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Topical Treatment of Acute Adenoviral Keratoconjunctivitis With 0.2% Cidofovir and 1% Cyclosporine
A Controlled Clinical Pilot Study
Jost Hillenkamp, MD;
Thomas Reinhard, MD;
Rudolf S. Ross, MD;
Daniel Böhringer, MD;
Olaf Cartsburg, MD;
Michael Roggendorf, MD;
Erik De Clercq, MD, PhD;
Erhard Godehardt, PhD;
Rainer Sundmacher, MD
Arch Ophthalmol. 2001;119:1487-1491.
ABSTRACT
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Objective To evaluate the efficacy of 0.2% cidofovir eyedrops and 1% cyclosporine
eyedrops administered 4 times daily (qid) to treat acute adenoviral keratoconjunctivitis.
Methods A randomized, controlled, double-masked study was conducted on 39 patients
with acute adenoviral keratoconjunctivitis of recent onset. Patients were
divided into 4 treatment groups: (1) cidofovir qid, (2) cyclosporine qid,
(3) cidofovir + cyclosporine qid, and (4) sodium chloride qid (control). The
diagnosis was confirmed using adenoviral polymerase chain reaction from conjunctival
swabs. Duration of treatment was 21 days.
Main Outcome Measures Severity of conjunctival hyperemia, conjunctival chemosis, superficial
punctate keratitis during treatment, and presence and severity of corneal
subepithelial infiltrates were evaluated using a clinical score. Duration
until subjective improvement of symptoms was recorded.
Results Subjective improvement of local symptoms was accelerated in the cyclosporine
group. All other clinically relevant variables showed no statistically significant
difference among the 4 treatment groups. Particularly, we did not find a difference
in the frequency of corneal subepithelial infiltrates at the end of treatment.
Conclusions Use of cidofovir, cyclosporine, or both did not accelerate the improvement
of clinical symptoms of acute adenoviral keratoconjunctivitis compared with
the natural course of the infection as demonstrated by this pilot study. This
might be because of the wide spectrum of the clinical course of the infection,
low sensitivity to cidofovir, too low of a concentration of cidofovir, or
early cessation of viral replication in the course of the infection. The effect
of a higher concentration of topical cidofovir with and without cyclosporine
requires investigation in a larger group of patients.
INTRODUCTION
ADENOVIRAL keratoconjunctivitis (AKC) was first described by Fuchs in
1889.1 In 1955, Jawetz et al2
identified adenovirus as the cause of the disease. Other authors3
isolated adenovirus types 8, 19, and 37 as the most frequent causative adenovirus
subtypes.
The natural course of the acute phase of AKC has a wide spectrum of
duration and intensity of local symptoms. After an incubation period of 2
to 14 days, symptoms usually begin in one eye, and the other eye becomes symptomatic
after 2 to 4 more days. Typical symptoms include conjunctival hyperemia and
chemosis, swelling of the conjunctival plica, and intense tearing. Conjunctival
pseudomembranes occur in some cases. Ipsilateral preauricular lymphadenopathy
is a fairly typical sign observed in many patients. Ocular adenoviral infections
are characterized by highly distressing local symptoms.3
It is the corneal involvement that sets AKC apart from other forms of
viral conjunctivitis. During the course of the infection, approximately 10
days after the onset of symptoms, corneal subepithelial opacities frequently
develop. These nummular opacities or infiltrates can impair visual function
and can persist for months to years.4 Histopathological
investigation of focal biopsy samples revealed subepithelial infiltrates of
lymphocytes, histiocytes, and fibroblasts accompanied by a disruption of the
collagen fibers of the Bowman layer.5-6
The pathogenesis of the nummular opacities most likely includes a persisting
viral replication in subepithelial keratocytes, triggering an immunological
host reaction. This hypothesis is supported by the clinical observation that
opacities usually resolve with topical corticosteroid treatment but recur
when corticosteroid use is discontinued.7
Conjunctival adenovirus infection is a highly contagious disease that
occurs worldwide sporadically and epidemically.8
Although not blinding, AKC remains the most common external ocular viral infection.
