THE TREATMENT OF HERPES SIMPLEX VIRUS EPITHELIAL KERATITIS BY Kirk R. Wilhelmus, MD, MPH ABSTRACT Purpose: Epithelial keratitis is the most common presentation of ocular infection by herpes simplex virus (HSV). Quantitative assessment of available therapy is needed to guide evidence-based ophthalmology. This study aimed to compare the efficacy of various treatments for dendritic or geographic HSV epithelial keratitis and to evaluate the role of various clinical characteristics on epithelial healing. Methods: Following a systematic review of the literature, information from clinical trials of HSV dendritic or geographic epithelial keratitis was extracted, and the methodological quality of each study was scored. Methods of epithelial cau- terization and curettage were grouped as relatively equivalent physicochemical therapy, and solution and ointment for- mulations of a given topical antiviral agent were combined. The proportion healed with 1 week of therapy, a scheduled follow-up day that approximated the average time of resolution with antiviral therapy, was selected as the primary out- come based on a masked evaluation of maximum treatment differences in published healing curves. The proportion healed at 14 days was recorded as supplemental information. Fixed-effects and random-effects meta-analysis models were used to obtain summary estimates by pooling results from comparative treatment trials. Hypotheses about which prognostic factors might affect epithelial healing during antiviral therapy were developed by multivariate analysis of the Herpetic Eye Disease Study dataset. Results: After excluding 48 duplicate reports, 14 nonrandomized studies, 15 studies with outdated or similar treatments, and 29 trials lacking sufficient data on healing or accessibility, 76 primary reports were identified. These reports involved 4,251 patients allocated to 93 treatment comparisons of dendritic epithelial keratitis in 28 categories and 9 comparisons of geographic epithelial keratitis in 6 categories. For dendritic keratitis, idoxuridine was better than place- bo at 7 days (combined odds ratio [OR], 3.59; 95% confidence interval [CI], 1.92-6.70), and at 14 days (OR, 4.17; 95% CI, 1.33-13.04), but pooling was limited by lack of homogeneity and low study quality. Direct comparisons at 1 week of treatment showed that trifluridine or acyclovir was significantly better than idoxuridine (OR, 3.12 and 4.56; 95% CI, 1.55-6.29 and 2.76-7.52, respectively), and indirect comparisons were also consistent with a clinically significant bene- fit. Vidarabine was not significantly better than idoxuridine in pooled treatment comparisons at 1 week (OR, 1.20; 95% CI, 0.72-2.00) but was better in 2 indirect comparisons (OR, 4.22 and 4.78; 95% CI, 1.69-10.54 and 2.15-10.65, respec- tively). At 14 days, trifluridine (OR, 6.05; 95% CI, 2.50-14.66), acyclovir (OR, 2.88; 95% CI, 1.39-4.78), and vidarabine (OR, 1.24; 95% CI, 0.65-2.37) were each better than idoxuridine. Trials of geographic epithelial keratitis also suggest- ed that trifluridine, acyclovir, and vidarabine were more effective that idoxuridine. Other topical antiviral agents, such as bromovinyldeoxuridine, ganciclovir, and foscarnet, appeared equivalent to trifluridine or acyclovir. Oral acyclovir was equivalent to topical antiviral therapy and did not hasten healing when used in combination with topical treatment. Antiviral agents did not increase the speed of healing when compared to debridement but reduced the risk of recrude- scent epithelial keratitis. The combination of physicochemical treatment with an antiviral agent seemed to be better than either physicochemical or antiviral treatment alone, but the heterogeneous cauterization and curettage techniques and the various treatment combinations limited valid quantitative summary effect measures. The combination of topi- cal interferon with an antiviral agent was significantly better than antiviral therapy at 7 days (OR, 13.49; 95% CI, 7.39- 24.61) but not at 14 days (OR, 2.36; 95% CI, 0.82-6.79). Finding apparent heterogeneity for some pooled estimates suggested that dissimilarities in patients, interventions, outcomes, or other logistical aspects of clinical trials occur across studies. Conclusions: The available evidence on the acute treatment of presumed HSV epithelial keratitis demonstrates the ° From the Department of Ophthalmology, Baylor College of Medicine, Houston. Supported by a Clinical Investigator Award (EY00377), cooperative agreement (EY09696), and core grant (EY02520) from the National Eye Institute; a Senior Scientific Investigator award from the Research to Prevent Blindness, Inc; and the Sid Richardson Foundation. Tr. Am. Ophth. Soc. Vol. 98, 2000 505 WVilhelmus effectiveness of antiviral treatment and shows the