Special Report

Treating Severe Viral Infections

Strategies for the management of HSV keratitis.

By C. Stephen Foster, MD, FACS, FACR, FAAO

The herpes simplex virus (HSV) is the most common infectious cause of corneal blindness in developed countries,^1,2 and of all its potential ocular manifestations, keratitis occurs most frequently.³ People who are immunosuppressed may be more susceptible to HSV keratitis; however, the epidemiology of the virus is such that the majority of patients we see with this condition are otherwise perfectly healthy. Any individual who has been colonized with HSV is at risk of having the virus reactivate from its dormant state in the trigeminal ganglion (or possibly the cornea itself) and migrate to the eye.

When the virus migrates to the corneal nerves, it typically produces a dendritic ulcer in the corneal epithelium. This linear, branching abnormality has an unmistakable appearance at the slit lamp and is brilliantly displayed with use of a vital dye (Figure 1). Dendritic ulcers are almost never caused by anything other than herpes virus, and particularly herpes simplex virus; therefore, when they are present, a diagnosis of HSV keratitis can generally be made with a high level of confidence.

Initial corneal HSV infections may be limited to the epithelium, but recurrences are likely to affect deeper layers of the cornea, increasing the risk for vision-threatening scarring and the need for penetrating keratoplasty.⁴ Because the extent of scarring is cumulative, the goals of therapy are to promptly eradicate the acute infection and to take steps to prevent recurrence. To meet both goals, I use minimal wiping debridement (MWD), a topical antiviral agent and, in many cases, long-term oral antiviral therapy.

Debridement and a Topical Antiviral Agent

My first step in treating acute HSV keratitis is to perform MWD. The physical removal of infected cells serves to limit the scope of the infection and the immune inflammatory response to it. I anesthetize the cornea and, using a dry cotton-tipped applicator, wipe off as many cells as I can, staining with lissamine green or with rose Bengal, as possible.

After MWD, I start the patient on a topical antiviral agent. Until recently, the only topical antiviral agent approved by the FDA for treatment of HSV keratitis in the United States was trifluridine 1%. Trifluridine is effective against HSV keratitis; however, its mechanism of action is nonselective. As a result, it is toxic to healthy cells.⁵ Also, trifluridine contains the preservative thimerosal, to which many patients have an allergic sensitivity.⁶

Figure 1. The dendritic ulcer has an unmistakable appearance at the slit lamp.

In 2009, the FDA approved another option for topical antiviral therapy, ganciclovir ophthalmic gel 0.15% (Zirgan, Bausch + Lomb). Zirgan is indicated for the treatment of acute herpetic keratitis (dendritic ulcers). It is designed to work selectively by specifically targeting HSV-infected cells. Zirgan is a prodrug that is phosphorolated primarily by virally infected cells. When viral enzymes activate Zirgan, it inhibits the synthesis of viral DNA in two ways:

1. Competitive inhibition—activated ganciclovir directly inhibits viral DNA polymerase, preventing viral replication

2. Chain termination—activated ganciclovir incorporates into viral DNA, preventing DNA synthesis.

In clinical studies, Zirgan gel was shown to be non-inferior to acyclovir ophthalmic ointment 3% (not available in the United States) in patients with dendritic corneal ulcers. In an open-label, randomized, controlled, multicenter trial involving 164 patients, clinical resolution (healed ulcers) at day 7 was achieved in 77% of cases (55/71) with Zirgan compared with 72% of cases (48/67) with acyclovir.⁷ In three randomized, single-masked, controlled, multicenter trials involving a total of 213 patients, clinical resolution at day 7 was achieved in 72% of cases (41/57) with Zirgan compared with 69% of cases (34/49) with acyclovir.^8-11 Clinical trial results also indicated patients tolerated Zirgan well. In rating tolerability, 75% of patients reported it to be “excellent,” and 97% reported it to be “good” or “excellent.”¹²

