This document summarizes a randomized controlled trial that evaluated the efficacy of topical corticosteroids for treating herpes simplex stromal keratitis. The trial involved 106 patients who were randomly assigned to receive either topical prednisolone phosphate plus trifluridine or placebo plus trifluridine. Patients receiving corticosteroids were less likely to have treatment failure and had faster resolution of stromal keratitis. The use of corticosteroids with antiviral cover was found to be effective for acute treatment of herpes simplex stromal keratitis.

1. Herpetic Eye Disease study- A
controlled trial of topical corticosteroids for herpes
simplex stromal keratitis
DR.KRISHNAPRIYA K

2. INTRODUCTION
• Herpes simplex keratitis is a leading cause of corneal opacification in the
United States, other industrialized countries, and developing nations
throughout the world.
• Despite the availability of antiviral agents that are effective in treating herpes
simplex epithelial keratitis, stromal inflammation that can lead to corneal
scarring and visual impairment develops in many patients
• The Herpetic Eye Disease Study (HERS) comprises a series of placebo-
controlled clinical trials designed to evaluate the acute treatment of herpes
simplex stromal keratitis or uveitis.
• The HEDS trial described here compared the effects of tritluridine plus either
topical corticosteroid or placebo in patients with herpes simplex stromal
keratitis who were not receiving a corticosteroid at randomization.

3. OBJECTIVE
• To evaluate the efficacy of topical corticosteroids in treating herpes
simplex stromal keratitis.

4. STUDY DESIGN
• Randomised ,double masked ,placebo controlled ,multicentre clinical trial

5. INCLUSION CRITERIA
• Patients ≥12 years
• Active stromal keratitis consistent with herpes simplex eye disease
• No use of topical or systemic cort2icosteriods within the 10 days before trial entry
• No active HSV epithelial keratitis of the involved eye
• No epithelial defect longer than 1.0mm of the involved eye
• No prior keratoplasty of the involved eye
• Not pregnant were eligible
• No previous participation in a Herpetic Eye Disease Study protocol

6. STUDY POPULATION
• Ophthalmologists in the vicinity of each clinical centre were asked to refer
patients to the study investigators
• Potential participants had to satisfy all eligibility criteria
• A negative urine pregnancy test for all women of child bearing potential

7. • 106 eligible patients in this trial between July 6, 1989, and February 26, 1992,
when enrollment was discontinued on the advice of the Data and Safety
Monitoring Committee.
• Of the eligible, enrolled patients, 49 were randomly assigned to the placebo group
and 57 to the steroid group.

8. • Stromal keratitis was defined as an area at least 2.5 mm2 of active corneal
stromal inflammation with diffuse or disciform inflammatory stromal edema
(non necrotizing stromal keratitis) or dense, opaque, inflammatory infiltration
(necrotizing stromal keratitis).

9. METHOD
• Patients were assigned to receive either topical prednisolone phosphate or
placebo in a double masked fashion using a random permuted block design
• Eyedropper bottles were packaged by the manufacturer & labelled with a
reference number & instructions for use
• The corticosteroid ophthalmic solution was formulated as 1%pedisolone sodium
phosphate & as 0.125%prednisolne sodium phosphate in buffered isotonic
aqueous solutions

10. • The same manufacturer provided placebo solutions containing a similar
formulations of vehicles & preservatives without active drug in identical
containers
• Trifluridine 1% ophthalmic solution was prepared in aqueous solution with acetic
acid ,sodium acetate ,sodium chloride & 0.001% thiomersol

11. • The protocol involved 10 weeks of treatment with the weekly examination ,
discontinuing the treatment regimen at the end of 10 weeks followed by 6 weeks
of biweekly visits & a final visit at 6 months
• Patients assigned to prednisolone phosphate & placebo followed the same dosing
schedule

13. • Patients with a non severe adverse reaction attributable to trifluridine at the 7
week visit or later remained in the study if another antiviral agent was not used
during the remaining study interval
• Patients received a cycloplegic agent such as 0.25% scopolamine solution at the
the discretion of ophthalmologist examiner
• Each patient was given a medication diary with week specific cards as a reminder
of the treatment regimen
• Compliance monitored by weighing the eyedropper bottles at each visit

14. CLINCAL EVALUATION
• A complete eye examination was performed at randomization , & re examination
were performed at scheduled visits
• After refinement of the subjective refraction , standardized best corrected visual
acuity ( measured in a trial frame or phoropter at a 4m test distance using
modified Bailey –lovie charts that were retroilluminated at 1025+/-50 lux in
general room illumination)was recorded at randomization , halfway through the
treatment regimen (at the 5 week visit), at the 16 week visit & or on the day of
withdrawl from the trial & at the final 6 month visit

15. • Slit lamp biomicroscope was performed at each study visit
• The area of stromal keratitis was calculated by multiplying the mean three
readings of the greatest diameter by means of 3 readings of greatest
perpendicular width
• For multiple lesions , each lesion was measured separatetly, & the total area used
was the sum of the individual areas
• At each study visit , the area was compared with the area measured at the initial
examination & with the area measured at the previous visit
• The affected area also measured in terms of depth, density, thickness, stromal
thinning, & endothelial dysfunction

16. • Anterior chamber cells were counted using a 1.0 * 0.5 mm sli beam at 45 degree
axis
• Intraocular pressure was determined at each visit by applanation or
pneumotonometry
• Photomicrography was performed on the day of randomization , at the 5 week
visit, & at either 16 week visit or the day of withdrawl from the study