log-logistic healing curve of treated dendritic epithelial keratitis. Topical trifluridine, acyclovir, and vidarabine were significantly more effective than idoxuridine but similar in relative effectiveness for dendritic epithelial keratitis. Physicochemical methods of removing infected corneal epithelium are effective, but adjunctive virucidal agents are needed to avert recrudescent epithelial keratitis. Whether debridement in combination with antiviral therapy is more beneficial than antiviral chemotherapy alone appears likely but remains inconclusive. The combination of topical interferon with an antiviral agent significantly speeds epithelial healing. Future trials of the acute treatment of HSV epithelial keratitis must aim to achieve adequate statistical power for assess- ing the primary outcome and should consider the effect of lesion size and other characteristics on treatment response. Tr Am Ophth Soc 2000;98:505-532 INTRODUCTION epithelial keratitis was reported by Kipp in 1880:8 Herpes simplex virus (HSV) is an important cause ofinfec- If the eye is examined shortly after the first symptoms of tious eye disease.' Epidemiologic data indicate a preva- irritation are noticed by the patient, 1 or 2 or more slightly lence of a history of ocular HSV disease in 149 people per raised, irregular, opaque lines of varying length will be found on 100,000 in a American city different parts of the surface of the cornea....On the following population North (95% confi- day these opaque lines have increased somewhat in length, dence interval [CI] of 115 to 183 per 100,000) and an inci- whilst at the same time the middle portion of the opacity has dence of 21 new and recurrent episodes per 100,000 per- been transformed into a shallow ulcer....[N]ot infrequently the son-years (95% CI of 18 to 23 episodes per 100,000 per- ulcer continues for days, and even weeks, to grow slowly in son-years).2 Over 400,000 Americans are estimated to have length, and at the same time sends out club-shaped, slightly sustained ocular HSV disease, and approximately 50,000 raised, grayish offshoots from its sides. In some of my cases the cases are predicted to occur annually in the United States. ulcer crept across the entire cornea.... Epithelial keratitis is the most common form of ocular HSV disease, accounting for approximately 80% of all In 1884, Grut9 introduced the term "dendrite" to cases.2 Dendritic epithelial keratitis, a branching pattern of describe the typical branching or zigzag shape, and epithelial infection and erosion, is the most common and Emmert"' published the first drawings of dendrites the fol- nearly pathognomonic form of HSV infection of the eye. lowing year. Coalescence ofpunctate herpetic keratitis was surmised to produce a dendritic figure." Various morpho- HISTORICAL BACKGROUND logic types were identified, including stellate,'2 multifocal, and limbal forms. Striate irregularities and epithelial ero- The recognition of dendritic keratitis emerged in early sions occasionally altered the linear pattern.'3 An irregular, medicine. A 10th-century manuscript that classified map-shaped geographic (formerly amoeboid) epithelial corneal diseases stated that "the fourth variety, found in keratitis was reported to be a consequence of progressive the outer zone of the cornea, is called.. branch-like, epithelial disease."' Staining with fluorescein and other because it resembles the ramification of a shrub."3 These dyes improved visibility'4"15 and had a weak antiviral effect.'6 distinctive features, however, were rarely mentioned in The typical topographic pattern of dendritic epithelial medieval writings. Eighteenth-century texts apparently keratitis enticed ophthalmologists. Animal experiments grouped herpetic keratitis with other types of ophthalmia showed that the dendrite's fractal geometry'7 probably or corneal ulcers.4 Its unique appearance was not widely results from intercellular spread and cytopathic effects of accepted until the 19th century. the virus, modified by the subbasal neural plexus under In 1808, Wardrop5 described a unilateral corneal the corneal epithelium, local cellular susceptibility to inflammation "accompanied with the sensation of a mote infection,'8 and reparative epithelial movement.'9 in the eye" that resembled "the small pustules, or aphthx, Clinical2" and pathological2' observations confirmed that as they are called, which are so frequently observed in the multifocal viral infection of the deep corneal epithelium cavity of the mouth, on the tongue [and] lips." He noted leads to successive stages that form a dendritic figure with that the ocular lesion would heal then recur, especially if surface ulceration. Viral spread during ill-timed corticos- triggered by cold air. MacKenzie' also mentioned