Antiviral treatment best defence for ocular herpes

By Roibeard O'hÉineacháin

NICE - Oral antiviral therapy can greatly reduce the recurrence rate of corneal herpetic disease whether used as a treatment for its clinical manifestations or as a prophylaxis in eyes undergoing potentially recurrence-inducing treatment such as penetrating keratoplasty (PK) or LASIK.

French ophthalmologist Joseph Colin MD said the major objectives of treating herpes simplex virus (HSV) keratitis are the preservation of normal vision because untreated disease recurrences can lead to visual loss.

"Antiviral therapy for HSV keratitis has gradually evolved and the challenge is now to determine the most appropriate strategies for using the antiviral options available," Dr Colin told the XX ESCRS Congress.

Keratitis due to the herpes simplex virus (HSV) is the leading cause of corneal blindness in Western countries. For example, the incidence of new cases per year in the US is 8.4 per 100,000 population and that of recurrences is 20.7 per 100,000 population.

Even if a vaccine for HSV-1 should become available, its uptake would have to be almost universal to be effective in preventing HSV keratitis.

An estimated 20% of children younger than five years and 40% to 60% of adults are infected with the virus. However, only 20% to 30% of those infected manifest clinical disease. Ocular manifestations develop in less than 1%, he pointed out.
Prophylactic vaccine

"Thus, although a highly effective prophylactic vaccine could potentially impact on the incidence of ocular HSV disease, it is unlikely that efforts to prevent HSV-1 transmission and acquisition would be practical or effective," Dr Colin said.
Ophthalmologists must therefore concentrate their efforts on careful management of the disease in patients with ocular manifestations of the HSV and the prevention of recurrences.

In addition, they should be aware of iatrogenic factors that can provoke both the initial manifestations and the recurrences of the condition.
"We know that recurrences can be induced by treatments including UV light in the form of excimer laser surgery, topical and systemic corticosteroids and latanoprost.

"Everything must be done to avoid trigger factors when we know the trigger factor for a specific patient. Of course we must be very careful and cautious when using drugs or instruments that can induce recurrences," he explained.

The severity of HSV keratitis generally increases with recurrence. In addition, the rate of recurrences after the first episode increases progressively with follow-up, reaching 40% after five years.

However, there is now good evidence that antiviral treatment not only reduces the duration and severity of HSV-keratitis but also helps prevent recurrences.
In a prospective study by the Herpetic Eye Disease Group (New England Journal of Medicine 1998; 339: 300-306), the rate of recurrences in 357 patients who received 400 mg oral acyclovir twice a day was only 19%.

That compared to a rate of 32% among 346 who received placebo. Furthermore, the rate of stromal recurrences was only 13% in the active treatment group compared to 27% for placebo.

"Therefore we can decrease the number of recurrences but currently we cannot entirely eliminate the recurrences. The optimum dose of oral acyclovir therapy has yet to be determined although the Herpetic Eye Disease Group trial demonstrated that a dose of oral acyclovir 400 mg twice daily was effective in preventing recurrences," Dr Colin added.

In cases with epithelial dendritic keratitis, the symptoms generally resolve within a week of the initiation of topical or oral antiviral treatment.
However, when the infection has begun to invade the stroma the situation becomes much more difficult and dangerous. In extreme cases, the scarring becomes so severe that penetrating keratoplasty (PK) becomes necessary and this in itself can increase the risk of further recurrences.

Moreover, patients undergoing PK for HSV keratitis present a different clinical profile from those with ocular HSV disease.
They are usually at the most severe end of the disease spectrum, and their disease will be influenced by iatrogenic factors involved in surgery and the use of topical corticosteroids. Therefore, the results of the patients in the Herpetic Eye Disease Group study cannot be directly extrapolated to patients with PK.

On the other hand, a study presented by Dr Van Rooij at last year's meeting of the American Academy of Ophthalmology indicated that a six month regimen of oral acylovir at a dosage of 400 mg twice can reduce the recurrence rate of the disease.
Dr Colin noted that oral treatment might have some advantages over topical therapy as it achieves higher drug levels in the anterior chamber and other sites of infection.

Furthermore, oral acyclovir does not interfere with healing after PK. He also suggested that there is a strong rationale for continuing the prophylactic regimen for up to one year

"Prophylactic antiviral therapy should be considered for all patients undergoing PK for ocular HSV disease. The optimum duration of prophylactic antiviral therapy following PKP for HSV keratitis has yet to be determined.

"Since most recurrences of ocular HSV disease occur in the first year, one year of postoperative antiviral therapy may be a reasonable minimum," he added.
In addition to the risk of provoking recurrences in patients with HSV, PK also has the potential to transmit the virus to previously uninfected individuals.

The virus is strongly implicated in a recently identified form of graft rejection called primary graft failure syndrome.
The features of the condition include a diffusely oedematous corneal graft on the first postoperative day which fails to clear without any known precipitating cause.

The syndrome occurs in 2% of corneal grafts. As many as one-third of donor corneas involved in such cases test positive for HSV DNA.
"Although graft-to-recipient transmission of HSV is extremely rare, the storage of corneas in eye banks offers the opportunity to safeguard against transmission of HSV.
"Routine visual examination of the endothelium will identify corneal buttons with obvious necrosis that may be caused by HSV. This should prevent infected tissue being released for transplant," Dr Colin said.

UV light from the sun is a well-recognised trigger for the re-activation of HSV. New research suggests the UV rays of the excimer laser have a similar effect on corneas infected with the disease.

This has been reported in humans undergoing refractive surgery and in the laboratory with rabbit eyes. However, rabbit eye studies also suggest that antiviral therapy in infection lowers the risk of HSV recurrence following laser surgery.
"The effect of antiviral prophylaxis on ocular HSV disease recurrence rates should be investigated in a clinical trial.

"But for now I would recommend antiviral prophylaxis following excimer laser surgery of the cornea in all cases of phototherapeutic keratectomy (PTK) for herpetic scar, in all cases of PRK-LASIK in patients with an history of HSV keratitis and in all patients with a corneal scar of unknown origin," Dr Colin said.

He predicted that the future would see further trials with antiviral agents to more precisely determine their role in the treatment of HSV keratitis.
In addition, valacyclovir, a pro-drug of acyclovir, will most likely come to the fore by virtue of its superior penetration into intraocular structures, he said.
Finally the prevention and cure of the condition may one day become possible in the form of vaccines and new means of suppressing or preventing viral latency.


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