The Treatment of Herpes Simplex Virus Epithelial Keratitis

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 cauterization and curettage were grouped as relatively equivalent physicochemical therapy, and solution and ointment formulations 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 outcome 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 Results: After excluding 48 duplicate reports, 14 nonrandomized studies, 15 studies with outdated or similar treatments, and 29 trials lacking sufficient data on healing or accessibility, 76 primary reports were identified.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 placebo 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 benefit. 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, respectively). 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 suggested 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 recrudescent 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 topical 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 assessing 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 in 1830 teroid use permits an expanding round pattern of geo- a peculiar ulcer that "spreads over the surface, rarely graphic epithelial keratitis. penetrating deeply into the substance of the cornea." With its clinical recognition, the pathogenesis of den- Horner, in 1871, was the first to link punctate epithelial dritic keratitis was variably attributed to a systemic illness keratitis with primary vesicular eruptions of the nose, such as malaria or influenza or to a neurogenic disorder. mouith, and face. The arborescent pattern of recurrent By 1920, Griiter22 demonstrated that dendritic keratitis

506 The Treatment ofHerpes Simplex Virus Epithelial Keratitis was due to a transmissible agent by transferring the infec- found to be helpful in "the small sordid sores..., which tion from an infected human eye to the rabbit cornea and take place upon the internal surface of the lips, the tip of subsequently inoculating a human cornea with material the tongue, the nipples, and the glans penis," was also used from a rabbit's experimental corneal infection. Herpes for treating corneal ulcers.?4 Various cauterizing and curet- simplex virus type 1 is established as the cause for nearly tage methods (Table I) have been commonly used.26-28 all cases of dendritic epithelial keratitis. Anesthetics and patching were also recommended by oph- Ocular disease is related to viral virulence and to host thalmic textbooks at the beginning of the 20th century. susceptibility. Factors such as fever and ocular trauma Topical corticosteroids, introduced in 1950, were found to were incriminated as predisposing to recurrences during worsen corneal destruction when administered during Griiter's experiments."3 During and after World War II, active epithelial keratitis.2' Antimetabolites were then clinical experience suggested that febrile illnesses, sun screened for potential clinical use.3" exposure, ocular injury, certain forms of stress, and other In 1962, Kaufinan3' reported the successful use ofidox- exogenous and endogenous stimuli could trigger recur- uridine in HSV epithelial keratitis. The potential impact of rent HSV epithelial keratitis. The prospective Herpetic idoxuridine was considered so important that an ophthal- Eye Disease Study indicates the multifactorial and uncer- mological journal announced the findings32 4 months before tain nature of various recurrence-enhancing factors. publishing the experimental animal data33 and 7 months before the first clinical series.?4 Idoxuridine's success led to EMERGENCE OF OPHTHALMIC ANTIVIRAL THERAPY the development of other pyrimidine and purine ana- logues,,v such as vidarabine36 and trifluridine.37'8 These anti- Treatment ofdendritic keratitis was initially based on anec- herpetic nucleosides were found to undergo phosphoryla- dotal experience.24 Bloodletting, purgatives, and poultices tion by cellular kinases to form nucleoside triphosphates were used for centuries. Cauterization with silver nitrate, that bind to virally encoded DNA polymerase and other

TABLE I: PROPOSED TREATMENTS FOR HSV EPITHELIAL KERATITIS BEFORE THE ANTIVIRAL ERA* Physical Methods of Curettage Radioactive cobalt Cryoapplication, with or without mechanical debridemiient Radioactive strontiutm Mechanical debridement with swab, inetallic instrnmment, or corn-eal Shortvaves impression T Ultraviolet light, wvithout or with dyes Thermocauiterization with electrocautery, steam cautery, or diatlhermy Visible light X-ravs Chemical Cauterizing or De-epithelializing Agents Chlorinated water Photoreactive Dyes Chromic acid Flulorescein Cupric sulfate Methylene blue Ethanol Neutral red Ether Proflavine Formalin Rose bengal Hydrogen peroxide Scarlet red Iodine, potassiu-m iodide, sodium iodide, and/or ethyliodide in alcohol or water solution or as vapor Enzymes Lactic acid Chymotrypsin or try'sin Para-aminobeinzene Hyaltironidase Phenol (carbolic acid) Riboniuclease Silver nitrate (Ilunar caustic) Trichloroacetic acid Antimetabolic Agents Turpentine Actinomycin Urea Benzylbenzimidazole Puiromycin Surgery Carbocyclic oxetanocin CG Argon laser Cytarabine Conjunctival flHp Diphenvlsulfonie Corneal incision Ethioniine Keratocentesis Ethyldeoxyiridiine Massage Florenal Tarsorrhaphy Fltiorodeoxvuridine Glucosamine Radiation Iododeoxycytidine Electric current 5-Mercaptouracil

