Herpetic Eye Disease Study

Herpetic Eye Disease Study A Controlled Trial of Topical Corticosteroids for Herpes Simplex Stromal Keratitis Kirk R. Wilhelmus, MD, Lauren Gee, MPH, Walter W. Hauck, PhD, Natalie Kurinij, PhD, Chandler R. Dawson, MD, Dan B. Jones, MD, Bruce A. Barron, MD, Herbert E. Kaufman, MD, Joel Sugar, MD, Robert A. Hyndiuk, MD, Peter R. Laibson, MD, R. Doyle Stulting, MD, PhD, Penny A. Asbell, MD, For the Herpetic Eye Disease Study Group* Purpose: To evaluate the efficacy of topical corticosteroids in treating herpes simplex stromal keratitis. Methods: The authors performed a randomized, double-masked, placebo-controlled, multicenter clinical trial of 106 patients with active herpes simplex stromal keratitis who had not received any corticosteroids for at least 10 days before study enrollment. Patients were assigned to the placebo group (n = 49) or the steroid group (topical prednisolone phosphate; n = 57); both regimens were tapered over 10 weeks. Both groups received topical trifluridine. Visual acuity assessment and slit-lamp biomicroscopy were performed weekly for 10 weeks, every other week for an additional 6 weeks or until removal from the trial, and at 6 months after randomization. Results: The time to treatment failure (defined by specific criteria as persistent or progressive stromal keratouveitis or an adverse event) was significantly longer in the steroid group compared with the placebo group. 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 according to best medical judgment. 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, non inflamed corneas after 16 weeks. At 6 months after randomization, no clinically or statistically significant differences in visual outcome or recurrent herpetic eye disease were identified between the steroid and placebo groups. Conclusions: The topical corticosteroid regimen used in this study was significantly better than placebo in reducing persistence or progression of stromal inflammation and in shortening the duration of herpes simplex stromal keratitis. Postponing steroids during careful observation for a few weeks delayed resolution of stromal keratitis but had no detrimental effect as assessed by visual outcome at 6 months. Ophthalmology 1994; 101: 1883-1896

Originally received: June 21, 1993. Revision accepted: June 17, 1994. * Members of the Herpetic Eye Disease Study are listed in the Appendix at the end of the preceding article. Presented in part at the American Academy of Ophthalmology Annual Meeting, Dallas, November 1992. Supported in part by cooperative agreements (EY07479, EY07480, EY07482, EY07483, EY07486, EY07487, EY07488, EY07489, and

EY07496) with the National Eye Institute, National Institutes of Health, and the United States Department of Health and Human Services, Bethesda, Maryland. IOLAB Corporation and Burroughs Wellcome Co. supplied the study medications. The authors have no proprietary interest in any of the drugs or devices used in this study. Reprint requests to Chandler R. Dawson, MD, Francis L Proctor Foundation, University of Califomia, San Francisco, San Francisco, CA 94143-0412.

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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. I Early clinical experiences2- 4 with topical corticosteroids showed a variable and sometimes unfavorable effect on herpes simplex stromal keratitis. Subsequent uncontrolled studies5- 8 reported more encouraging results with combined corticosteroid and antiviral therapy. While corticosteroids are implicated in increasing the severity of herpetic stromal keratitis, prolonging its course, and predisposing to secondary complications,9 topical corticosteroids with a protective antiviral agent frequently are used to reverse the inflammatory response and to improve corneal clarity. Consensus on the role of topical corticosteroids in the management of herpetic stromal keratitis is lacking. ID The Herpetic Eye Disease Study (HEDS) comprises a series of placebo-controlled clinical trials designed to evaluate the acute treatment of herpes simplex stromal keratitis or uveitis. II ,12 The HEDS trial described here compared the effects oftrifluridine plus either topical corticosteroid or placebo in patients with herpes simplex stromal keratitis who were not receiving a corticosteroid at randomization.

Patients and Methods Details of the study design, including treatment allocation, testing procedures, and quality-control measures, are provided in the Manual ojOperations. 13 All information was recorded on standardized data collection forms and transferred to a computerized database for cross-checking and compilation. The study design was approved by the institutional review board at each participating institution, and informed consent was obtained before study enrollment.

Study Population Ophthalmologists in the vicinity of each clinical center were asked to refer patients to the study investigators. Potential participants had to satisfy all eligibility criteria before study enrollment (Table 1). A negative baseline urinary pregnancy test was required for all women of childbearing potential. Sexually active patients who were capable of conceiving children were advised to use an effective method of birth control while receiving treatment and for 3 months thereafter. 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 (nonnecrotizing stromal keratitis) or dense, opaque, inflammatory infiltration (necrotizing stromal keratitis). Punctate cellular changes in the adjacent corneal stroma and residual opacification from previous disease were disregarded when determining the area of involvement.

Treatment Patients were assigned to receive either topical prednisolone phosphate or placebo in a double-masked fashion using a random permuted-blocks design with a separate sequence for each clinical center. Eyedropper bottles were packaged by the manufacturer and labeled with a reference number and instructions for use. Identical vials of number-coded medication distributed to each clinical center sequentially were assigned as patients were randomized. The corticosteroid ophthalmic solution was formulated as 1% prednisolone sodium phosphate and as 0.125% prednisolone sodium phosphate in buffered isotonic aqueous solutions containing biphosphate, sodium phosphate anhydrous, sodium chloride, edetate disodium, and 0.01% benzalkonium chloride. The same manufacturer provided placebo solutions containing a similar formulation of vehicles and preservatives without active drug in identical containers. Trifluridine 1% ophthalmic solution was prepared in an aqueous solution with acetic acid, sodium acetate, sodium chloride, and 0.001% thimerosal.

Table 1. Eligibility Criteria • • • • • • • • • •

12 yrs of age or older Active stromal keratitis consistent with herpes simplex eye disease No use of a topical or systemic corticosteroid within 10 days before trial entry" No active herpes simplex epithelial keratitis of the involved eye No epithelial defect longer than 1.0 mm of the involved eye No prior keratoplasty of the involved eye No prior allergy or adverse reaction to prednisolone phosphate or trifluridine Not pregnant No previous participation in a Herpetic Eye Disease Study protocol Judged likely to adhere to protocol therapy and to return for re-examinations

" Patients who used topical corticosteroids were eligible for another Herpetic Eye Disease Study trial.

