Herpetic Eye Disease study.pptx

About herpetic study

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 in­ flammation 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 cor­ ticosteroid 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 mm 2 of active corneal stromal inflammation with diffuse or disciform inflammatory stromal edema (non necrotiz­ ing stromal keratitis) or dense, opaque, inflammatory in­ filtration (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

12. 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

13. 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

14. 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

15. 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

16. 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

17. I ncrease in total area of stromal keratitis of 10 mm 2 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 mea­ surement or 3+ cells or more in the anterior chamber for 2 weeks

18. Significant vision decrease was defined as dete­ rioration of visual acuity by four lines or more from base­ line 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 medi­ cation .

19. An overall assessment was made at each follow-up visit and categorized as no active inflammation (resolved ); ac­ tive inflammation persistent without resolution , improved since study entry and improved since the last visit ; active inflammation persistent without resolution , i mproved 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 inflam­ mation after initial resolution.

20. 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 re­ current herpetic eye disease were compared between the two groups by the Kaplan-Meier method using the Man­ tel-Haenszel form of the log-rank test

21. 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 .

22. Determination of the difference in time to treatment fail­ ure 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 ha d failed treatment

23. 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 cortico steroids

24. 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

25. Comparison between visual acuity measured at random­ ization 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.

26. DISCUSSION The use of anti-inflammatory therapy with a topical cor ticosteroid 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

27. We found that patients with herpes simplex stromal keratitis who received a tapered regimen of topical cor­ ticosteroids were more likely to successfully complete the treatment course and had more rapid resolution of stromal keratitis than those who received a similar reg­ imen 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

28. 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

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

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