BackgroundInfection of the eye by herpes simplex virus (HSV) is a leading cause of corneal blindness in the United States and other countries. The infection can lead to corneal scarring and neovascularization, permanent endothelial dysfunction and corneal edema, secondary glaucoma, and cataract. Despite the availability of topical antiviral agents that are highly active against HSV keratitis, there is still no known effective method for reducing the frequency of recurrence or severity of stromal keratitis and iridocyclitis. In addition, the prognosis is poor for recovery of good vision following penetrating keratoplasty for actively inflamed or highly vascularized herpetic corneas.
On the basis
of both animal and human studies, the antiviral agent acyclovir may both
treat and prevent recurrence of HSV disease. However, no consensus yet
exists on the use of acyclovir in the management and prevention of herpetic
DescriptionHEDS-II consists of two randomized, placebo-controlled trials that are assessing the role of oral acyclovir in the management of herpetic eye disease and one epidemiologic study that is investigating risk factors, including stress, for the development of ocular recurrences of the disease. The organizational structure consists of a national coordinating center, eight regional coordinating clinical centers, and approximately 60 clinical sites. The clinical sites where patients are enrolled and followed include both university-based and community-based practices.
Herpes Simplex Virus Epithelial Keratitis Trial: HEDS-EKT evaluated the benefit of oral acyclovir given during treatment of an acute HSV keratitis (dendritic or geographic keratitis) in preventing the occurrence of later blinding complications. Patients entered the trial within 7 days of onset. All patients received standard treatment with a topical antiviral and were randomized to receive either oral acyclovir (400 mg five times a day for 21 days) or a placebo. Patients had eight visits within a 12-month followup period. The primary outcome was the time to the first occurrence of stromal keratitis or iridocyclitis in the study eye (eye with epithelial keratitis at time of study entry). The HEDS-EKT recruitment goal was 502 patients.
Acyclovir Prevention Trial: HEDS-APT evaluated the benefit of long-term acyclovir treatment in patients with a recent history of HSV eye disease but no current active disease. To be eligible, a patient must have experienced any kind of ocular herpes simplex infection (blepharitis, conjunctivitis, keratitis, or iridocyclitis) in the preceding year. The infection must have been inactive and untreated for at least the previous 30 days. Patients were randomized to receive either oral acyclovir (400 mg twice a day) or placebo for 1 year. Five followup visits occurred during the 1-year treatment period and an additional three followup visits during the 6-month post-treatment period. Episodes of recurrent HSV eye disease during the trial were treated with topical corticosteroids and antivirals as indicated, but patients continued to receive the oral acyclovir or placebo for the entire 365-day period. The primary outcome was the time to the first recurrence of any type of HSV eye disease in either eye. The recruitment goal was 696 patients.
Recurrence Factor Study: HEDS-RFS is evaluating the effect of psychological,
environmental, and biological factors on recurrences of herpetic eye disease.
Patients recruited into the HEDS-APT trial are eligible to participate
in HEDS-RFS if they are 18 years or older. At entry, all subjects fill
out a questionnaire to estimate the negative affectivity trait measure.
Subjects also fill out a short questionnaire every week for 52 weeks to
track acute and chronic stressors (e.g., illnesses, injuries, menstrual
periods, sun exposure, emotional and financial stresses). The investigators
ensure patient privacy by the patientsí mailing of the weekly logs directly
to the HEDS National Coordinating Center.
ResultsHerpes Simplex Virus Epithelial Keratitis Trial (HEDS-EKT)
Patient recruitment in the HEDS-EKT trial was stopped on the recommendation of the Data and Safety Monitoring Committee after 287 of the originally planned 502 patients were enrolled because of a lack of any suggestion of efficacy of the treatment protocol in the accrued results. The study found that in the treatment of acute HSV epithelial keratitis, there was no benefit from the addition of oral acyclovir to treatment with topical trifluridine in preventing the development of stromal keratitis or iritis. Importantly, the study found that the risk of stromal keratitis or iridocyclitis was quite low in the year following an episode of epithelial keratitis treated with topical trifluridine alone. This risk is much lower than the published risk in the literature.
Acyclovir Prevention Trial (HEDS-APT)
Of the 703 patients, 357 were randomly assigned to the acyclovir group, and 346 to the placebo group. All patients were followed for all forms of ocular and nonocular recurrences during a 12-month treatment period, followed by a six-month observation period. The acyclovir group received oral acyclovir 400 mg twice daily for 12 months. Only four percent of patients in the acyclovir group and five percent in the placebo group stopped treatment because of side effects. One-half of these side effects were due to gastrointestinal upset; some patients may have had intolerance to the lactose contained in the study capsules (Treatment medication that does not contain lactose is now available).
Scientists found that the drug acyclovir, taken by mouth, reduced by 41 percent the probability that any form of herpes of the eye would return in patients who had the infection in the previous year. Importantly, researchers noted a 50 percent reduction in the rate of return of the more severe form of the disease -- stromal keratitis -- among patients who had this infection during the past year.
In addition to the main findings, doctors also noted that during the 12 months of treatment:
There are no
results yet available from the HEDS RFS.