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Wilhelmus et al . Herpetic Eye Disease Study: Corticosteroids The protocol involved 10 weeks of treatment with weekly examinations (1 additional examination was scheduled during the first week, at 3 days), discontinuing the treatment regimen at the end of the 10 weeks, followed by 6 weeks of biweekly visits and a final visit at 6 months. Patients assigned to prednisolone phosphate (steroid group) and those assigned to placebo (placebo group) followed the same dosing schedule (Table 2). Patients with a nonsevere 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 hydrobromide solution at the discretion of the ophthalmologist examiner. Each patient was given a medication diary with week-specific cards as a reminder of the treatment regimen. Compliance was monitored by weighing the eyedropper bottles at each study visit. Patients withdrawn from the study were treated with non-standard regimens of antiviral and/or steroid at the discretion of the ophthalmologist examiner and were reevaluated at 16 weeks and at 6 months after randomization.

Clinical Evaluation A complete eye examination was performed at randomization, and re-examinations were performed at scheduled visits (Table 2). After refinement of the subjective refraction, standardized best-corrected visual acuity (measured in a trial frame or phoropter at a 4-m test distance using modified Bailey-Lovie charts that were retroilluminated at 1025 ± 50 lux in general room illumination of 500 ± 250 lux) was recorded at randomization, halfway through

the treatment regimen (at the 5-week visit), at the 16week visit and/or on the day of withdrawal from the trial, and at the final 6-month visit. At all other study visits, visual acuity using the most recent subjective refraction was obtained using any visual acuity chart. Slit-lamp biomicroscopy was performed at each study visit using a Haag-Streit 900 slit-lamp biomicroscope with variable slit reticule (Haag-Streit, Waldwick, NJ). The area of stromal keratitis was calculated by multiplying the mean of three readings of the greatest diameter by the mean of three readings of the greatest perpendicular width. For multiple lesions, each lesion was measured separately, and 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 and with the area measured at the previous visit. The affected areas also were assessed in terms of depth, density, thickness, stromal thinning, and associated endothelial cell dysfunction. Anterior chamber cells were counted using a 1.0 X 0.5-mm slit beam at a 45° axis. Other clinical findings that were recorded were flare, synechiae, iris atrophy, cataract, and fundus abnormalities. Intraocular pressure was determined at each visit by applanation tonometry or pneumotonometry. Photomicrography was performed on the day of randomization, at the 5-week visit, and at either the 16-week visit or the day of withdrawal from the study. 14 Patients withdrawn from the study (for treatment failure or other reasons) before 16 weeks were not scheduled for re-evaluation until the l6-week visit. The 6-month visit was required for all randomized patients. Upon closure of the study to further enrollment, follow-up continued as specified by the protocol for all randomized patients.

Table 2. Study Medications and Follow-up Schedule for Patients Remaining in Trial Follow-up Visits Week

Treatment Days

Study Drug*

1 % Trifluridine

Target Day

Time Window

1 1 2 3 4 5 6 7 8 9 10 11-12 13-14 15-16 26

0-6 0-6 7-13 14-20 21-27 28-34 35-41 42-48 49-55 56-62 63-69 70-83 84-97 98-111 182

1% 8X/day 1% 8X/day 1% 6X/day 1% 4X/day 1% 2X/day 1% IX/day 0.125% 4X/day 0.125% 2X/day 0.125% IX/day 0.125% IX/day 0.125% IX/day None None None None

4X/day 4X/day 4X/day 4X/day 2X/day 2 X/day 2X/day 2 X/day 2 X/day 2X/day 2 X/day None None None None

3 7 14 21 28 35 42 49 56 63 70 84 98 112 182

2-4 5-10

11-17 18-24 25-31 32-38 39-45 46-52 53-59 60-66 67-73 77-91 92-105 106-119 152-212

• Topical prednisolone phosphate solution or placebo (vehicle and preservatives); percentage applies to the corticosteroid concentration.

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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 defined as any one of the following conditions: development of a new zone of nonnecrotizing or necrotizing stromal keratitis of 15 mm 2 or greater; increase in total area of stromal keratitis of7.5 mm 2 or by 75% of the previous area depending on the size of the previous lesion; or increase 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 measurement or 3+ cells or more in the anterior chamber for 2 weeks. Significant vision decrease was defined as deterioration of visual acuity by four lines or more from baseline as measured on the Bailey-Lovie chart. Treatment success was defined as completion of the lO-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. 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.

Study Design The study was designed as a two-group, double-masked, randomized study to evaluate the null hypothesis: for patients with herpes simplex stromal keratitis who are not currently being treated with a corticosteroid, a topical corticosteroid is no different from a topical placebo in the time to treatment failure. The sample size was chosen so that a 5%, two-tailed test would have a 90% chance of detecting a doubling of the median time to treatment failure. The planned total sample size was projected to be 178 patients, based on an expected median time to failure of 6 weeks in the corticosteroid-treated arm, a 20% allowance for loss to followup, and hence a need for 88 events (treatment failures).

Statistical Analysis Baseline characteristics of the two treatment groups were compared by the chi-square test or the Wilcoxon ranksum 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

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two groups by the Kaplan-Meier method using the Mantel-Haenszel form of the log-rank test. Proportions ofpatients remaining event-free (i.e., proportion who had not failed treatment) were estimated from the Kaplan-Meier curves, and confidence intervals were calculated by the method of Rothman. 15 Confidence intervals for the medians were obtained by the method of Simon and Lee l6 ; those for the differences of medians used the standard errors of the medians. Cox regression was used to analyze the time to treatment failure, resolution of stromal keratitis, and recurrent herpetic eye disease incorporating the stratification by center, and testing was based on the score statistic. Delta betas were calculated to assess whether results could be due to a small set of influential observations, and no such observations were found. In the analyses of risk reduction, patients failing for reasons not part of the specified event definition were censored at the time they were removed from the trial. Proportions of patients in each visual acuity category were compared by the exact Wilcoxon test. Reductions in risk and confidence intervals were determined by proportional-hazards analyses. All reported P values are based on two-tailed tests. Interim analyses at planned intervals were reviewed by an independent Data and Safety Monitoring Committee that began to monitor for early termination after 1 year of accrual when 39 patients had been enrolled. The method 0'1 of Lan and DeMets 17 was used to monitor for early trial termination, and the boundary was constrained to be not more than 5.0 in absolute value. The B-value of Lan and Wittes 18 was plotted as a function of current trend as supplementary information.