The economic and social price of this community epidemic also remains high.
Currently, no specific antiviral therapy is available to shorten the
course of the infection, to improve the distressful clinical symptoms, to
stop the viral replication, and to avoid the development of corneal opacities.
Cidofovir or HPMPC, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine,
a broad-spectrum antiviral agent,9 has demonstrated
significant antiviral activity in the adenovirus type 5 McEwen/New Zealand
rabbit ocular model.10 In 1996, Gordon et al11 first reported the clinical efficacy and safety of
topical cidofovir in the treatment of a patient with proven AKC.
Cyclosporine is a well-established immunosuppressant that has been used
in the prevention of transplant rejection for 20 years.12
Topical cyclosporine was used effectively in the treatment of Mooren ulcers,13 vernal keratoconjunctivitis,14
ulcerative keratitis associated with rheumatoid arthritis,15
anterior uveitis,16 and Thygeson punctate keratitis.17-18
Furthermore, topical cyclosporine was reported to be valuable in the
treatment of patients with AKC-related corneal opacities.4
To our knowledge, the effect of cyclosporine eyedrop administration on the
course of the acute phase of AKC has not yet been investigated. Topical administration
of cyclosporine might alter the host's local immune response, conserving the
ability of virus elimination, while ameliorating the distressing symptoms
of the acute phase of AKC. The development of corneal opacities in the late
phase of AKC might be inhibited by early use of topical cyclosporine.
From our long-standing positive clinical experiences in the standard
treatment of deep forms of herpetic anterior segment infection with a combination
of virustatic agents and corticosteroids,19
we suspected that treatment with cidofovir combined with cyclosporine might
be superior to the respective monotherapies.
The aim of this study was to investigate the efficacy of cidofovir eyedrops
with and without cyclosporine eyedrops in the treatment of the acute phase
of AKC and to evaluate the ability of both agents as monotherapy and combined
therapy to shorten the course of the acute phase of AKC and to prevent the
development of corneal opacities in the late phase of the infection.
PATIENTS AND METHODS
We designed this randomized controlled study according to the CONSORT
statement.20 Approval was obtained from the
ethics committee of the Heinrich-Heine-University, Düsseldorf, Germany.
CLINICAL INVESTIGATION
A total of 39 patients with acute, previously untreated AKC of recent
onset were randomly divided into 4 treatment groups of 9 or 10 patients each:
(1) 0.2% cidofovir eyedrops 4 times daily to both eyes; (2) 1% cyclosporine
eyedrops 4 times daily to both eyes; (3) 0.2% cidofovir eyedrops and 1% cyclosporine
eyedrops 4 times daily to both eyes; and (4) sodium chloride eyedrops 4 times
daily to both eyes as a control group (Figure
1). The allocation sequence was generated by chance and was concealed
until the patient was randomized. Patients of either sex who were 18 years
or older were eligible. Patients with any other ocular anterior segment morbidity,
pregnant women, and patients taking any other topical ocular medication were
excluded from the trial. We admitted 17 women and 22 men (age range, 23-85
years; average age, 44.9 years).
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Study design. All 39 patients were randomized to 1 of 4 groups; had
outcome measures evaluated on days 0, 3, 6, 12, and 21; and completed the
trial.
