
in
Table
1.
One
patient
treated
with
acyclovir
failed
to
present
regularly
for
follow-up,
though
he
responded
favourably
in
that
his
geographic
ulcer
had
healed
when
he
returned
10
days
after
beginning
therapy.
He
is
not
included
in
the
analysis.
There
were
no
treatment
failures,
nor
were
there
any
untoward
reactions
that
necessitated
withdrawal
of
therapy.
One
patient
developed
an
allergic
reac-
tion
that
subsided
on
withdrawing
the
atropine
drops.
The
results
were
evaluated
on
the
basis
of
the
number
of
days
it
took
the
ulcers
to
heal
in
each
group.
The
distribution
of
healing
times
for
patients
in
both
treatment
groups
is
set
out
in
Fig.
1.
A
cumulative
frequency
curve
indicating
the
pattern
of
healing
in
each
group
is
displayed
in
Fig.
2.
Clearly
the
patterns
are
very
similar,
and
a
logrank
analysis
indicates
that
the
difference
between
the
Table
1
Distribution
o
patients
with
dendritic
or
geographic
ulcers
to
treatment
group
to
receive
idoxuridine
(IDU)
or
acyclovir
(ACV)
IDU
ACV
Geographic
4
2*
Small
dendritic
14*
14*
Large
dendritic
12 14
Total
30
30
Patients
with
marked
inflammatory
reaction
in
the
corneal
stroma
and
anterior
chamber.
curves
is
likely
to
have
occurred
by
change
(P>0
05).
When
the
geographic
ulcers
are
excluded
from
the
analysis
the
difference
between
the
groups
is
even
less
(Fig.
3).
100%
r
ULCERS
HEALED
80
60
40
20
ACV
N
=
29
A
0
IDU
N
=
30
-A
I
I
-
-
_____j
5
10
15
25
DAYS
Fig.
2
Cumulative
frequency
graph
of
the
time
taken
to
heal
of
59
herpetic
corneal
ulcers
(54
dendritic,
S
geographic)
treated
with
acyclovir
(A
CV)
or
S-iodo-2'
deoxyuridine
(IDU).
l
o
r
ULCERS
HEALED
80
60
NO
ULCERS
40
ACV
N
=28
IDU
N
=26
20
I
5
10
15
20
25
DAYS
Fig.
1
Histogram
of
healing
times
of
herpetic
ulcer
s
treated
with
acyclovir
(ACV)
and
5-iodo-2'
deoxyuridine
(IDU).
5
10
15
DAYS
Fig.
3
Cumulative
frequency
graph
of
the
time
taken
to
heal
of
54
dendritic
ulcers
treated
with
acyclovir
(ACV)
or
S-iodo-2'
deoxyuridine
(ID
U).
.
.
.
I
764
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A
comparison
of
acyclovir
and
idoxuridine
as
treatment
for
ulcerative
herpetic
keratitis
Discussion
The
results
of
this
trial
establish
that
acyclovir
is
an
effective
antiviral
agent
for
treating
ulcerative
herpetic
keratitis,
since
it
is
at
least
as
active
as
IDU.
It
is
to
be
expected
that
such
a
trial
will
yield
a
null
result.
The
majority
of
ulcers
are
dendritic
rather
than
geographic.
IDU
is
so
effective
for
dendritic
ulcers,
with
100%
of
patients
being
healed
within
14
days,
that
there
is
little
chance
of
another
antiviral
agent
bringing
about
a
significant
improvement
on
what
is
achieved
with
IDU.
This
is
not
to
say
that
a
null
result
is
insignificant,
but
it
demands
that
trials
be
well
designed,
carefully
con-
ducted,
and
the
data
be
analysed
in
an
appropriate
manner.
A
further
limitation
of
trials
evaluating
antiviral
agents
as
treatment
for
dendritic
ulcers
is
that
they
do
not
provide
any
information
on
chronic
toxicity,
as
the
majority
of
patients
complete
the
treatment
programme
in
less
than
2
weeks.
This
is
a
major
limitation,
since
it
is
the
toxicity
of
antivirals
that
limits
their
clinical
usefulness.
Since
it
is
established
that
acyclovir
is
as
effective
as
IDU
in
the
treatment
of
ulcerative
herpetic
keratitis,
the
next
step
is
to
evaluate
the
drug
in
situations
in
which
currently
employed
therapeutic
measures
are
less
than
universally
satisfactory.
Geographic
ulcers
are
generally
more
difficult
to
treat
than
dendritic
ulcers.
They
have
been
shown
to
represent
a
different
level
of
challenge
and
are
capable
of
demonstrating
a
difference
between
antiviral
agents
that
cannot
be
appreciated
when
only
dendritic
ulcers
are
studied.5
Herpetic
corneal
ulcers
which
have
failed
to
heal
with
IDU
or
debridement
are
another
difficult
problem
with
which
to
challenge
a
prospective
new
topical
antiviral
agent.
Stromal
keratitis
is
also
a
form
of
herpetic
eye
disease
often
resistant
to
current
therapy.
An
important
challenge
is
to
conduct
trials
directed
at
evaluating
this
new
antiviral
agent
in
these
sight-threatening
conditions.
Because
of
its
remarkably
low
toxicity
and
high
specificity,
acyclovir
is
a
drug
with
exciting
therapeutic
poten-
tial.
References
1
Schaeffer
HJ,
de
Miranda
P,
Elion
GB,
Bauer
JD,
Collins
P.
9-(Hydroxyethoxymethyl)
guanine
activity
against
viruses
in
the
herpes
group.
Nature
1978;
272:
583-5.
2
Falcon
MG,
Jones
BR.
Acycloguanosine:
antiviral
activity
in
the rabbit
cornea.
Br
J
Ophthalmol
1979;
63:
422-4.
3
Coster
DJ,
Jones
BR,
Falcon
MG.
Role
of
debridement
in
the
treatment
of
herpetic
keratitis.
Trans
Ophthalmol
Soc
UK
1977;
97:
314-7.
4
Jones
BR,
Coster
DJ,
Fison
PN,
Thompson
GM,
Cobo
LM,
Falcon
MG.
Efficacy
of
acycloguanosine
(Wellcome
248U)
against
herpes
simplex
corneal
ulcers.
Lancet
1979;
i:
243-4.
5
Coster
DJ,
Jones
BR,
McGill
JI.
Treatment
of
amoeboid
herpetic
ulcers
with
adenine
arabinoside
or
trifluoro-
thymidine.
Br
J
Ophthalmol
1979;
63:
418-21.
765
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herpetic keratitis.
idoxuridine as treatment for ulcerative
A comparison of acyclovir and
D J Coster, K R Wilhelmus, R Michaud and B R Jones
doi: 10.1136/bjo.64.10.763
1980 64: 763-765 Br J Ophthalmol
http://bjo.bmj.com/content/64/10/763
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