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. Two additional patients (1 assigned to placebo and 1 to corticosteroid), who were randomized but later judged ineligible based on prerandomization data, were excluded from all analyses as approved by the Data and Safety Monitoring Committee. The imbalance in the numbers of patients assigned to the steroid and placebo groups resulted from the termination of randomization of new patients before all of the clinical centers had completed enrollment of the predetermined numbers of patients. The two groups of study patients were similar with respect to demographic characteristics (Table 3), clinical history (Table 4), and ophthalmic findings (Table 5) at randomization. The statistical criterion for early trial termination based on the primary objective (determination of the time to treatment failure) was first satisfied at the second interim

Wilhelmus et al . Herpetic Eye Disease Study: Corticosteroids Table 3. Demographic Characteristics of Eligible Patients at Randomization* Characteristic Age (yrs) Mean ± standard deviation Range Sex M F Race White Black Hispanic Asian

Steroid Group (n = 57)

Placebo Group (n = 49)

47 ± 17 16-81

49 ± 18 13-79

32 (56%) 25 (44%)

29 (59%) 20 (41%)

43 (75%) 10 (18%) 3 (5%) 1 (2%)

32 (65%) 10 (20%) 5 (10%) 2(4%)

• There were no significant differences for any of the comparisons shown.

analysis (unstratified), 15 months after randomization had begun, at which time 29 treatment failures had occurred. The stratified statistic satisfied the criterion at the fourth interim analysis, 25 months after randomization had begun, at which time 49 events had occurred. The Data and Safety Monitoring Committee postponed terminating the trial and requested additional follow-up beyond the 6month interval from randomization on some patients to better understand the sequelae of treatment. Further enrollment was halted at the sixth interim analysis, 31 months after randomization had begun, at which time 60 of the 88 events estimated to be required had occurred. Reasons for early trial termination included a statistically significant difference in the primary outcome between the treatment groups, no convincing evidence of an altered incidence of recurrences in either arm, and little chance that additional data would substantially enhance the conclusions of the study.

Compliance The missed-visit rate before trial removal or the end of 16-week treatment/observation period was 4.5% for the placebo group and 3.5% for the steroid group. There was no difference in compliance with the study treatment regimen between the two groups.

Time to Treatment Failure 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). This effect was not diminished (i.e., P remained < 0.001) by stratifying the analysis by clinical center, nor by converting patients censored for the primary analysis (see Table 6) into treatment failures at the time of censoring. 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

(Fig 1). By 16 weeks, 28 patients (49%) in the steroid group and 37 patients (76%) in the placebo group had failed treatment (Table 6). The median time to treatment failure was 98 days for the steroid group (95% confidence interval, 81 to > 120 days; follow-up did not continue long enough to determine the outer endpoint) and 17 days for the placebo group (95% confidence interval, 14-27 days); the difference in median time to treatment failure between the treatment groups was 81 days (95% confidence interval, 72-90 days). Reviewing the data from the trial led to refinement of the endpoint into two sets of treatment failure conditions (Table 7): (1) causes of treatment failure related to conditions of worsening or lack of improvement of stromal keratouveitis, and (2) adverse events such as epithelial keratitis, toxicity, or hypersensitivity. For the patients removed from the trial because of worsening or lack ofimprovement, the hazard ratio of the steroid group compared with the placebo group was 0.32 (95% confidence interval, 0.18-0.59; P < 0.001). The risk of an adverse event was similar between the two treatment groups (hazard ratio, 0.43; 95% confidence interval, 0.12-1.55; P = 0.2).

Resolution of Stromal Keratitis Evaluation of resolution and other events that occurred after the study medications were stopped was complicated by the post-study treatment that patients subsequently received. Seventy-six percent of the placebo group received topical corticosteroids before resolution. When all patients were considered, including those whose keratitis resolved with trial medications and those who were removed from the trial and treated at the discretion of the ophthalmologist examiner, the time from randomization to resolution of active herpes simplex keratitis was significantly shorter overall for the steroid group than the placebo group (Fig 2) (corticosteroid group: median, 26 days, 95% confidence interval, 14-49 days; placebo group: median, 72 days, 95% confidence interval, 44-123 days; 95% confidence interval of the difference in the medians, 14-58 days; P < 0.001). By 16 weeks after randomization, the total duration of topical corticosteroid use was similar in both groups. When comparing only the patients who were treatment successes (i.e., who completed the trial and whose keratitis resolved with trial medication; 30 patients total, 19 in the steroid group and 11 in the placebo group; Fig 2 and Table 8), the time to resolution was not significantly different overall (P = 0.19). The median time-to-resolution in this subgroup was 20 days in the steroid group and 37 days in the placebo group (95% confidence interval of the difference between the two medians, 13-21 days; this comparison focuses on a single point over the length of the time to resolution observation interval, in contrast to the overall comparison that yielded P = 0.19). Figure 3 illustrates the rate of decrease of the area of stromal keratitis for these two success subgroups. Adverse Events Five patients were removed from the trial because of dendritic epithelial keratitis that occurred during the use of

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Table 4. Clinical History at Randomization* Clinical History

Steroid Group (n = 57)

Placebo Group (n = 49)

5(9%) 10 (18%) 8 (14%)

6 (12%) 5 (10%) 3 (6%)

41 ± 18 4-79

41 ± 17 8-76

11 (19%) 1 (2%) 3 (5%) 9 (16%) 2(4%)

14 (29%)

2.7 0-44.0

1.2 0-61.3

13

20 0-735

36 (63%) 1 (2%) 7 (12%) 33 (58%) 4(7%) 13 (23%) 13 (23%) 1 (2%)

33 (67%) 2(4%) 6 (12%) 31 (63%) 1 (2%) 16 (33%) 16 (33%) 2 (4%)

20 (35%) 2 (4%)

19 (39%) 2(4%

Previous conditions Prior ocular surgery Prior ocular trauma Nasolabial herpes simplex disease within the last 2 yrs History of HSV eye disease Age at initial diagnosis of HSV eye disease (yrs) Mean ± standard deviation Range Patients with HSV eye disease within 2 yrs before randomization, exclusive of the episode under study Any HSV eye disease Blepharoconjunctivitis Epithelial keratitis Stromal keratitis Iridocyclitis Time (yrs) from initial diagnosis of HSV eye disease before randomization for this episode Median Range Duration (days) of current symptoms Median Range Medication history Within 2 yrs before randomization Any antiviral Topical idoxuridine Topical vidarabine Topical trifluridine Oral acyclovir Any corticosteroid Topical corticosteroid Oral corticosteroid Within 14 days before randomization Any antiviral Corticosteroid (> 10 days only) HSV

0-224

2(4%) 5 (10%) 8 (16%) 1 (2%)

= herpes simplex virus .