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POLYMERASE CHAIN REACTION
The diagnosis of AKC was made by clinical examination (J.H.) and confirmed
by adenoviral polymerase chain reaction (PCR) from ocular swabs (R.S.R. and
M.R.). Confirmation by PCR usually required 4 to 7 days. We initially admitted
all eligible patients with a clinical diagnosis of AKC to the study, but only
patients with a positive PCR result remained in the study for continued treatment
with study medication and statistical evaluation. Patients with a negative
PCR result withdrew from the study and were seen for clinical reevaluation
of the diagnosis. Polymerase chain reaction has been described as a highly
suitable method for the detection of adenovirus in ocular swabs.21
For detection of adenovirus DNA by PCR, DNA was extracted using a viral
DNA kit (Qiagen, Hilden, Germany). For nested PCR, general primers derived
from the well-conserved hexon gene sequence were used that could detect all
adenovirus types: HexA 5'-GCC GCA GTG GTC TTA CAT GCA CAT C-3'
(PCR 1, nt 18858 to 18882, numbering according to human adenovirus type 2
GenBank sequence J01917); HexB 5'-CAG CAC GCC GCG GAT GTC AAA GT-3'
(PCR 1, nt 19136 to 19158); ADP-1 5'-CCA GGA CGC CTC GGA GTA CCT-3'
(PCR 2, nt 18888 to 18908), and ADP-2 5'-GGA AGC CAT ATC AAG CAC AC-3'
(PCR 2, nt 19112 to 19131). Amplified DNA from the second PCR was fractionated
using 1% agarose gel electrophoresis, and the 243–base pair fragment
was visualized using UV fluorescence after staining with ethidium bromide.
CIDOFOVIR AND CYCLOSPORINE EYEDROPS
Cidofovir and cyclosporine eyedrops were obtained from the pharmacy
of Heinrich-Heine-University. Cidofovir was prepared as a 0.2% solution in
a sodium borate buffer (pH 8.2) with 0.01% thiomersal preservative as previously
described by Gordon et al.11 The uncompromised
antiviral potency of cidofovir eyedrops for 12 months after preparation was
confirmed at the Rega Institute for Medical Research, Catholic University,
Leuven, Belgium (E.D.). Cyclosporine eyedrops were prepared in peanut oil
as a 1% solution. All patients were also treated with preservative-free topical
lubrication.
Duration of treatment was 21 days. Patients gave informed consent and
were examined on admission to the study and 3, 6, 12, and 21 days after the
onset of treatment.
At each visit, local ocular inflammation was photodocumented to evaluate
the severity of inflammation using a clinical score. After randomization,
both patient and physician (J.H.) knew the treatment, but the photodocumentation
of each patient visit was evaluated by an experienced ophthalmologist (T.R.)
in a masked fashion.
STATISTICAL EVALUATION
We evaluated and recorded the length of time until subjective improvement of the typical distressing symptoms. In addition,
the following objective variables were evaluated
using a clinical score: (1) conjunctival hyperemia (0 indicates no; 1, mild;
and 2, severe); (2) conjunctival chemosis (0 indicates no; 1, mild; and 2,
severe); (3) superficial punctate keratitis (0 indicates no; 1, mild; and
2, severe); (4) corneal subepithelial infiltrates (0 indicates no; 1, few
[<10]; and 2, many [ 10]); and (5) the Schirmer test (with topical anesthesia)
(0 indicates >15 mm; 1, 5-15 mm; and 2, <5 mm).
The subjective variable and objective variables 1 through 3 and 5 were
statistically evaluated (by E.G.) using 2-factorial analysis of variance (general
linear model, Duncan multiple range test). Variable 4 was statistically evaluated
using the  2 test (Pearson test). We used SPSS version 8.1
for MS-Windows NT 4.0 software (SPSS Inc, Chicago, Ill).
RESULTS
No significant ocular toxic effects from using either topical cidofovir
or cyclosporine were observed. Four patients complained of mild local burning
associated with administration of cyclosporine eyedrops, but no patient decided
to withdraw from the study.
The duration of complaints (interval between the first onset of symptoms
and admission to the study) ranged from 1 to 7 days for all patients except
2 (10 and 14 days), who were both randomized to the cidofovir + cyclosporine
group, thus leading to a statistically significantly (P = .03) longer duration of symptoms in that group. We therefore reevaluated
all variables without taking into account patients with a duration of symptoms
longer than 6 days. Thirty-three patients remained, and there was no statistically
significant difference in duration of symptoms among the 4 treatment groups.
