Ganciclovir Gel: An Important New Treatment Option for Herpes Keratitis

Ganciclovir Gel: An Important New Treatment Option for Herpes Keratitis

Ganciclovir Gel: An Important New Treatment Option for Herpes Keratitis
Francis Mah, MD

Ganciclovir ophthalmic gel delivers multiple advantages in the treatment and prophylaxis of herpetic keratitis and shows potential for effectiveness against other viral ocular infections.

For over a decade I have followed the topical ganciclovir story. In Europe, for example, topical ganciclovir gel has long been part of the standard of care treatment for herpetic dendritic keratitis along with acyclovir ointment. As a corneal specialist, I see this sight-threatening infection on an almost daily basis and have long wanted the option of a topical drug that is less toxic to the ocular epithelium than trifluridine. The recent introduction of 0.15% ganciclovir ophthalmic gel (Zirgan®; Bausch + Lomb) has delivered this beneficial option.

An estimated 60,000 new or recurrent cases of dendritic herpes simplex (HSV) keratitis are diagnosed in the United States each year.1 While comprehensive ophthalmologists and optometrists may go weeks between cases, it remains high on their radar as a leading cause of permanently decreased vision and a major indication for corneal transplantation.

The majority of ocular HSV epithelial infections will resolve without damaging vision. But we have no way to determine which cases will progress to corneal stromal scarring, melting, or even perforation. Consequently it is imperative to treat HSV keratitis promptly and effectively. Even a first episode can progress, and recurrences increase the likelihood of scarring and vision loss.2

In addition, intense light exposure and ocular trauma—including trauma due to ocular surgery or contact lenses—can trigger outbreaks in those with latent herpes simplex type 1 (HSV1) infection.3 The application of unprotected topical steroids can further increase severity especially in an undiagnosed or misdiagnosed patient.4  Thus, prophylaxis may be prudent pre- and post-surgery in patients with a prior history of ocular HSV, while co-administration of an antiherpetic agent is highly recommended when these patients use ocular steroids.

Previous Limitations

Before ganciclovir gel, our options for treatment or prophylaxis included topical 1% trifluridine solution (Falcon) and oral medications, including acyclovir, valacyclovir, and famciclovir. Each option had its drawbacks. The oral antivirals have shown effectiveness against herpes keratitis in clinical trials but are not FDA approved for ocular infections, which gives some patients and treating clinicians pause. The bigger drawback is that oral agents expose the entire body to a medication needed only in the eye. Though this family of antiviral drugs has low toxicity, in general it is desirable to avoid systemic exposure when practical. In addition, these drugs can pose a danger to patients with compromised kidney function, while pediatric and obstetric dosing remains a concern.

Topical trifluridine is effective against ocular HSV infection, but comes with a number of disadvantages. It has toxic effects on healthy as well as infected cells, and the danger this poses increases with duration of use. In addition, trifluridine is preserved with thimerosal, which can cause allergic sensitization and even cicatricial changes of the conjunctiva and limbus—a significant concern when treating a condition infamous for recurrences. A third concern involves trifluridine’s relatively limited mechanism of action, which is more prone to engendering resistance than ganciclovir, acyclovir, and their kin.

Advantages of Ganciclovir Gel

Outside the United States, ganciclovir 0.15% ophthalmic gel has become part of the standard of care in the topical treatment of herpetic keratitis, owing to its efficacy, low toxicity, and ease of use and dosing.5 In the three clinical trials leading to its FDA approval, Zirgan produced resolution by day 7 in 72% to 77% of patients.6
 
As a prodrug, ganciclovir is inert until phosphorylated by thymidine kinase, an enzyme present at high levels in HSV-infected cells. As a result, ganciclovir spares healthy tissue. Once activated, ganciclovir both inhibits viral DNA polymerase and incorporates into the viral DNA primer strand rendering it nonfunctional. This dual action reduces the likelihood of resistance.

Zirgan is preserved with benzalkonium chloride (BAK), which, although known to cause low-grade, short-term toxicity to the eye, is considered safe and effective.

Integrating Ganciclovir into Practice

The clinician should consider herpetic infection whenever a patient seeks treatment for decreased vision, ocular discomfort, redness, or foreign body sensation. Diagnosis rests on the classic dendritic presentation, generally evident on vital dye staining.

For uncomplicated epithelial herpes keratitis, I recommend starting application of Zirgan five times a day, reducing by one drop every four or five days until the patient is down to one drop per day. If there are signs of a large geographic ulcer, uveitis, or corneal stromal involvement including melting, I add oral acyclovir or valacyclovir to maximize viral eradication. HSV stromal keratitis or uveitis generally warrants the addition of topical steroids. In these cases, anti-herpetic coverage is particularly crucial as steroids can worsen or even stimulate an epithelial infection. It is important to inquire about previous outbreaks, as recurrence warrants long-term prophylaxis with either ganciclovir gel or oral antivirals—particularly if there has been corneal scarring.
 
I likewise screen for a history of ocular HSV and initiate prophylaxis for keratorefractive and cataract surgery one day pre- and at least seven days post-surgery. As mentioned previously, intense light exposure and ocular trauma are known triggers for recurrence. In an age of premium refractive and cataract surgery, it particularly behooves us to avoid postsurgical complications such as HSV keratitis or uveitis. In addition, when a patient has a history of recurrent HSV ocular events and the patient is a candidate for corneal transplant (PKP or DSAEK) or glaucoma surgery, long-term antiviral prophylaxis is highly recommended.

In addition, there are some interesting off-label reports which may require further study.  Ganciclovir has shown efficacy against some adenoviral strains, shortening the time to resolution of adenoviral conjunctivitis, for example, to 7.7 days (vs 18.5 days with artificial tears).7 Other studies suggest possible efficacy in treating ocular shingles or herpes zoster ophthalmicus (Varicella zoster).8

The Bottom Line

The recent introduction of 0.15% ganciclovir ophthalmic gel provides a less toxic and more easily dosed topical treatment for dendritic herpes keratitis and a new option for the prophylaxis of recurrent infections. In addition, preliminary studies suggest off-label effectiveness against adenoviral conjunctivitis and ocular shingles.
 

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Francis S. Mah, MD, is medical director of the University of Pittsburgh School of Medicine’s Charles T. Campbell Ophthalmic Microbiology Laboratory, an associate professor of ophthalmology and pathology, and a corneal specialist within the school’s cornea, external disease, and refractive surgery service. Dr. Mah is a consultant for or receives research support from: Alcon Laboratories, Allergan, Inspire Pharmaceuticals, and InSite Vision. Refractive Eyecare senior editor Jessica Sachs assisted in the preparation of this manuscript.
 

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References

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6.     Hoh HB, Hurley C, Claoue C, Viswalingham M, Easty DL, Goldschmidt P, Collum LM. Randomised trial of ganciclovir and acyclovir in the treatment of herpes simplex dendritic keratitis: a multicentre study. Br J Ophthalmol. 1996;80:140-3.
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8.     Kim SJ, Equi R, Belair ML, Fine HF, Dunn JP. Long-term preservation of vision in progressive outer retinal necrosis treated with combination antiviral drugs and highly active antiretroviral therapy. Ocul Immunol Inflamm. 2007;15(6):425-7.