507 Wilhelmus

TABLE I (CONTINUED): PROPOSED TREATMENTS FOR HSV EPITHELIAL KERATITIS* Methisoprinol Zinc sulfate Methylaminodeoxyuridine Oxymethylmethyluracil Antibiotics Parafluorophenylalanine Chloramphenicol Propyldeoxyuridine Chlortetracycline Reticulose Cycloserine Riboazauracil Lysozyme Riodoxolate Neomycin Tromantadine Optochin Tyrothricin Oxolinic acid Penicillin Antiseptics and Other Chemical Agents Streptomycin Acetyl cysteine Sulfadiazine Bismuth tribromophenate Tetracycline Boric acid and boroglycerin solutions Viomycin Calomel dust Catgut Systemic Agents Citral Amphetamine Cupric sulfate solution Antibiotics and antivirals Epinephrine Autoinoculation of corneal isolate Ergotamine and dihydroergotamine Bee venom Ethoxyphenylphenacylaminobenzoic acid Benzylbenzimidazone Formyltriiodide Brewer's yeast Gamma globulin, IgG, or Fab fragment Campolon Glutathione Cowpox, smallpox, and typhoid vaccines Heparin solution Growth hormone Hydroxyethylbiguanide Isoprinosine Leukocyte extract Lactoflavin Mercuric ammonium chloride Levamisole Mercuric oxide Liver extract Mercurochrome (merbromin) Milk injection Methylsalicylate Panthesine Placental extract Quinacrine Polyinosinic-polycycytidylate Snake venom toxoid Procaine and other anaesthetics Sodium bicarbonate Quinine bisulfate Sodium iodide Silver nitrate and silver protein solutions Thymostimulin Strychnine Transfer factor Tocopherol Uric acid Undecylenic acid Vitamins A, Bi, B6, B12,C, D, niacin, riboflavin, and paraaminobenzoate Xenalazone Xenalamine Zinc oxide Whole blood injection * Treatments were reported to be potentially beneficial in 1 or more case reports or clinical series in the 20th century but have not been adequately assessed for efficacy or safety in clinical trials f Mechanical debridement has been used with the application of acetone, iodine, ether, formol, phenol, cupric sulfate, zinc sulfate, silver nitrate, and mercuric chloride solutions; with gamma globulin; and with parafluorophenylalanine and other antiviral agents. enzymes. Acyclovir was subsequently developed to be debridement methods, and the role of interferon. selectively activated in virus-infected cells by virally Many clinical trials have been performed on the acute induced thymidine kinase and to selectively inhibit viral treatment of dendritic epithelial keratitis. Surveys of antivi- DNA polymerase.3940 While idoxuridine was removed ral pharmacology and of HSV eye disease have evaluated from the marketplace in several countries in the early different commercially available agents, but a systematic 1990s because of low demand, vidarabine, trifluridine, review of all comparative clinical studies has not and acyclovir are in widespread use for the treatment of previously been undertaken. Ad hoc power calculations HSV epithelial keratitis. Ganciclovir, foscarnet, bro- suggest that many trials reporting no statistically movinyldeoxyuridine, cidofovir, and other drugs are under significant difference between treatments were too small to clinical investigation. Controversies persist, however, detect an anticipated effect size. This meta-analysis about the optimal antiviral agent, the effectiveness of attempted to compile all randomized trials on the therapy