We also did not find a statistically significant difference for the subjective
variable and objective variables 1 through 4. The difference in the measurements
of the Schirmer test remained unchanged. In this evaluation, length of time
until subjective improvement of symptoms was not statistically significantly
different among the 4 treatment groups.
Use of cyclosporine, but not cidofovir, accelerated the subjective improvement
of clinical symptoms related to the acute phase of AKC (P = .046) (Table 1).
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Table 1. Two-Factorial Analysis of Variance*
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For variables 1 through 3, we were unable to prove a statistically significant
difference using 2-factorial analysis of variance among the 4 treatment groups
for conjunctival hyperemia, conjunctival chemosis, and superficial punctate
keratitis (Table 1).
According to the clinical score, we compared the number of patients
with severe corneal infiltrates with patients with either mild or no corneal
infiltrates (variable 4). As evaluated using the 2 test (Pearson
test), the incidence of corneal infitrates was not affected by application
of cidofovir. There might have been a weak trend toward a lower incidence
of corneal infiltrates in the cyclosporine group (Table 2).
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Table 2. Corneal Opacities*
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Evaluation of the Schirmer test showed that eyes treated with cidofovir
were statistically significantly less dry, as evaluated using 2-factorial
analysis of variance (general linear model, Duncan multiple range test) (P = .048). There might have been a weak tendency toward
dryer eyes in the cyclosporine group (Table
1).
COMMENT
The inhibitory effect of cidofovir in vitro on adenovirus types 1, 5,
8, and 19 isolated from patients with AKC has been described.22
The efficacy of cidofovir has also been documented in vivo. Cidofovir demonstrated
significant antiviral activity in the adenovirus type 5 McEwen/New Zealand
rabbit ocular model.10, 23
However, to our knowledge, there is to date only one case report providing
information on the safety and possible efficacy of topical 0.2% cidofovir
administration. Gordon et al11 treated a 31-year-old
patient with proven adenoviral conjunctivitis. Symptoms improved markedly
within 4 days, and all clinical findings completely resolved within 7 days;
the cornea remained clear, and the other eye, which had received prophylactic
treatment, remained free of symptoms.11
To our knowledge, the present study provides the first data on the treatment
of AKC with topical cidofovir in a controlled clinical trial. Our observations
indicate, in accordance with those of Gordon et al,11
that topical 0.2% cidofovir is a well-tolerated drug without evidence of local
or systemic adverse effects. Our pilot study, however, did not demonstrate
a statistically significant effect of the tested treatment regimens on the
natural course of the acute phase of AKC. Only the subjective improvement
of the distressing local symptoms was accelerated by cyclosporine application.
We did not find a statistically significant difference among the 4 treatment
groups in the frequency of corneal infiltrates at the end of 21 days of treatment.
Keratoconjunctival infection is usually associated with intense tearing
during the first days of the acute phase of the disease. During the further
course of the infection, the intense tearing subsides and patients often develop
a dry eye syndrome.24 Eyes treated with topical
cidofovir were not as dry as those treated with either sodium chloride or
cyclosporine, as indicated by the Schirmer test (P
= .048). This result might indicate a therapeutic effect of cidofovir. The
observed weak tendency toward dryer eyes in the cyclosporine group might be
secondary to the immunosuppressant properties of cyclosporine. This theory
would be in accordance with the findings of Trauzettel-Klosinski et al24 of a significant incidence of severe dry eyes in
patients with AKC treated with topical corticosteroids.
There are several possible explanations for the failure of cidofovir
to show the clinical efficacy that might have been expected from the antiviral
activity demonstrated in vitro22 and in the
rabbit ocular model10, 23 (see
the following paragraphs).
CONCENTRATION OF CIDOFOVIR
We administered 0.2% cidofovir 4 times daily. Gordon et al10
showed that 0.2% cidofovir administered 4 to 5 times daily limited adenoviral
replication in the adenovirus type 5/New Zealand rabbit ocular model. Cidofovir,
0.5% and 1%, administered only twice daily was not superior but equally effective.
