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Antiviral Drug Sharply Reduces Return of Herpes of the Eye

July 29, 1998

Researchers have found that an antiviral drug, often used to suppress genital herpes, also decreases the recurrence of herpes of the eye. A paper detailing these findings is published in the July 30, 1998 issue of The New England Journal of Medicine.

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. Stromal keratitis causes scarring of the cornea, which can lead to loss of vision and possibly blindness. Recurring episodes of stromal keratitis can often result in the need for a corneal transplant.

“This drug is the first treatment that helps prevent herpes of the eye from returning,” said Dr. Carl Kupfer, director of the National Eye Institute (NEI), part of the Federal government’s National Institutes of Health (NIH) and the agency that supported the clinical trial. “The results of this study should change medical practice.”

Herpes of the eye, or ocular herpes, is caused by the herpes simplex virus. This infection can produce a painful sore on the eyelid or surface of the eye and cause inflammation of the cornea, the transparent tissue that covers the front of the eye. The less severe forms of ocular herpes include blepharitis, conjunctivitis, and epithelial keratitis. The more severe form of ocular herpes is stromal keratitis, which causes the body’s immune system to attack and destroy an inner layer of the cornea. Stromal keratitis is more difficult to treat than less severe ocular herpes infections.

An estimated 400,000 Americans have had some form of ocular herpes. Previous studies show that once people develop ocular herpes, they have up to a 50 percent chance of having a recurrence. This second flare-up could come weeks or even years after the initial occurrence. Each year, nearly 50,000 new and recurring cases are diagnosed in the United States, with the more serious stromal keratitis accounting for about 25 percent.

The clinical trial called the Acyclovir Prevention Trial (APT) followed 703 patients who had herpes of the eye during the preceding year, but did not currently have an active case of the disease. Of this number, 357 received acyclovir by mouth, and 346 received a placebo. Researchers discovered that the probability of a recurrence of any form of ocular herpes during the treatment period was significantly lower in the acyclovir group (19 percent) than in the placebo group (32 percent). This represents a reduction by 41 percent between the two groups.

Among the 703 patients, researchers examined 337 patients with a prior history of the more serious stromal keratitis. Acyclovir reduced the rate of recurrences of stromal keratitis from 28 percent to 14 percent, a difference of 50 percent between the two groups. The study medication caused no serious side effects.

“The study clearly shows that acyclovir therapy can benefit people with all forms of ocular herpes,” said Dr. Kirk Wilhelmus, professor in the Department of Ophthalmology at the Baylor College of Medicine and chairman of the APT clinical trial. “Ocular herpes can be painful, chronic, and disabling. This new treatment will improve people’s quality of life. Those who have had the more serious stromal keratitis will benefit the most.”

Dr. Wilhelmus noted that not all patients had the same benefit from taking acyclovir. “Patients should consult with their eye care professionals to see if prolonged use of acyclovir is right for them,” he said.

Researchers also found that oral acyclovir reduced the risk of herpes infections in other parts of the body, particularly the mouth and face, by 43 percent. During the 12-month treatment period, 20 percent of patients in the group receiving acyclovir had at least one herpes infection affecting the mouth or face, as compared with 35 percent of patients in the placebo group.

Once treatment stopped, the rate of ocular herpes or herpes affecting the mouth and face did not increase, according to Dr. Wilhelmus. “During the six months after treatment ended, the percentages of herpes recurrences affecting the eye or the mouth and face was the same in both the treatment and placebo groups,” he said.

The Acyclovir Prevention Trial is part of a larger study called the Herpetic Eye Disease Study that is supported through cooperative agreements with the NEI. The APT was conducted at 74 university and community-based clinical sites nationwide, reporting to eight regional centers. A list of the regional centers is attached.

The National Eye Institute, part of the National Institutes of Health, is the Federal government’s lead agency for vision research, and supports between 70 to 80 percent of basic and applied vision research in the United States.



The Acyclovir Prevention Trial

Ocular Herpes

Like other herpetic infections, herpes of the eye remains a controllable, but incurable, problem. In one large, unrelated study, researchers found that recurrence rate of ocular herpes was 10 percent within one year, 23 percent within two years, and 63 percent within 20 years. Some factors believed to be associated with recurrence include fever, stress, sunlight, and eye injury.