508 The Treatment of Herpes Simplex Virus Epithelial Keratitis of HSV epithelial keratitis and to present objective summa- ["cornea" or "keratitis" "dendrite or "dendritic"], using a ry effect measures that would enable evidence-based deci- search strategy to identify controlled trials.42 The Cochrane sion making4' in the management ofocular HSV disease. In Controlled Trials Register, the indices of Ophthalmic addition, the largest trial of HSV epithelial keratitis, per- Literature, and the reference lists of primary reports, formed by the Herpetic Eye Disease Study Group, was review articles, and corneal textbooks were searched for used to evaluate prognostic factors affecting comeal epithe- additional relevant articles. Abstracts of meetings of the lial healing during antiviral therapy of dendritic keratitis. Association for Research in Vision and Ophthalmology, the American Academy of Ophthalmology, the Ocular METHODS Microbiology and Immunology Group, and the International Conference on Herpetic Eye Diseases were SEARCH STRATEGY reviewed for clinical studies of herpetic keratitis. Retrieved articles were copied and translated as need- Studies were selected according to the scheme outlined in ed. The following criteria were applied to select studies for Fig 1. Articles were identified by manually searching Index inclusion in the meta-analysis: concurrent enrollment into Medicus from 1960 through 1965 and Excerpta Medica 2 or more treatment groups, original data, enrollment cri- Ophthalmology from 1960 to 1973 and by conducting teria specifying active HSV epithelial keratitis, outcome computerized searches of MEDLINE from 1966 through assessment by slit-lamp biomicroscopy, and data available 1999 and of EMBASE from 1974 through 1999, without for the proportions healed at 7 or 14 days after trial entry. language restrictions. Electronic searching used the text The study population was restricted to patients with active words ["herpes", "herpetic" or "simplex"] combined with dendritic, dendrogeographic, or geographic epithelial keratitis; studies ofpatients with stromal keratitis were excluded ifepithelial keratitis was not present. Therapeutic inter- Electronic searching Abstracts from Bibliographic using key words and meetings and citations from ventions included placebo, physical debridement, chemi- delimiters for clinical conference textbooks and reports of HSV keratitis proceedings screened papers cal cauterization, topical ophthalmic antiviral agents, or oral antiviral agents. The outcome was the proportion Titles and available abstracts screened for resolved within the immediate follow-up period after study clinical studies of HSV epithelial entry. For multiple publications using all or part of the keratitis same study population, the most detailed study reporting

Papers copied and the largest sample was selected. reviewed DATA ABSTRACTION Reports based on inadequate Reports of randomized clinical data, nonconcurrent allocation, trials accepted or irrelevant treatments Data extraction used a predetermined protocol and profor- excluded .~~~~~~~~~~~~~~~~~~~~~~~~ ma but was not masked. Data were abstracted from the full articles to describe the population, the method oftreatment Data extracted and study quality scored Duplicate reports identified allocation, any cointerventions or adjunctive treatment, and the examination method used to diagnose healing. Specific information extracted from published Similar treatment groups Blinded comparison reports included year and language of report, country combined within trials [ of healing curves where each trial was performed, authorship and biostatistical collaboration, number of centers, form of epithelial

Odds ratios and risk keratitis, range and distribution of patient age and sex, differences, with confidence limits, of individual treatment method of outcome assessment, study treatments and comparisons number allocated to each treatment group, concomitant medications, cumulative number healed on follow-up Homogeneity assessment and summary effect measures for days, and any evaluated effect of baseline variables on direct and indirect treatment comparisons healing. The formulation, concentration, and frequency were noted for all study treatments. When possible, Interpretation of available evidence dosage forms were grouped together for a given treatment for analyses. For example, idoxuridine solution and idox- FIGURE 1 uridine ointment were combined in the summary tables. Flow chart of process used to identify, extract, and analyze relevant data from published randomized clinical trials evaluating herpes simplex In addition, while studies with n treatment groups could virus (HSV) epithelial keratitis. contribute up to n!/[2(n-2)!] treatment comparisons,