17. • Treatment failure was defined as worsening of stromal keratitis or uveitis at any
scheduled visit , no change in stromal inflammation in the first 2 weeks or 3 later
consecutive weeks or occurrence of an adverse event
• Increased severity of stromal keratitis was defied as any one of the following
Development of a new zone of non necrotizing or necrotizing stromal keratitis
of 15mm2 or greater
Increase in total area of stromal keratitis of 7.5 mm2 or by 75% of the previous
area depending on the size of previous lesion

18. • Increase in total area of stromal keratitis of 10 mm2 or by 100% of the initial area,
depending on the size of the initial lesion.
• No change was defined as less than a 10% change in the area of stromal
keratitis.
• Increased severity of iridocyclitis was defined as a two-step or greater increase of
cells in the anterior chamber compared with the best attained measurement or
3+ cells or more in the anterior chamber for 2 weeks

19. • Significant vision decrease was defined as deterioration of visual acuity by four
lines or more from baseline as measured on the Bailey-Louie chart.
• Treatment success was defined as completion of the 10-week regimen of study
medications, resolution of active inflammation during the 16-week
treatment/observation interval, and no reactivation or recurrence for 6 weeks
without medication.

20. • An overall assessment was made at each follow-up visit and categorized as no
active inflammation (resolved); active inflammation persistent without
resolution, improved since study entry and improved since the last visit; active
inflammation persistent without resolution, improved since study entry yet not
improved since the last visit; active inflammation persistent without change since
study entry; active inflammation persistent without resolution and worse since
study entry; or recurrent active inflammation after initial resolution.

21. STATISTICAL ANALYSIS
• Baseline characteristics of the two treatment groups were compared by the chi-
square test or the Wilcoxon rank-sum test for categorical variables and by
Student's t test for continuous variables.
• Days from randomization to treatment failure, resolution of stromal keratitis, and
recurrent herpetic eye disease were compared between the two groups by the
Kaplan-Meier method using the Mantel-Haenszel form of the log-rank test

22. RESULTS
• Nine clinical centers screened 430 patients with clinically presumed herpes simplex
stromal keratitis or uveitis, of whom 305 met the eligibility criteria for one of three
trials then open for randomization, and enrolled 106 eligible patients in this trial
between July 6, 1989, and February 26, 1992, when enrollment was discontinued
on the advice of the Data and Safety Monitoring Committee.
• Of the eligible, enrolled patients, 49 were randomly assigned to the placebo group
and 57 to the steroid group.

23. • Determination of the difference in time to treatment failure between the steroid
and placebo groups showed a highly significant benefit in favor of the steroid
group (P < 0.001)
• Fifteen patients (26%) in the steroid group and 36 patients (73%) in the placebo
group were treatment failures before completing the 10-week course of trial
medications
• By 16 weeks, 28 patients (49%) in the steroid group and 37 patients (76%) in the
placebo group had failed treatment

25. • Compared with placebo, corticosteroid therapy reduced the risk of persistent or
progressive stromal keratouveitis by 68%.
• The time from randomization to resolution of stromal keratitis and uveitis
was significantly shorter in the steroid group compared with the placebo
group even though both groups included patients who were removed from
the study and treated with topical corticosteroids

27. • Nineteen (33%) of the steroid-treated patients and 11 (22%) of the placebo-
treated patients completed the 10 weeks of protocol therapy and had stable,
noninflamed corneas after 16 weeks

28. • Comparison between visual acuity measured at randomization and 6 months
later showed a similar degree of visual improvement between the two
treatment groups.
• Fifty-nine percent of eyes in the placebo group and 61% of eyes in the steroid
group had an improvement in visual acuity of two lines or more on the Bailey-
Lovie chart from the day of randomization to the final 6-month examination
• 72% of the portion of the placebo group who showed improvement had failed
trial medication and subsequently received topical corticosteroids.

30. DISCUSSION
• The use of anti-inflammatory therapy with a topical corticosteroid for herpes
simplex stromal keratitis has been an unresolved issue
• Corticosteroids are contraindicated during herpes simplex viral infection of the
ocular surface but are used to suppress herpes simplex stromal keratitis

31. • We found that patients with herpes simplex stromal keratitis who received a
tapered regimen of topical corticosteroids were more likely to successfully
complete the treatment course and had more rapid resolution of stromal keratitis
than those who received a similar regimen of placebo.
• Patients randomized to placebo were more likely to fail the trial, to fail earlier,
and, despite subsequent corticosteroid therapy, to take significantly longer to
achieve resolution

32. CONCLUSION
• This clinical trial provides a basis for the judicious use of corticosteroids with
protective antiviral cover in the acute treatment with herpes simplex stromal
keratitis who have not recently received corticosteroid therapy
• We found that patients administered a progressively decreasing regimen of
prednisolone phosphate with trifluridine took longer to worsen & improved
faster than a comparable placebo group
• The use & indications of topical corticosteroids for many infectious &
inflammatory corneal diseases remain to be more clearly determined
• This study demonstrates the efficacy of topical corticosteroids with topical
antiviral prophylaxis in the acute treatment of herpes simplex stromal keratitis

33. LIMITATION
• A potential limitation of this trial was the use of a clinical, rather than virologic,
case definition.
• Serologic testing can show prior exposure, but noninvasive laboratory asessment
that proves the etiology of herpes simplex stromal keratitis is not available

34. THANK YOU………..