EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.
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50 EW CORNEA May 2012 Pharmaceutical focus Going viral: First-line treatment for HSV keratitis by Maxine Lipner Senior EyeWorld Contributing Editor What agents practitioners are turning to H erpes simplex virus (HSV) keratitis is probably one of the leading causes of corneal blindness in developed countries, according to Terrence P. O'Brien, M.D., professor of ophthalmology, Bascom Palmer Eye Institute, Uni- versity of Miami Miller School of Medicine."It's a highly prevalent condition that affects thousands of people throughout the United States each year," he said. So what are prac- titioners reaching for here? This is what EyeWorld found. Edging out epithelial keratitis There are three different forms of HSV keratitis. "The principle forms are epithelial, stromal, and then there may be intraocular or endothe- liitis, sometimes called keratou- veitis," Dr. O'Brien said. "The most common form is epithelial keratitis." Minimal wiping debridement followed by the use of a topical an- tiviral has been at the heart of treat- ment. "Over time that involved trifluridine [Viroptic, GlaxoSmith- Kline, Middlesex, England], which is an agent that is used eight or nine times a day—roughly every 2 hours while awake until there is a resolu- tion," Dr. O'Brien said. "It's a heavy dosing frequency and long treat- ment duration." The drug has evolved by default as the leading antiviral in the U.S. marketplace. "It was the survivor to some of the earlier generation an- tivirals such as idoxuridine [Stoxil, GlaxoSmithKline] or vidarabine [Vira-A, Monarch Pharmaceuticals, Bristol, Tenn.]," Dr. O'Brien said. "Those went off the market due to excessive toxicity and borderline efficacy." Meanwhile, he pointed out that one product, acyclovir ointment, the standard in Europe and Asia for treating epithelial keratitis, re- mained off U.S. shelves. "This was in part because the maker of the oint- ment was the same maker of trifluri- dine so it didn't want to compete against its own market leader," Dr. O'Brien said. "So trifluridine evolved as the first-line therapy after mini- mal wiping debridement." Unfortunately, there has been a downside to this. "The problem that many clinicians noted was that the very frequent application and the necessity of a long treatment dura- tion led to common toxicity with keratoconjunctivitis that often would prolong the course of the keratitis or exacerbate this," Dr. O'Brien said. Part of the toxicity, in addition to the drug being a non-se- lective antiviral agent, was likely the thimerosal preservative in the tri- fluridine. "Thimerosal was particu- larly toxic especially when administered every couple of hours as was required," Dr. O'Brien said. Because of all this some clini- cians began to look for alternatives including oral antiviral agents. "Oral acyclovir [various manufacturers], oral famciclovir [Famvir, Novartis Pharmaceuticals, Basel, Switzerland], and oral valacyclovir [Valtrex, GlaxoSmithKline] were frequently used especially in people who had other comorbid conditions such as dry eye, blepharitis, and ocular sur- face disease to try to reduce the toxi- city of the topical trifluridine," he said. This, however, came with its own difficulties. "The problem is in order to get a sufficiently high con- centration of the antiviral in the tear film we need to dose with fairly high systemic doses, and these agents can cause systemic adverse reactions including hepatotoxicity and, less commonly, renal toxicity," Dr. O'Brien said. That's why he sees an alterna- tive antiviral medication, Zirgan (ganciclovir, Bausch + Lomb, Rochester, N.Y.), as a welcome addi- tion to the U.S. market. "This is a selective antiviral in that it targets only those cells infected by virus as opposed to human as well as viral- infected cells," Dr. O'Brien said. "It's a more selective agent, therefore it has less cytotoxicity." He pointed out that the ganciclovir gel formula- tion seems to be somewhat sooth- ing. "It may have some effect in promoting surface healing via a mechanism other than the antiviral mechanism," he said. "So this agent has gained widespread acceptance." Zirgan can also be dosed less fre- quently—just five times a day for 1 week as opposed to eight or nine times for trifluridine. Stromal keratitis strategies When it came to stromal keratitis, oral agents were at the hub of treatment, according to John D. Sheppard, M.D., professor of oph- thalmology, microbiology, and mo- lecular biology, Eastern Virginia Medical School, Norfolk, Va. "Stro- mal disease implies a deeper involve- ment and characteristically involves scars, haze, and ectasia," Dr. Sheppard said. "The characteristic ectatic or thinning pattern of stro- mal herpes is an accelerated poste- rior float—the posterior surface of the affected area is steeper and thus the thinning occurs from within." When stromal herpes involves the visual axis it can be visually debili- tating. "Each subsequent occurrence further compromises the vision and induces more thinning, more scar- ring, and the ingrowth of more blood vessels," he said. "The entire strategy for stromal herpetic disease is to prevent recurrences." The drug of choice for many years for stromal herpetic keratitis prevention was acyclovir. "Acyclovir is a great drug, it's inexpensive, it was generic, but we had to use a high dose for an outbreak—as much as 400-800 milligrams five times a day," Dr. Sheppard said. He also found the highly variable dose to be somewhat difficult. "Acyclovir is not a pro-drug and has a highly variable GI absorption rate," he said. "So one patient given 400 milligrams has a high blood level and another patient given exactly the same 400 mg dose may have a very low blood level." Dr. Sheppard saw the advent of the pro-drug Valtrex as a welcome addition. "Valtrex is basically the same drug in the blood stream but at much more reliable concentrations," he said. One downside was that until 2 years ago this was an expen- sive medication that would cost HSV keratitis (pictured here) affects thousands of people in the U.S. each year Source: Edward J. Holland, M.D.