• No significant differences were detected for any of the comparisons shown.

study medications (at day 55 for I patient in the placebo group, and at days 24, 26, 35, and 63 for 4 patients in the steroid group). In the course of the to-week treatment interval, two patients in the placebo group were withdrawn (and counted as treatment failures) because of allergic conjunctivitis attributed to trifluridine that developed at I and 9 days, respectively. In addition, follicular conjunctivitis developed in three patients in the corticosteroid group at 35, 49, and 59 days, respectively, attributed to the trifluridine solution; and punctate corneal epithelial erosions developed in one patient in the corticosteroid group at 42 days. These four patients were continued in the trial and not counted as treatment failures, but the trifluridine was discontinued at 56, 49, 59, and 49 days, respectively. An epithelial defect developed in four patients (at days II, 14, and 76 for 3 patients in the placebo

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group and at day 7 for I patient in the steroid group), and these patients were removed from the study. We found no cases of cataract or glaucoma attributed to the study medications.

Visual Outcome Comparison between visual acuity measured at randomization and 6 months later (Fig 4) showed a similar degree of visual improvement between the two treatment groups (Table 9). 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. Sixty-seven

Wilhelmus et al . Herpetic Eye Disease Study: Corticosteroids Table 5. Ophthalmologic Findings at Randomization* Findings Study eye Right Left Characteristics of stromal keratitis Type of stromal keratitis Nonnectrotizing only Necrotizing only Mixed Total area (mm2 ) Median Range Location in corneat Anterior one third Middle one third Posterior one third Density Iris details visible Iris details partially obscured Iris details obscured Corneal swelling or edema None Localized Generalized Corneal thinning None 1%-50% decrease from normal Endothelial dysfunction and stromal edema surrounding the keratitis None Pseudoguttata Edema within 2 mm of lesion edge Edema ~2 mm from lesion edge Iridocyclitis Anterior chamber cells (cells/field) 0-4 5-10 11-20 21-50 Unable to assesst Anterior chamber flare None Faint Iris easily seen Iris details hazy Unable to assesst Posterior synechiae Iris atrophy Cataract Intraocular pressure >21 mmHg Best-corrected visual acuity Median 20/40 or better 20/50 to 20/190 20/200 or worse

Steroid Group (n = 57)

Placebo Group (n = 49)

31 (54%) 26 (46%)

26 (53%) 23 (47%)

51 (89%) 3(5%) 3 (5%)

45 (92%) 3(6%) 1 (2%)

23.4 3.5-169.8

24.5 6.8-120.5

48 (84%) 46 (81%) 47 (82%)

44 (90%) 39 (80%) 39 (80%)

19 (33%) 26 (46%) 12 (21%)

9(18%) 25 (51%) 15 (31%)

4(7%) 31 (54%) 22 (39%)

5 (10%) 28 (57%) 16 (33%)

54 (95%) 3(5%)

46 (94%) 3(6%)

28 (49%) 10 (18%) 14 (25%) 5(9%)

25 (51%) 6(12%) 15 (31%) 3(6%)

38 (67%) 11 (19%) 5(9%) 1 (2%) 2(4%)

30 (61%) 12 (24%) 6(12%) 0 1 (2%)

22 (39%) 18 (32%) 10 (18%) 5(9%) 2(4%) 2(4%) 2(4%) 19 (33%)

19 (39%) 17 (35%) 10 (20%) 2(4%) 1 (2%) 3(6%) 2(4%) 14 (29%)

9 (16%)

8(16%)

20/63 22 (39%) 23 (40%) 12 (21%)

20/50 23 (47%) 14 (29%) 12 (24%)

• No significant differences were detected for any of the comparisons shown.

t t

More than one third may be involved. Due to inadequate visualization of the anterior chamber.

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percent of each group had a best-corrected visual acuity of 20/40 or better at 6 months after randomization.

-:---:---!~-, ,-------,

Recurrent Herpes Simplex Eye Disease We sought two categories of recurrent herpes simplex eye disease: (1) dendritic epithelial keratitis during study treatment, and (2) any form of herpes simplex eye disease after discontinuation of treatment. For the former, dendritic epithelial keratitis developed in five patients (1 in the placebo group and 4 in the steroid group) during the use of the study medications. For the latter, analysis of recurrent herpes simplex eye disease was complicated by the necessity for patients to first attain resolution of stromal inflammation before being able to experience a recurrence of stromal keratitis. This resulted in differing lengths of follow-up between the two treatment groups; patients in the corticosteroid group were followed longer for recurrence because they achieved resolution of their disease faster than patients in the placebo group. Interpretation is also more difficult because patients failing their randomly assigned study treatment were subsequently treated according to best medical judgment. In 22 (24%) of the 92 patients who achieved resolution of stromal keratitis present at randomization, recurrent herpes simplex eye disease developed more than 2 weeks after stopping topical corticosteroids, and all episodes were stromal keratitis. There was no significant difference between the two treatment groups (Fig 5, P = 0.9), although none of the 11 patients in the placebo group who were successes at 16 weeks had a recurrence during the remainder of the 6-month follow-up period.

Discussion The use of anti-inflammatory therapy with a topical corticosteroid for herpes simplex stromal keratitis has been

---\ _ ~~1!__________,

'... _--------,

-:--:-~-,

'--------!__ :

Steroid

_._,

'._._--

(15)

Days after Randomization Figure L Kaplan-Meier estimates of the proportion of patients randomized to placebo (solid line, n = 49) or corticosteroid (dashed line, n = 57) who have not yet satisfied the treatment failure criteria. Log-rank analysis showed a statistically significant difference (P < 0.(01). Patients who were removed from the study for other reasons and did not meet the treatment failure criteria or who were lost to follow-up were censored. Numbers in parentheses are patients still under observation in each group at days 14,35, 70, and at the time of the last treatment failure, respectively.

an unresolved issue. 19 ,2o Corticosteroids are contraindicated during herpes simplex viral infection of the ocular surface but are used to suppress herpes simplex stromal keratitis. 21 Several options of corticosteroid administration are available. 22 A previous placebo-controlled clinical trial

