Herpetic Eye Disease Study (HEDS) I

• To evaluate the efficacy of topical corticosteroids in treating herpes simplex stromal keratitis in conjunction with topical trifluridine.
• To evaluate the efficacy of oral acyclovir in treating herpes simplex stromal keratitis in patients receiving concomitant topical corticosteroids and trifluridine.
• To evaluate the efficacy of oral acyclovir in treating herpes simplex iridocyclitis in conjunction with treatment with topical corticosteroids and trifluridine.

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.

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.

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.

No longer recruiting. Comments: Completed.

Completed, with results published. Comments: Completed.

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.