509 \Vilheltiis treatment groups were commingled when the 2 treat- 2000) and graphically displayed with Intercooled Stata 6.0 ments were considered sufficiently similar in biological (Stata Corporation, College Station, Tex, 1999).5° Analyses type and effect. for estimating a summary effect measure were based on a Informiiation from all patients was extracted for trials fixed-effects model using a variance-based method51 for that enrolled patients with either dendritic or geographic homogeneouis comparisons and on the DerSimonian- epithelial keratitis. Data from trials enrolling excluisively Laird random-effects model for direct comparisons show- geographic epithelial keratitis were evaluated separately. ing statistical heterogeneity. Under a null hypothesis of no Data for patients with only geographic epithelial keratitis association, the variation between trials was assessed by a were also recorded separately when the published report chi-square test for homogeneity. P values less than 0.10 provided this suibset of information. were considered to indicate heterogeneity. An overall study quality score from 0 to 100, using 28 categories of internal validity components pertaining to Indirect Comlparisons stuidy design, analysis, and presentation,43 was based on Despite the large number of clinical trials performed on the methodology provided in the published report. Power HSV epithelial keratitis, the multiple combinations ofvar- was estimated for published trials using the reported pro- ious treatments resulted in little data directly comparing portions healed at 7 days, an alpha of 0.05, and no conti- single antiviral agents against a placebo or a common con- nuity correction. " trol. Instead of pooling data into a biased aggregate from multiple studies, indirect comparisons were used to eval- OUTCOME MEASURE uate treatment effects across studies. Indirect comparisons between treatments that were compared to a com- The principal time point for comparison was chosen by a mon treatment were made by estimating a summary OR preanalysis review in which an independent reviewer eval- as the ratio of the natural logarithm of the OR from a uated all published trials that presented graphs. direct comparison to the natural logarithm ofthe OR from Treatment comuparisons were also based on the median the other direct comparison.5' Since eligibility criteria time to resolution with 95% CIs for the difference were similar for different trials, no interaction was expect- between medians estimated by a nonparametric method,45 ed between the patient subgroups and the size of the but these resuilts are not presented becauise all antiviral overall treatment effect. Thus, given trials comparing 2 treatments did not give similar healing distributions and different treatments (A and C) to a common treatment because some physical methods (eg, minimal wiping (B) and their respective Mantel-Haenszel summary odds debridement) were complicated by recrudescent epithe- ratios [ORNiHAB) and ORNIH(CB], an effect size estimate for lial infection. the indirect comparison between treatment A and treatment C was calculated. ANALYSIS RESULTS Effect Measuire Trial results were summarized as an odds ratio (OR) of The searching strategy identified 178 reports of clinical proportions healed using standard methods to estimate trials of HSV epithelial keratitis. Forty-eight duplicate confidence limits.4fi4 Most treatments of HSV epithelial reports were excluded (Table II) but were used to provide keratitis result in a high probability of healing, and the supplemental information to the primary report. Fifty- odds ratio is an appropriate ratio effect measure. Few of eight reports were excluded for methodological reasons or the published trials reviewed for this study provided rela- applicability (Table III). Seventy-six reports published tive risk estimates, so standard fourfold tables were con- between 1963 and 1997 that had a randomized or non- structed with columns for treatment groups and rows for randomized concurrent study design were retained for presence or absence of healing at a given follow-up day. A this meta-analysis. Of these reports, 53 took place in more effective treatment that accelerated healing was Europe, 13 in North America (including 1 performed in expressed as an odds ratio greater than 1. The 95% confi- the United States and Great Britain), 10 in Asia, 1 in dence limits (CL) for the odds ratio were estimated from Africa (including 1 also reporting a European trial), and 1 the variance.4" in Australia. Sixty reports were published in the English The overall measure of association for direct treat- language. Sixty-one studies took place at a single center; ment comparisons was estimated by the Mantel-Haenszel the multicenter trials involved between 2 and 60 sites. method as a weighted average of ORs from trials directly A total of 4,251 patients were reported in the 76 cita- comparing 2 treatments.49 Pooled ORs were calculated tions included in the meta-analyses. The median and with RevMan 4.1 (Update Software, Oxford, England, mean sample sizes of included studies were 50 and 57,

510 The Treatment of Herpes Simplex Virus Epithelial Keratitis

TABLE II. DUPLICATE OR PRELIMINARY REPORTS IDENTIFIED IN SYSTEMATIC REVIEW OF PUBLISHED CLINICAL TRLALS ON HSV EPITHELLAL KERATITIS