Table 6. Patient Response to Study Medications at 16 Weeks Treatment Response Treatment failure Treatment success' Completed study medications and stromal keratitis continued, but without satisfying failure criteria Lost to follow-up or medication misuset Removed from study because of probably misdiagnosis Days from randomization to treatment failure Median (95% confidence interval) 25th percentile 75th percentile

Steroid Group (n = 57)

Placebo Group (n = 49)

28 (49%) 19 (33%)

37 (76%) 11 (22%)

1 (2%) 8(14%) 1 (2%)

0 1 (2%) 0

98 (81 to> 120) 65 >120

17 (14 to 27) 12 76

• Number of patients completing lO-week study medication regimen with a stable, noninflamed cornea at the 16-week observation and without further treatment.

t

Two patients, one each in the placebo and steroid groups, were lost to follow-up. Five patients in the steroid group were recorded as medication misuse because of irregular use of study medications (4) or use of oral prednisone for emphysema (1). Two patients in the corticosteroid group discontinued study medications because of emergency thoracic surgery (1) or adenoviral conjunctivitis (1).

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Wilhelmus et al . Herpetic Eye Disease Study: Corticosteroids Table 7. Reasons for Treatment Failure at 16 Weeks No. of Patients Steroid Group

Causes of Treatment Failure Worse or no improvement· Increased area of stromal keratitist Lack of improvement of stromal keratitis'!' Increased or persistent iridocyc1itis§ Marked decrease in visual acuityll Investigator judged need for alternative therapy Voluntary withdrawal from study or discontinuation of medications No. of patients

=

P

<0.001

6 1 3 5

14

4

3 31

0.32 (0.18, 0.59)

o 1 5

2 1 3 6

0.43 (0.12, 1.55)

28

37

0.35 (0.20, 0.60)

3 3

4

23

Adverse event during use of study medications Allergic conjunctivitis Herpes simplex epithelial keratitis Epithelial defect> 1 mm in diameter No. of patients

CI

Proportion (95% CI)

12

7

4

Total no. of patients: treatment failure, all causes

Risk Reduction

Placebo Group

0.2 <0.001

confidence interval.

* Reasons for treatment failure add to more than total because several patients had multiple events at time of trial removal.

t

Either development of a new zone of stromal keratitis :2:15 mm2; or increase in total area of stromal keratitis by :2:7.5 mm2 for prior area of 0.0-9.9 mm2, by :2:15 mm2 for prior area of 10.0-19.9 mm2, or by :2:75% for prior area of :2:20.0 mm2; or increase in total area of stromal keratitis by :2:10 mm2 for initial area of 2.5-9.9 mm2, by :2:20 mm2 for initial area of 10.0-19.9 mm2, or by :2:100% for initial area of :2:20 mm2•

t Stromal keratitis persists with < 10% change in area and no stepwise improvement in depth, density, thickness, or endothelial dysfunction of stromal keratitis. § Either :2:two-step increase of anterior chamber cells compared with best condition previously achieved during study or :2:21 cells/field for 2 consecutive weeks.

II Deterioration of best-corrected visual acuity by :2:4 lines on the Bailey-Lovie chart from baseline visual acuity.

evaluated the use of a topical corticosteroid, betamethasone 0.01 % five times daily, in the management of herpes simplex disciform stromal keratitis. 23 ,24 Based on evalu-

ation of corneal thickness and iridocyclitis, patients treated with corticosteroid healed more rapidly than those taking the placebo. While this trial used a fixed corticosteroid

,

"

;,

,,

.,,-!..,

1:,

-4 "

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Figure 2. Kaplan-Meier estimates of the proportion of patients initially randomized to either placebo (solid line, n = 49) or corticosteroid (dashed line, n = 57) who subsequently had resolution of stromal keratitis with study medications or with discretionary medications after trial removal. Log-rank analysis showed a statistically significant difference (P < 0.001). Numbers in parentheses are patients still under observation in each group at days 30, 60, 100, 150, and at the last observation, respectively. Arrowheads = each success.

Days after Randomization

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Table 8. Days from Randomization to Resolution of Stromal Keratitis No. of Patients'

Median (25th, 75th percentiles)

Treatment Outcome

Steroid Group

Placebo Group

Steroid Group

Placebo Group

P

Treatment failures Treatment successes All patients

28 19 57

37 11 49

36 (19, 112) 20 (14,39) 26 (14, 49)

106 (64, 158) 37 (24, 54) 72 (44,123)

0.01 0.19 <0.001

* Numbers of patients sum to less than the total randomized to each group because some patients did not satisfy either the treatment failure or success

criteria (see Table 6).

sessment that proves the etiology of herpes simplex stromal keratitis is not available. While one third of the study population did not have a history of previous herpes simplex eye disease, patient characteristics were similar between the two treatment groups. The corticosteroid regimen used in this trial was prednisolone phosphate that began at a high concentration and frequency and then progressively decreased in a predetermined manner. We based this standardized schedule on previous clinical experiences, suggesting that increasingly gradual reduction is needed as the dosage is diminished. 25 Because our goal was to choose a treatment plan that could not only show efficacy but also would be used in a parallel trial assessing supplemental oral acyclovir, we attempted to devise a regimen wherein a proportion of patients might require additional therapy. Thus, 10 weeks of tapered corticosteroids was apparently too brief for many patients. One half of the corticosteroid group who failed did so during the 6 weeks of observation just after the corticosteroid medication was discontinued. Therapy may need to be tapered more slowly for most patients with herpes simplex stromal keratitis,

dosage schedule and did not identify a significant difference in visual outcome between the two groups, the findings stimulated further investigation into the management of herpes simplex stromal keratitis. 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. We note that 22% of the patients treated with placebo successfully completed the trial and had resolution of stromal keratitis at a rate (>50% reduction in the area of stromal inflammation within the first 2 weeks of treatment) comparable to the patients treated with corticosteroid who achieved treatment success. 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 as100 90 C>

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Figure 3. Comparison of the area of stromal keratitis (mm2) for patients successfully completing the 16-week treatment/observation period (solid line = the placebo group. n = 11; dashed line = the corticosteroid grouP. n = 19). Vertical bars = the standard error of the mean.