SEROTYPE DEPENDENCY
Adenovirus demonstrated serotype-dependent differences in in vitro infectivity
titers and clinical course. Adenovirus type 8 was the most frequent serotype
in 106 positive adenoviral cultures, causing significantly more often a severe
clinical course with marked eyelid edema than other serotypes. Adenovirus
types 3 and 4 were associated with higher infectivity titers than other serotypes.
Infectivity and the clinical course of AKC are serotype dependent.25
Cidofovir proved to be effective against adenovirus types 1, 5, and
6 in the rabbit model,10, 26 but
a relative resistance of adenovirus type 19 to cidofovir application was reported.22 Variants of adenovirus type 5 with different sensitivity
to topical treatment with 0.5% cidofovir in the rabbit ocular model have been
described by Araullo-Cruz et al.27 Consequently,
the efficacy of cidofovir in patients might also be serotype dependent. Patients
enrolled in our study were probably infected with various adenovirus types.
Because we were unable to statistically prove a therapeutic effect of either
cidofovir or cyclosporine treatment in this pilot study, we did not further
extend this investigation by identifying adenoviral serotypes. Regarding statistical
analysis, dividing our data according to adenoviral serotypes would have further
decreased the number of patients in each treatment group.
PHARMACOKINETICS
Eyedrops can be washed out by intense tearing; in addition, regular
conjunctival absorption of eyedrops can be impaired in patients with severe
conjunctival chemosis and swelling of the conjunctival plica.
VIRAL REPLICATION AND ONSET OF TREATMENT
The New Zealand rabbit ocular model of adenovirus type 5 infection showed
a duration of viral replication of 9 days, with a peak on day 3. The symptoms
of AKC after the phase of viral replication are thought to be caused by the
host's immune response.28 Treatment with cidofovir
in the rabbit model began 24 hours after inoculation.26
Treatment of our patients began 1 to 7 days (mean, 3.5 days) after the onset
of symptoms, when patients first came to our clinic. Cidofovir might have
been effective in the rabbit ocular model because treatment began early in
the course of the infection, whereas treatment of our patients might have
failed because it did not start until the phase of viral replication had almost
been completed. On the other hand, cyclosporine use might be effective because
of its suppressant effect on the local symptoms caused by the host's immune
response.
The trend toward earlier improvement of local symptoms in the acute
phase and a lesser incidence of corneal infiltrates with topical cyclosporine
treatment warrants further investigation in a greater number of patients.
Furthermore, the effect of using a higher concentration of topical cidofovir,
with and without cyclosporine, requires investigation in a greater number
of patients.
Because of the wide spectrum of duration and intensity of local symptoms
of the natural course of the acute phase of AKC, a possible topical treatment
will ultimately have to be investigated in a multicenter trial once the necessary
pilot studies have been completed.
AUTHOR INFORMATION
Accepted for publication February 12, 2001.
Presented at the annual meeting of the Association for Research in Vision
and Ophthalmology, Fort Lauderdale, Fla, April 30 to May 5, 2000.
We thank Gerlinde Westphal, Helen Basler, and Kerstin Bisgiel for their
expert technical assistance.
Corresponding author: Jost Hillenkamp, MD, Department of Ophthalmology,
The Rayne Institute, St Thomas' Hospital, Lambeth Palace Road, London SE1
7EH, England (e-mail: hillenka{at}hotmail.com).
From the Eye Hospital (Drs Hillenkamp, Reinhard, Böhringer, Cartsburg,
and Sundmacher) and the Department of Biometry in the Department of Cardiovascular
and Thoracic Surgery (Dr Godehardt), Heinrich-Heine-University, Düsseldorf,
Germany; the Institute of Virology, Essen University, Essen, Germany (Drs
Ross and Roggendorf); and the Rega Institute for Medical Research, Catholic
University, Leuven, Belgium (Dr De Clercq).
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