In contrast to trifluridine, Zirgan is preserved with benzalkonium chloride (BAK) rather than thimerosal. While BAK has been shown to cause low-grade toxicity to ocular surface cells, this typically occurs only after long-term and frequent use of ophthalmic medications, as might be required by patients with glaucoma. In addition, the recommended dosing for Zirgan is less burdensome for patients. Zirgan is labeled for application 5 times per day until the ulcer heals, and then 3 times per day for 7 days. The trifluridine label advises 1 drop every 2 hours while awake for a maximum daily dosage of 9 drops. It further recommends treatment for an additional 7 days once the corneal ulcer has re-epithelialized, 1 drop every 4 hours while awake for a minimum dosage of 5 drops per day.

Given its profile compared with trifluridines, Zirgan is currently my preferred topical agent for treating HSV keratitis. Rather than tapering, I prescribe application 5 times per day, typically for a 10- or 14-day course, until based on the clinical examination, I no longer suspect live virus is still present. Dendritic ulcers are obvious to see and it is similarly obvious when they are gone. Residual epithelial irregularities, the so-called dendrite ghost, can sometimes remain at the Bowman's or basement membrane level, but staining with a vital dye alleviates any doubt as to complete healing. I prefer to use lissamine green, which I think provides better visualization than other dyes. Also, it stains infected epithelial cells in a particular pattern. A palisade of stained cells, much like soldiers lined up on the field of battle, is seen. If the pattern is less precise or random or splotchy, it usually indicates a condition that is caused by something other than active virus.

When prescribing Zirgan, I emphasize to patients that they should not wear contact lenses during treatment. (See also “Important Risk Information for Ganciclovir Ophthalmic Gel 0.15%,” below.)

Oral Therapy

One can make the argument that when a patient has his or her first episode of HSV keratitis, treating with Zirgan is good medical practice and chronic oral antiviral therapy is not necessary. While I do not object to that, my priorities are to eliminate the acute infection decrease the risk of recurrence. Therefore, I base my approach on years of clinical experience and what I would want if I were the patient. Therefore, I prefer the three-pronged approach of MWD, Zirgan and long-term oral therapy. I apprise my patients of this and educate them on the pros and cons, but leave the decision to them. However, should they have a second recurrence, I advocate much more strongly for the addition of chronic oral therapy.

Neal Barney, MD, and I published on the potential of long-term oral therapy to reduce the rate of recurrence of HSV keratitis.^13,14 The National Eye Institute subsequently conducted the Herpetic Eye Disease Study (HEDS). HEDS found that long-term suppressive therapy with oral acyclovir reduces the rate of recurrent HSV epithelial keratitis and stromal keratitis.¹⁵

The recommendation from HEDS was that appropriate patients should take 400 mg of acyclovir twice daily. I have modified that in my practice in the interest of fostering better patient compliance and based upon my experience in this matter. I prescribe one 800-mg tablet per day, to be taken with breakfast. Also, patients in HEDS were evaluated after 12 months of oral therapy. In my practice, I treat with oral acyclovir in an open-ended mode, taking my cue from dermatologists who have treated patients with recurrent genital herpes for many, many years with oral acyclovir.

Final Thoughts

Ophthalmologists outside the United States have had Zirgan available to them since 1995, and it continues to be a key weapon in their armamentarium, as it is in mine.

HSV infection can affect ocular structures other than the cornea, causing conjunctivitis, episcleritis, scleritis, uveitis and retinitis. When this occurs, making a correct diagnosis can be difficult. Quite some time can pass without the presence of any confirmatory clinical diagnostic features. For example, a patient may have a small localized area of recurrent scleritis, and in the absence of any diagnostic features such as a dendritic ulcer on the overlying conjunctiva, the ophthalmologist may label the condition idiopathic and treat with steroids. What then becomes a relapsing, remitting anterior segment inflammatory problem may be sorted out only when the area is biopsied and either immunohisto-chemistry or polymerase chain reaction analysis is employed and reveals herpes in the tissue. Similarly, if HSV migrates to the uveal tract, it will eventually create patches of missing iris pigment epithelium. These defects have very few causes other than HSV and varicella zoster, and they are visible if the retroillumination technique is employed.