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Wilhelmus et al . Herpetic Eye Disease Study: Corticosteroids arations may carry less risk of recurrent epithelial disease,27 antiviral cover continued throughout the entire duration of study medication (topical corticosteroid or placebo). Recurrent epithelial keratitis is possible even with concomitant trifluridine. This trial was not designed to evaluate any therapeutic effect oftrifluridine therapy on stromal inflammation because both treatment groups used an identical antiviral regimen. As 76% of the placebo group were removed from the trial for treatment failure, usually because of progressive stromal keratitis and/or iridocyclitis, the results of this trial concur with prior clinical studies28 ,29 that a topical antiviral agent alone does not control stromal keratitis. Further understanding of the mechanisms of viral infection and immune responses in the pathogenesis of herpes simplex stromal keratitis 30- 32 may offer future therapeutic options.

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Visual Acuity at Randomization Figure 4. Comparison of best~corrected visual acuity for patients tested with a Bailey-Lovie chart at study entry and at 6 months after randomization, regardless of whether patients used only study medications or also used discretionary topical corticosteroids during the follow-up interval. x = placebo or delayed-onset corticosteroid use (n = 42); 0 = corticosteroid group (n = 52); HM = hand motions; NLP = no light perception; dashed lines = one Bailey-Lovie chart line on either side of the line of identity.

Topical Antiviral Prophylaxis Previous clinical trials have shown that an antiviral agent can reduce the occurrence of herpes simplex epithelial keratitis significantly during corticosteroid use,7,26 but the optimal dosage schedule has not been determined. This trial used topical trifluridine four times daily for the first 3 weeks then twice daily throughout the remaining 7 weeks of study therapy. While more dilute corticosteroid prep-

Visual Outcome Herpes simplex stromal keratitis is an important cause of visual loss.33 In this study two-thirds of individuals achieved visual acuity of 20/40 or better, and vision improved by two or more lines from study entry to 6 months later in 61 % of study patients. Immediate corticosteroid treatment was not required for better visual outcome because the visual results in the placebo group, three fourths of whom worsened and had a delay in corticosteroid use, were similar. Based on vision at 6 months after randomization, delaying corticosteroid therapy until stromal keratitis worsened or failed to improve did not disadvantage patients evaluated in this study.

Recurrent Herpes Simplex Eye Disease This study primarily evaluated the effects of topical corticosteroids on stromal keratitis. We also sought to determine if the use of topical corticosteroids affected the risk of subsequent herpes simplex eye disease though the trial

Table 9. Visual Outcome of Study Eye at 6 Months after Randomization Visual Acuity Best-corrected visual acuity 6 mos after entry 20/13-20/40 20/50-20/190 20/200 or worse Change in visual acuity from randomization to 6 mos Worsened by ~2 lines No improvement Improvement 2-3 lines 4-5 lines :?6 lines

Steroid Group (n = 52)

Placebo Group (n = 42)*

35 (67%) 13 (25%) 4(8%)

28 (67%) 9 (21%)

5 (10%) 15 (29%)

3 (7%) 14 (33%)

13 (25%) 11 (21%) 8 (15%)

9(21%) 8 (19%) 8 (19%)

5 (12%)

No Significant differences were detected for any of the comparisons shown. Study population does not include 12 patients who were not evaluated after withdrawal from the study . • Includes 31 patients removed from study and treated with topical corticosteroids.

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(17)

1.0

Figure 5. Kaplan-Meier estimates of the proportion of patients randomized to placebo (solid line, n = 17) or corticosteroid (dashed line, n = 43) according to the time of onset of recurrent herpes simplex eye disease, measured from the date of stopping topical corticosteroids (study or off-study eye drops) after resolution of st romal keratitis (P = 0.8). Numbers in parentheses are patients still under observation in each group at days 30, 60, 100 (steroid only), 150 (steroid only), and at the time of the last p atient who resolved, respectively.

Volume 101, Number 12, December 1994 ,

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was not designed for this purpose. Prior studies26 •34 of patients with herpes simplex stromal keratitis found that in 15% to 21 % of patients treated with a topical corticosteroid recurrent dendritic keratitis developed, and 27% to 64% sustained recurrent stromal keratitis within 2 years. During the 6-month follow-up period in the current study, epithelial keratitis developed in 5% of patients during treatment, and 24% of patients manifested a new episode of stromal keratitis. We found no difference between the treatment groups in the time to onset of subsequent herpes simplex eye disease or in the overall use of corticosteroids. Longer follow-up than that used for this study is required to determine recurrence rates precisely and to judge the long-term safety and efficacy of steroid therapy.

ical corticosteroids were used immediately upon randomization or delayed until trial removal had no significant effect on the visual acuity at 6 months after randomization or on the time to onset of recurrent herpetic eye disease during the 6-month follow-up. Thus, rapid improvement of stromal keratitis can be achieved with immediate corticosteroid therapy, but topical corticosteroid use can be safely deferred for some patients with careful observation. The use and indications of topical corticosteroids for many infectious and inflammatory corneal diseases remain to be more clearly determined. 35 This studydemonstrates the efficacy of topical corticosteroids with topical antiviral prophylaxis in the acute treatment of herpes simplex stromal keratitis.

Conclusions

References

This clinical trial provides a basis for the judicious use of corticosteroids with protective antiviral cover in the acute treatment of patients 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 and improved faster than a comparable placebo group. The success rate with the fixed corticosteroid regimen used in this trial was only 33%, and further, steroid use frequently extended beyond the 10 weeks of study treatment. Our study also found that 22% of patients had resolution of stromal keratitis without any corticosteroid and that the stromal keratitis of these patients cleared at approximately the same rate as those who were successfully treated with corticosteroids, showing a 50% reduction in the area of stromal keratitis within 2 weeks. Whether top-

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l. Liesegang TJ. Epidemiology of ocular herpes simplex. Nat-

2. 3. 4. 5. 6. 7.

ural history in Rochester, Minn, 1950 through 1982. Arch Ophthalmol 1989; I07: 1160-5. Jones B. The management of ocular herpes. Trans Ophthalmol Soc UK 1959;79:425-37. Thygeson P, Hogan MJ, Kimura SJ. The unfavorable effect of topical steroid therapy on herpetic keratitis. Trans Am Ophthalmol Soc 1960;58:245-62. Remky H, Amann L. AuslOsungs-, Begiinstigungs- und Lokalisationsfaktoren bei Keratitis disciformis. Klin Monatsbl Augenheilkd 1961 ;138:527-34. Kaufman HE, Martola E-L, Oohlman CH. Herpes simplex treatment with IOU and corticosteroids. Arch Ophthalmol 1963;69:468-72. Thomas CI, Purnell EW, Rosenthal MS. Treatment of herpetie keratitis with IOU and corticosteroids. Report of 105 cases. Am J Ophthalmol 1965;60:204-17. Patterson A, Jones BR. The management of ocular herpes. Trans Ophthalmol Soc U K 1967;87:59-84.

