Purpose
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To evaluate the
efficacy of topical corticosteroids in treating herpes simplex stromal
keratitis in conjunction with topical trifluridine.
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To evaluate the
efficacy of oral acyclovir in treating herpes simplex stromal keratitis
in patients receiving concomitant topical corticosteroids and trifluridine.
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To evaluate the
efficacy of oral acyclovir in treating herpes simplex iridocyclitis in
conjunction with treatment with topical corticosteroids and trifluridine.
Background
Herpes simplex
keratitis is a leading cause of corneal opacification in the United States,
other industrialized countries, and developing nations throughout the world.
An estimated 450,000 people in the United States can develop recurrent
episodes of the disease and about 46,000 episodes of HSV eye infection
every year. Herpetic eye disease is the most common infectious cause of
corneal blindness in this country.
Despite the
availability of antiviral agents that are effective in treating herpes
simplex epithelial keratitis, inflammation in the corneal connective tissue
and iris that can lead to corneal scarring and visual impairment develops
in many patients. Prior to the HEDS-I trials, the role of topical corticosteroids
in the management of HSV stromal keratitis was uncertain; some animal and
human studies suggested there was a benefit to treatment whereas others
suggested harm. The value of adding an oral antiviral agent to treatment
with topical corticosteroids and topical antivirals also was unknown.
The HEDS-I
trials were developed to assess the efficacy of topical corticosteroids
and oral acyclovir in treating HSV stromal keratitis and iridocyclitis.
Description
HEDS-I consisted
of three randomized, placebo-controlled trials. The organizational structure
consisted of a data coordinating center and eight clinical centers.
All patients
received the topical antiviral trifluridine as prophylaxis against recurrences
of HSV epithelial ulceration. Patients were evaluated weekly for 10 weeks,
every other week through week 16, and again at 6 months. The primary outcome
was the time to development of preset criteria for treatment failure during
the 16-week period of examination. Protocol-specific descriptions of the
three trials follow.
Herpes Stromal
Keratitis, Not on Steroid Trial (HEDS-SKN):
Patients with
active HSV stromal keratitis who had not used a topical corticosteroid
in the preceding 10 days were randomized to treatment with topical prednisolone
phosphate drops or topical placebo drops. A treatment schedule, starting
with 8 drops a day of 1 percent prednisolone phosphate for 7 days, was
progressively decreased over 10 weeks in such a way that patients received
1 drop per day of 1/8 percent prednisolone for the last 3 weeks of treatment.
Placebo drops were given by the same schedule.
Herpes Stromal
Keratitis, on Steroid Treatment (HEDS-SKS):
Patients with
active HSV stromal keratitis who already were being treated with a topical
corticosteroid were randomized either to oral treatment with 200 mg acyclovir
capsules (400 mg five times daily) for 10 weeks or to the identical dose
of placebo capsules. Patients also received topical prednisolone phosphate
in the dosage schedule described above for the SKN trial.
Herpes Simplex
Virus Iridocyclitis, Receiving Topical Steroids (HEDS-IRT):
Patients with
active HSV iridocyclitis were randomized either to oral treatment with
200 mg acyclovir capsules (400 mg five times daily) for 10 weeks or to
the identical dose of placebo capsules. Patients also received topical
prednisolone phosphate in the dosage schedule described above for the SKN
trial.
Patient
Eligibility
Eligibility criteria
common to the three protocols included age 12 years or older, no active
HSV epithelial keratitis, no prior keratoplasty of the involved eye, and
not pregnant. Protocol-specific criteria are noted in the description above.
Results
Herpes Stromal
Keratitis, Not on Steroid Trial (HEDS-SKN):
Patient recruitment
was stopped on the recommendation of the Data and Safety Monitoring Committee
after 106 of the originally planned 176 patients were enrolled. Compared
with the patients in the placebo group, the patients who received prednisolone
phosphate drops had faster resolution of the stromal keratitis and fewer
treatment failures. However, delaying the initiation of corticosteroid
treatment did not affect the eventual outcome of the disease, in that visual
acuity was similar in the two groups at 26 weeks.
Herpes Stromal
Keratitis, on Steroid Treatment (HEDS-SKS):
One hundred
and four patients were enrolled in this trial. Over the 16-week followup
period, there was no difference in the rate of treatment failure between
the two groups. Thus, there was no apparent benefit in the addition of
oral acyclovir to the treatment regimen of a topical corticosteroid and
a topical antiviral.
Herpes Simplex
Virus Iridocyclitis, Receiving Topical Steroids (HEDS-IRT):
The trial
was stopped because of slow recruitment after only 50 of the originally
planned 104 patients were enrolled during a 4-year recruitment period.
Treatment failures occurred at a higher rate in the placebo group than
in the acyclovir group. Although the number of patients enrolled in this
trial was too small to achieve statistically conclusive results, the trend
in the results suggests a benefit in adding oral acyclovir to the treatment
of HSV iridocyclitis in patients receiving topical corticosteroids and
trifluridine prophylaxis.
Publications
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Herpetic Eye Disease
Study Group: A controlled trial of oral acyclovir for iridocyclitis caused
by herpes simplex virus. Arch Ophthalmol 114: 1065-1072, 1996.
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Wilhelmus KR,
Dawson CR, Barron BA, Bacchetti P, Gee L, Jones DB, Kaufman HE, Sugar J,
Hyndiuk RA, Laibson PR, Stulting RD, Asbell PA: Risk factors for herpes
simplex virus epithelial keratitis recurring during treatment of stromal
keratitis or iridocyclitis. Br J Ophthalmol 80: 969-972, 1996.
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Barron BA, Gee
L, Hauck WW, Herpetic Eye Disease Study: A controlled trial of oral acyclovir
for herpes simplex stromal keratitis. Ophthalmology 101: 1871-1882, 1994.
-
Wilhelmus KR,
Gee L, Hauck WW, Herpetic Eye Disease Study: A controlled trial of topical
corticosteroids for herpes simplex stromal keratitis. Ophthalmology 101:
1883-1896, 1994.
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Dawson CR, Hauck
WW, Jones DB, Kaufman HE, Gee L, Barron BA, Wilhelmus KR: The Herpetic
Eye Disease Study (HEDS). Clinical characteristics of randomized patients
with herpetic stromal keratitis and iridocyclitis prior to initiating treatment
[Abstract]. Invest Ophthalmol Vis 33: 1134, 1992.
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Dawson CR, Jones
DB, Kaufman HE, Barron BA, Hauck WW, Wilhelmus KR: Design and organization
of the Herpetic Eye Disease Study Group (HEDS). Curr Eye Res 10: 105-110,
1991.
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Dawson CR, Jones
DB, Wilhelmus KR, Kaufman HE, Barron BA, Hauck WW: Evaluation of corneal
inflammatory disease: The Herpetic Eye Disease Study (HEDS) [Abstract].
Invest Ophthalmol Vis Sci 32: 1221, 1991.
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Dawson CR: The
Herpetic Eye Disease Study. Arch Ophthalmol 108: 191-192, 1990.
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Dawson CR, Jones
DB, Kaufman HE, Barron BA, Hauck WW, Wilhelmus KR: The Herpetic Eye Disease
Study: Strategies of design and data analysis [Abstract]. Invest Ophthalmol
Vis Sci 31: 553, 1990.
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