The development of more effective, less toxic antiviral treatments has improved the prognosis for patients with herpes simplex keratitis.
Herpes simplex is the most common cause of viral keratitis and a major cause of ocular morbidity and blindness (Figure 1). Initial infection with herpes simplex virus 1 (HSV-1) typically occurs in early childhood and is lifelong. After infection, periodic outbreaks may occur.
An estimated 60% of the US population shows evidence of HSV-1 infection, and approximately 1% of these persons develop ocular outbreaks—resulting in nearly 20,000 primary cases of dendritic keratitis each year.1,2 In addition, genital herpes, caused by a related virus, HSV-2, is one of the most common causes of severe neonatal ocular infections. Complications of herpetic keratitis include corneal scarring and opacities, in some cases so severe as to warrant corneal transplant.
For most of the 20th century, debridement was our only therapeutic intervention for herpetic keratitis. In the 1970s, Herbert Kaufman developed iododeoxyuridine (IDU), the world’s first effective antiviral, for the treatment of herpetic keratoconjunctivitis. Soon after, he further improved our treatment efficacy by developing trifluridine. Unfortunately, both IDU and trifluridine proved relatively nonselective in their action—inhibiting DNA synthesis in healthy as well as HSV-infected cells. As a result, they can produce epithelial toxicity and further damage the cornea.,
Gertrude Elion gave us the next great advance with acyclovir, introducing a new family of antiviral molecules that activate preferentially in virally infected cells and, so, are sparing of healthy tissue (Table 1). In the years since, acyclovir’s molecular derivatives have included valacyclovir, famciclovir, and ganciclovir—all of which have demonstrated clinical efficacy against herpetic infections, with continued low rates of viral resistance (confined primarily to immunocompromised patients).
Avoiding Trifluridine Toxicity
Given trifluridine’s potential for epithelial toxicity, many eyecare clinicians switched to oral acyclovir for treatment of ocular herpetic infection. Though generally safe, systemic use does pose a danger to patients with compromised kidney function, and systemic exposure in children and pregnant women remains a concern.
In Europe and elsewhere outside North America, acyclovir ophthalmic ointment came into widespread use in the 1980s. Ophthalmic ganciclovir followed with a gel formulation that took advantage of ganciclovir’s greater solubility. In clinical trials, ganciclovir gel was proven as effective as acyclovir ointment, with patients reporting a general preference for ganciclovir, finding that it produced less blurring and stinging or burning than acyclovir ointment.,
In 2007, the US Food and Drug Administration granted ganciclovir gel orphan drug designation and in 2009 approved it for the treatment of acute superficial herpes keratitis (dendritic ulcers). With this approval, US physicians and their patients gained a topical treatment not only less toxic than trifluridine, but also more convenient with dosing at five times (rather than nine times) per day.
The Need for Prophylaxis
Recurrent herpetic keratitis can result in extensive corneal damage and blindness, and recurrence in a corneal graft can trigger graft rejection. The need for effective prophylaxis is particularly great in patients receiving corneal transplant, as their need for post-transplant steroids increases both the risk of herpetic reactivation and the severity of any resulting ocular infection.
As a coauthor of the Herpetic Eye Disease Study (HEDS), I welcomed the clear confirmation that the long-term use of oral acyclovir reduces the risk of herpetic keratitis recurrence by close to 50%.6 It is reasonable to hope that topical ganciclovir might further enhance prophylaxis or serve as an alternative when systemic exposure should be avoided.
Recently, Tabbara and colleagues reported the results of a prospective case series involving the long-term use of ganciclovir gel with patients prone to recurrence of herpes keratitis, including several who had undergone corneal grafts for herpetic scarring.
During 2 years of follow-up, none of the six patients on prophylactic ganciclovir developed a recurrence. By contrast, recurrence occurred in three of the ten patients who did not receive prophylaxis. The researchers reported no significant ocular side effects during the 2-year study.
Studies with animal models of herpetic keratitis provide additional support for prophylactic use, with application of ganciclovir gel preventing corneal lesions in latently infected or HSV-challenged mice and rabbits.8-10 Given these results, the prophylactic use of ganciclovir gel appears promising. Larger studies are needed to confirm benefit and determine optimal prophylactic dosing and frequency.
Efficacy Against Other Ocular Infections
Adenovirus keratoconjunctivitis can produce significant patient discomfort and visual disturbances. Its extreme contagiousness warrants patient isolation, resulting in time lost from work or school. Lacking effective treatments, we welcome a small but growing body of evidence that suggests ganciclovir may have efficacy against these infections.
This evidence includes studies employing cell culture and animal models as well as two small unmasked clinical trials, which demonstrated reductions in both recovery time and subepithelial opacities.11-13 In one of these studies 18 patients with adenoviral keratoconjunctivitis received either ganciclovir gel or artificial tears. The mean recovery time in the ganciclovir-treated group (9 patients) was 7.7 days (range: 7 to 12 days) vs 18.5 (range: 7 to 30) days for patients receiving artificial tears. Only two of the patients treated with ganciclovir developed opacities vs seven of the patients receiving artificial tears.
Ganciclovir also appears to be a powerful in vitro inhibitor of the herpes zoster virus. However, we currently lack clinical studies examining the efficacy of ophthalmic ganciclovir in the treatment of herpes zoster ophthalmicus, or “ocular shingles.”
THE BOTTOM LINE
The introduction of ganciclovir gel is the latest advancement in a 50-year history of progress in the treatment and prevention of herpetic keratitis. In addition, early evidence suggests ganciclovir’s efficacy against other types of viral ocular infections.
Penny A. Asbell, MD, FACS, MBA, is director of the cornea service and refractive surgery center and a professor in the department of ophthalmology at Mount Sinai School of Medicine in New York, NY. Dr. Asbell states that she has received research funding or served on the speaker bureaus of Alcon Laboratories, Allergan, Aton Pharma, Bausch + Lomb, Merck Pharmaceuticals, Inspire, Clinical Research Consultants, Johnson & Johnson, Pfizer, Santen, and Vistakon Pharmaceuticals. A Refractive Eyecare staff writer assisted in the preperation of this article.
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