Wilhelmus et al . Herpetic Eye Disease Study: Corticosteroids 8. Aronson SB, Moore TE Jr. Corticosteroid therapy in central stromal keratitis. Am J Ophthalmol 1969;67:873-96. 9. Thygeson P. Historical observations on herpetic keratitis. Surv Ophthalmol 1976;21 :82-90. 10. O'Day DM. Corticosteroids: an unresolved debate [editorial]. Ophthalmology 1991 ;98:845-6. 11. Dawson CR. The Herpetic Eye Disease Study [editorial]. Arch Ophthalmol 1990; 108: 191-2. 12. Dawson CR, Jones DB, Kaufman HE, et al. Design and organization of the herpetic eye disease study (HEDS). Curr Eye Res 1991; IO(Suppl): 105-10. 13. Herpetic Eye Disease Study Group: Manual of Operations. Version 3.4, May 1990. Available from: National Technical Information Service (Accession #PB93-17 545 3). 14. Merin LM, Wilhelmus KR, Herpetic Eye Disease Study Group. Anterior segment photography in the Herpetic Eye Disease Study. J Ophthalmic Photogr 1992;14:34-8. 15. Rothman KJ. Estimation of confidence limits for the cumulative probability of survival in life table analysis. J Chronic Dis 1978;31:557-60. 16. Simon R, Lee YJ. Nonparametric confidence limits for survival probabilities and median survival time. Cancer Treat Rep 1982;66:37-42. 17. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659-63. 18. Lan KKG, Wittes J. The B-value: a tool for monitoring data. Biometrics 1988;44:579-85. 19. Ostler HB. Glucocorticoid therapy in ocular herpes simplex. I. Limitations. Surv Ophthalmol 1978;23:35-43. 20. Pavan-Langston D, Abelson MB. Glucocorticoid therapy in ocular herpes simplex. II. Advantages. Surv Ophthalmol 1978;23:35, 43-8. 21. Cohen EJ, Laibson PRo The use of corticosteroids in herpes simplex keratitis. In: Blodi FC, ed. Herpes Simplex Infections of the Eye. New York: Churchill Livingstone, 1984;10916. 22. Wilhelm us KR. Diagnosis and management of herpes simplex stromal keratitis. Cornea 1987;6:286-91.

23. Collum LMT, Logan P, Ravenscroft T. Acyclovir (Zovirax) in herpetic disciform keratitis. Br J Ophthalmol 1983;67: 115-18. 24. Power WJ, Hillery MP, Benedict-Smith A, Collum LMT. Acyclovir ointment plus topical betamethasone or placebo in first episode disciform keratitis. Br J Ophthalmol 1992;76: 711-13. 25. Williams HP, Falcon MG, Jones BR. Corticosteroids in the management of herpetic eye disease. Trans Ophthalmol Soc UK 1977;97:341-4. 26. Sundmacher R. Trifluorothymidinprophylaxe bei der Steroidtherapie herpetischer Keratouveitiden. Klin Monatsbl Augenheilkd 1978;173:516-19. 27. Tassy A, Mathieu D, Combes A. Collyres corticoides a minima dans les poussees inflammatoires des keratites herpetiques. Bull Soc Ophtalmol Fr 1989;89:877-80. 28. Behrens-Baumann W, Quentin C-D, Vogel M. Acyclovir versus Trifluorthymidin in der Therapie der stromalen Herpes-Keratitis. Klin Monatsbl Augenheilkd 1986; 189: 286-8. 29. Collum LMT, Power WJ, Collum A. The current management of herpetic eye disease. Doc Ophthalmol 1992;80:201-5. 30. Pepose JS. Herpes simplex keratitis: role ofviral infection versus immune response. Surv Ophthalmol 1991 ;35:345-52. 31. Cook SD, Hill JH. Herpes simplex virus: molecular biology and the possibility of corneal latency. Surv Ophthalmol 1991 ;36: 140-8. 32. Liesegang TJ. Biology and molecular aspects of herpes simplex and varicella-zoster virus infections. Ophthalmology 1992;99:781-99. 33. Claoue CMP, Menage MJ, Easty DL. Severe herpetic keratitis. I: Prevalence of visual impairment in a clinic population. Br J Ophthalmol 1988;72:530-3. 34. Shimomura Y, Ohashi Y, Maeda N, et al. Herpetic keratitis therapy to reduce recurrence. Curr Eye Res 1987 ;6: 105-10. 35. Stern GA, Buttross M. Use of corticosteroids in combination with antimicrobial drugs in the treatment of infectious corneal disease. Ophthalmology 1991;98:847-53.

Discussion by Jay S. Pepose, MD, PhD This component of the herpetic eye disease study addresses a major controversy in ophthalmology-the efficacy and safety of topical corticosteroids (with antiviral cover) in herpetic stromal keratitis-in the context of a randomized, double-masked, placebo-controlled, multicentered clinical trial. The potential impact of the study group's findings is great, given an estimated prevalence of 400,000 patients with ocular herpes simplex nationally, I in one fifth of whom some form of stromal disease develops.2.3 Herpes simplex stromal keratitis results in frequent office visits and time lost from work. Furthermore, permanent structural damage from ocular herpes simplex is the cause of approximately 3% of all patients who have had penetrating keratoplasty in recent years in the United States. 4- 6 The study group's rejection of the null hypothesis that topical corticosteroid is not different than placebo in the time to treatment failure of herpes stromal keratitis depends crucially on the From the Departments of Ophthalmology and Visual Sciences and Pathology, Washington University School of Medicine, St. Louis.

assumption that patients enrolled in the study with stromal keratitis truly have ocular herpetic disease. Because herpes simplex stromal keratitis may present with various patterns, the differential diagnosis of stromal keratitis is extensive, and includes other forms of microbial keratitis, such as varicella zoster, Acanthamoeba, Epstein-Barr virus, or syphilitic keratitis, as well as nonmicrobial conditions such as Cogan syndrome and keratitis secondary to connective tissue disorders. The determination of antiherpes simplex serum antibodies 7•8 may have been useful in patients in the Herpetic Eye Disease Study (HEDS) who have no prior history of ocular herpes simplex or evidence of systemic disease suggesting another diagnosis. In such patients whose etiology of stromal disease may be ambiguous, a negative test for herpes simplex antibodies has a high probability of excluding the diagnosis of herpes simplex. 9 Other laboratory tests, such as syphilis serology using a specific antitreponemal test, would further ensure that patients do not have diagnoses that should lead to exclusion. The possibility that some patients enrolled in the study did not have herpes simplex stromal keratitis is raised by the finding