When we are faced with these types of recurring problems, we can place the patient on oral antiviral therapy. If the signs and symptoms resolve, we have a circumstantial indication that herpes is the culprit. Remembering to consider herpes infection as part of the differential diagnosis in perplexing cases is always prudent.

References

1. Liesegang TJ. Herpes simplex virus epidemiology and ocular importance. Cornea 2001;20(1):1-13.
2. Liesegang TJ, Melton LJd, Daly PJ, et al. Epidemiology of ocular herpes simplex. Incidence in Rochester, Minn, 1950 through 1982. Arch Ophthalmol 1989;107:1155-1159.
3. Wilhelmus KR. The treatment of herpes simplex virus epithelial keratitis. Trans Am Ophthalmol Soc 2000;98:505-532.
4. Tabbara KF, Noorjehan AB. Topical ganciclovir in the treatment of acute herpetic keratitis. Clin Ophthalmol 2010;4:905-912.
5. Villarreal EC. Current and potential therapies for the treatment of herpes virus infections. Prog Drug Res 2003;60:263-307.
6. Hong J, Bielory L. Allergy to ophthalmic preservatives. Curr Opin Allergy Clin Immunol 2009;9(5):447-453.
7. Colin J, Hoh HB, Easty DL, et al. Ganciclovir ophthalmic gel (Virgan 0.15%) in the treatment of herpes simplex keratitis. Cornea 1997;16(4):393-399.
8. Hoh HB, Hurley C, Claoue C, et al. Randomised trial of ganciclovir and acyclovir in the treatment of herpes simplex dendritic keratitis: a multicentre study. Br J Ophthalmol 1996;80:140-143.
9. Transphyto. Etude Clinique comparative multicentrique de l'effet de l'instillation de GV 550 dans l'herpès cornéen superficiel. Clermon-Ferrand. France: Rapport Clinique No 42-2.GV 550/02.90;1993. Dossier d'AMM.
10. Transphyto. Etude Clinique comparative multicentrique de l'effet de l'instillation de GV 550 dans l'herpès cornéen superficiel. Clermon-Ferrand. France: Rapport Clinique No 44.GV 550/12.90-46.GV 550/07.90;1993. Dossier d'AMM.
11. Transphyto. Etude Clinique comparative randomisée en simple insu de l'effet de l'instillation de ganciclovir gel ophtalmique dans le traitement de l'herpès cornéen superficiel. Clermont-Ferrand. France: Rapport clinique No 47.GV 550/09.90;1993. Dossier d'AMM.
12. Transphyto. Etude multicentrique comparative de l'effet de l'instillation de VIR-GAN dans l'herpès cornéen superficiel. Clermont-Ferrand. France: Rapport Clinique No 64GV 550/04.92-66GV 550/06.92;1994. Dossier d'AMM
13. Foster CS, Barney NP. Systemic acyclovir and penetrating keratoplasty for herpes simplex keratitis. Documenta Ophthalmologica 1992;80:363-369.
14. Barney NP, Foster CS. A prospective randomized trial of oral acyclovir following penetrating keratoplasty for herpes simplex keratitis. Cornea 1994;13:232-236.
15. Herpetic Eye Disease Study Group. Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis. Arch Ophthalmol 2000;118(8):1030-1036.

C. Stephen Foster, MD, is a clinical professor in the Department of Ophthalmology at Harvard Medical School. He created the Ocular Immunology and Uveitis Service at the Massachusetts Eye and Ear Infirmary and he directs an ocular research laboratory at the Massachusetts Eye Research and Surgery Institution. He teaches cataract, corneal microsurgery and vitreal surgery for inflammatory eye disease and can be reached at sfoster@mersi.com or (617) 621-6377.