"For those who practice evidence-based medicine, we still know relatively little about how to treat ocular HSV," noted Dr. Liesegang, professor of ophthalmology, Mayo Clinic, Jacksonville, FL.
The HEDS were a series of cohort and randomized clinical trials undertaken through a cooperative agreement between the National Eye Institute and the National Institutes of Health. Although originally organized to evaluate the efficacy of oral acyclovir (Zovirax, GlaxoSmithKline) for stromal disease, the HEDS program included investigations of topical steroids for stromal keratitis and oral acyclovir for HSV iridocyclitis, epithelial keratitis, and the prevention of recurrent active infection in patients with any history of ocular HSV disease.
Dr. Liesegang reviewed the results of the HEDS and how he has incorporated those findings in his own approach to managing HSV keratitis.
A placebo-controlled HEDS investigated oral acyclovir (400 mg taken 5 times a day for 10 weeks) for the treatment of disciform or necrotizing stromal keratitis in patients also receiving topical prednisolone sodium phosphate (Inflamase, Novartis Ophthalmics) and trifluridine (Viroptic, Monarch Pharmaceuticals Inc.). The results showed no benefit to adding the oral antiviral medication—about three-fourths of patients in both study groups had no response to treatment. Results did suggest a benefit in patients with necrotizing keratitis, however, and Dr. Liesegang noted a strong rationale for treating that subset of patients with oral acyclovir.
A second study randomly assigned patients with active HSV stromal keratitis being treated with topical trifluridine to use of topical prednisolone phosphate or placebo. Its results showed that the topical steroid had a significant benefit for reducing progression of the stromal inflammation and shortening the time to resolution of the stromal keratitis. Those benefits were achieved without an increase in the risk of recurrent disease. Postponing the steroid treatment for a few weeks during observation was associated with a delay in resolution of the stromal keratitis, but it did not adversely affect the visual outcomes at the end of the 6-month study, noted Dr. Liesegang.
"Steroid treatment also had an acceptable side-effect profile, and I recommend its use for patients with disciform and necrotizing stromal HSV keratitis, recognizing that it will not have a positive effect on visual acuity outcomes," he said.
In the HEDS of iridocyclitis treatment, patients received topical prednisolone phosphate and trifluridine and were randomly assigned to acyclovir 400 mg taken 5 times daily or placebo for 10 weeks. Due to slow recruitment, that trial was stopped when only about half of the planned 104 subjects were enrolled.
Analyses of data from the evaluable patients showed treatment failure rates of 50% in the acyclovir group and 68% in the placebo group. A possible benefit of acyclovir became evident after 3 weeks of follow-up, however, and on that basis, it was concluded that oral acyclovir may benefit HSV iridocyclitis.
"Oral acyclovir seems reasonable because HSV has often been isolated from the anterior chamber in eyes with herpetic iridocyclitis, and in my own practice, I use it together with topical steroids," Dr. Liesegang said.
The efficacy of oral acyclovir for preventing stromal keratitis or iritis in patients with HSV epithelial keratitis also was investigated in a HEDS. In that trial, all patients were treated with topical trifluridine and randomly assigned to receive oral acyclovir or placebo for 3 weeks. After 12 months of follow-up, the oral antiviral treatment had no benefit for preventing HSV stromal keratitis or iritis. Subgroup analyses showed stromal keratitis or iritis were more frequent in patients with a history of prior HSV stromal keratitis or iritis (23% versus 9%).