The less severe forms of ocular herpes include epithelial keratitis, conjunctivitis, and blepharitis. The more severe form of ocular herpes stromal keratitis can lead to corneal scarring and can be associated with secondary glaucoma and cataract. Standard treatment with antiviral eyedrops or ointment helps to stop the herpes virus from multiplying. However, until the APT, there was still no known effective method for reducing the frequency of ocular herpes recurrence.

The APT Protocol

The Acyclovir Prevention Trial (APT) is a multicenter randomized clinical trial designed to determine if the antiviral drug acyclovir, given orally, would prevent herpes simplex virus infection from recurring in the eyes of patients who had the infection in the past.

To be eligible for participation, patients must have experienced a form of ocular herpes in one or both eyes during the preceding year. This infection had to be inactive and untreated for at least the previous 30 days before enrollment. About 29 percent of the enrolled patients had experienced one previous episode of ocular herpes; 71 percent experienced multiple previous recurrences. The most common types of prior ocular herpes were epithelial keratitis (47 percent), stromal keratitis (16 percent), and both epithelial keratitis and stromal keratitis (32 percent). About 49 percent of patients had a history of fever blisters or other previous symptoms of herpes of the mouth and/or face.

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. The other group received placebo capsules that were identical in appearance and taste to the acyclovir capsules. Study medication (acyclovir or placebo) was continued for the full 12 months regardless of whether a recurrence occurred.

Herpes recurrences were classified as either superficial ocular infections (blepharitis, conjunctivitis, and/or epithelial keratitis); stromal keratitis; or iritis. When patients had a recurrence of ocular herpes, they were treated with standard topical medication, but continued to receive the oral acyclovir or placebo for the entire 365-day period.

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).

Glaxo Wellcome supplied to APT investigators over a half million free capsules of its brand name acyclovir, called Zovirax®.

Secondary Findings

In addition to the main findings, doctors also noted that:

  • During the 12 months of treatment, oral acyclovir reduced the incidence of epithelial keratitis from 11 percent to nine percent, and the incidence of stromal keratitis from 13 percent to eight percent.
  • During the 12-month treatment period, four percent of patients in the acyclovir group and nine percent in the placebo group had more than one recurrence.

Herpetic Eye Disease Study Centers

Chandler R. Dawson, M.D
Francis I. Proctor Foundation
University of California, San Francisco
San Francisco, CA

R. Doyle Stulting, M.D., Ph.D.
Emory Eye Center
Atlanta, GA

Joel Sugar, M.D.
Eye Center
University of Illinois, Chicago
Chicago, IL

Bruce A. Barron, M.D.
Louisiana State University Eye Center
New Orleans, LA

New York
Penny A. Asbell, M.D.
Department of Ophthalmology
The Mount Sinai Medical Center
New York, NY

Elisabeth J. Cohen, M.D.
Wills Eye Hospital, Cornea Clinic
Philadelphia, PA

Kirk R. Wilhelmus, M.D.
Cullen Eye Institute
Baylor College of Medicine
Houston, TX

Robert A. Hyndiuk, M.D.
The Eye Institute
Medical College of Wisconsin
Milwaukee, WI


Resource Centers

Chairman’s Office

Chandler R. Dawson, M.D.
Francis I. Proctor Foundation
University of California, San Francisco
153 Parnassus Avenue, Room 5347
San Francisco, CA 94143-0412
Telephone: (415) 476-2658

Coordinating Center

Roy W. Beck, M.D., Ph.D.
Pamlea S. Moke, M.S.P.H.
Jaeb Center for Health Research, Inc.
3010 E. 138th Avenue, Suite 9
Tampa, FL 33613
Telephone: (813) 975-8690

NEI Representative

Natalie Kurinij, Ph.D.
National Eye Institute
National Institutes of Health
Executive Plaza South, Suite 350
6120 Executive Boulevard, MSC 7164
Bethesda, MD 20892-7164
Telephone: (301) 496-5983



  • Acyclovir for The Prevention of Recurrent Herpes Simplex Virus Eye Disease. Herpetic Eye Disease Study Group. N Engl J Med. 1998 Jul 30. PubMed