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Volume 101, Number 12, December 1994

that in the placebo group, a lack of a history of herpes simplex eye disease was the characteristic that was prognostic of a treatment success, with a rapid decrease in the area of stromal inflammation. It is this group without a history of ocular herpes simplex in which the diagnosis is perhaps the most suspect, and it is of interest that they have a different and better prognosis than patients with a previously documented history of ocular herpes simplex. It is, of course, possible that patients, after initial presentation of herpes stromal keratitis, do have a better prognosis, a result that is consistent with previous reports of a lower incidence of stromal necrosis and permanent structural alterations after the initial occurrence of ocular herpes. 2 Given the documented difference in outcome associated with a history of ocular herpes in the placebo group, as well as the potential mixed enrollment discussed above, it is important to stratify the data for the steroid treatment group by a history of ocular herpes and to make pairwise comparisons of the KaplanMeier curves for all four groups. Once stratified based on a history of ocular herpes, does the time to resolution of stromal inflammation for steroid and placebo successes differ among the four groups? The conclusion that trifluridine and topical corticosteroids is superior to trifluridine and placebo in limiting the duration and progression of herpetic stromal keratitis is consistent with the previous work of Collum and colleagues. to These investigators showed faster healing of herpetic disciform disease with a combination of topical acyclovir and dilute steroid drops versus topical acyclovir alone. The results reported herein expand their conclusions in as much as the HEDS includes patients with necrotizing stromal disease, provides a more comprehensive severity assessment, studies a fixed progressive taper of prednisolone phosphate, and determines prognostic risk factors for clinical and visual outcome. Dr. Wilhemus and the HEDS group should be commended for addressing an important management problem in ocular herpes. Cumulative clinicopathologic and experimental studies have shown that herpes simplex stromal keratitis is an immunologically mediated disorder, with local corneal inflammation comprised predominantly of macrophages and T cells. 1I The mechanisms by which corticosteroids playa beneficial role in treating herpes simplex stromal keratitis are likely to be multifactorial and complex. These may include a reduction in corneal Langerhans cell number and function,12 decreased expression of cellular adhesion molecules and human leukocyte antigens on corneal cells,II.13,14 diminished release of cytokines and oxygen-free radicals by infiltrating macrophages and lymphocytes,15-17 and changes in corneal endothelial cell function, 18 Additional clinical and laboratory studies are needed to elucidate underlying disease and treatment mechanisms and to further delineate improved therapies for herpes simplex stromal keratitis, References 1. Liesegang TJ, Melton LJ III, Daly PJ, Ilstrup DM, Epide-

miology of ocular herpes simplex, Incidence in Rochester, Minn, 1950 through 1982. Arch Ophthalmol 1989;107: 1155-9,

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2, Liesegang T J. Epidemiology of ocular herpes simplex. Natural history in Rochester, Minn, 1950 through 1982, Arch Ophthalmol 1989;107:1160-5. 3, Wilhelm us KR, Coster DJ, Donovan HC, et aL Prognostic indicators of herpetic keratitis, Analysis of a five-year observation period after corneal ulceration, Arch Ophthalmol 1981 ;99: 1578-82. 4, Brady SE, Rapuano CJ, Arentsen JJ, et aL Clinical indications for and procedures associated with penetrating keratoplasty, 1983-1988. Am J Ophthalmol 1989; 108: 118-22, 5. Mohamadi P, McDonnell JM, Irvine JA, et aL Changing indications for penetrating keratoplasty, 1984-88 [letter], Am J Ophthalmol 1989;107:550-2, 6, Mamalis N, Anderson CW, Kreisler KR, et aL Changing trends in the indications for penetrating keratoplasty, Arch Ophthalmol 1992;110:1409-11. 7. Nahmias AJ, Lee FK, Beckman-Nahmias S, Sero-epidemiological and -sociological patterns of herpes simplex virus infection in the world, Scand J Infect Dis Suppl 1990;69: 19-36, 8. Ashley RL, Militoni J, Lee F, et aL Comparison of Western blot (immunoblot) and glycoprotein G-specific immunodot enzyme assay for detecting antibodies to herpes simplex virus types 1 and 2 in human sera, J Clin Microbiol 1988;26: 662-7. 9, Wilhelm us KR, Darougar S, Forsey T, Treharne JD, Sequential antibody changes following ulcerative herpetic keratitis, Br J Ophthalmol 1986;70:354-6, 10. Collum LMT, Logan P, Ravenscroft T. Acyclovir (Zovirax) in herpetic disciform keratitis. Br J Ophthalmol 1983;67: 115-8. 11. Pepose JS, Herpes simplex keratitis: role of viral infection versus immune response. Surv Ophthal 1991 ;35:34552. 12, Pepose JS. The relationship of corneal Langerhans cells to herpes simplex antigens during dendritic keratitis. Curr Eye Res 1989;8:851-8. 13. Elner VM, Dutt S, Pavilack MA, et al. Intercellular adhesion molecule-1 (ICAM-I) and HLA-DR antigens in herpes keratitis. Ophthalmology 1992;99: 1400-7. 14. Pepose JS, Gardner KM, Nestor MS, et aL Detection of HLA class I and II antigens in rejected human corneal allografts. Ophthalmology 1985;92: 1480-4. 15, Han J, Thompson P, Beutler B. Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med 1990;172:391-4. 16. Pinkston P, Saltini C, Muller-Quernheim J, Crystal RG. Corticosteroid therapy suppresses spontaneous interleukin 2 release and spontaneous proliferation of lung T lymphocytes of patients with active pulmonary sarcoidosis. J ImmunoI1987;139:755-60, 17. Baughman RP, Lower EE, The effect of corticosteroid and methotrexate therapy on lung lymphocytes and macrophages in sarcoidosis. Am Rev Respir Dis 1990;142:1268-71. 18, O'Brien WJ, Guy J, Taylor JL. Pathogenesis of corneal oedema associated with herpetic eye disease, Br J Ophthalmol 1990;74:723-30.