MAIN REPORT DUPLICATE REFERENCE

Colin et al, 1983"" Coliin et al, 1982111 Colin et al, 1982112 Collum et al, 1980113 Colltim and Benedict-Simith, 19801" Collomiii et al, 1982"5 Collum et al, 1986"1 Colltim et al, 1985"- Collum et al, 1985"8 Coster et al, 197669 Jones et al, 19751'19 McGill et al, 1975'120 MeKinniion et al, 1975121 Coster et al, 197792 Jones et al, 1976122 Jones et al, 19769' Coster et al, 197966 Coster et al, 197669- Coster et al, 19806O Jones et al, 19811'2 Jones et al, 1980124 de Koning et al, 1982123 de Koning et al, 1981126 de Koning et al, 198327 Graupner and Muller, 1968'" Gratipner et al, 1969129 Guerra et al, 19791"1 Guerra et al, 1970I12 Hart et al, 1965'3' Brightman et al, 19655' Hoang-Xuan et al, 1984'" Hoang-Xuan et al, 1983'3 Kitano et al, 1983'" Kitano, 1984196 La Lau et al, 1982'3 La Lao et al, 1982 13 La Lato et al, 1981'39 Luntz and MacCallum, 1963' Lointz aind MacCallutimi, 1963'"' Markham et al, 197772 Markham et al, 197914} McGill et al, 1981'42 McGill and Tormey, 1982'43 McGill et al, 1981'4 Tormey et al, 1981'45 Meurs and van Bijsterveld, 1985146 Meoirs and van Bijsterveld, 1985"1' Meoirs and vzan Bijsterveld, 1985147 Meoirs and van Bijsterveld, 198614 Patterson and Jones, 1967'49 Jonies, 1967v Pavan-Langston and Buchanan, 1976'5' Chin, 1978152 Dresner and Seamans, 1975153 Hyidiuk et al, 1975'54 Laibson et al, 1975'55 Laibson and Krachmer, 19Y7S5 Pavan-Langston, 1975'5 Pavan-Langston, 1977'" Pavan-Langston and Foster, 1977'59 Pavain-Langston, 1979"I) Pavan-Langston et al, 198116' Laibson et al, 1982162 Power et al, 1991'f3 Power et al, 1991164 Sundmacher et al, 19765i Sundmacher et al, 197695 Sundmacher et al, 1981,5 Sundmacher et al, 19781'X Sundmacher et al, 1981'16 Uchida, 1982 3 Uchida et al, 198164- Uchida, 1982167 Uchida, 1981' Yamazaki, 198461' van Bijsterveld and Post, 19807$ vani Bijsterveld and Post, 1981166 Yeakley et al, 1981169 Laibson et al, 1982162 Young et al, 198276 Yooing et al, 198276

"Not excluded because additional data included. respectively (range, 9 to 287 participants per study). None healing.53 Of the 35 reports providing average age of of the studies reported pretrial sample size estimation, enrolled patients, the median age was 47 years (range of although 1 trial did plan to enroll a certain number of average age, 33 to 56). Of the 42 trials reporting the sex of patients on the basis of an outcome other than epithelial enrolled patients, the mean male-female ratio was 2.1

511 Wilhelmus

TABLE III. CLINICAL TRLALS OF HSV EPITHELIAL KERATITIS EXCLUDED FROM META-ANALYSIS

STUDY TREATMENT GROUPS

Nonconcurrent treatment allocation Abboud, 1967170 Idoxuridine vs iodinization Bianchetti and Witmer, 196417' Idoxuridine solution vs ointment Gilkes, 1963172 Idoxuridine vs chemical cauterization Gundersen, 1936'°4 lodinization vs antiseptics Herbort et al, 1987'73 Trifluridine with or without debridement Marquardt and Roth, 1971174 Idoxuridine vs cauterization Matalia, 1987'5 Idoxuridine vs vidarabine vs trifluridine vs acyclovir Morimoto et al, 1986176 Idoxuridine vs acyclovir Reim, 1965'77 Idoxuridine vs debridement Shiota et al, 1979178 Trifluridine vs vidarabine Tommila, 1963'79 Interferon-a vs iodinization Zajacz and Kovaics, 1968180 Mechanical or thermal debridement vs placebo Zirm et al, 1981181 Trifluridine with or without debridement or immunoglobulin vs iodinization Dundarov et al, 1998182 Nigericin with interferon-a vs control Outdated treatment Graupner and Muller, 196627 Fluorophenylalanine vs idoxuridine Graupner and Muller, 1968'1 Fluorophenylalanine vs idoxuridine Graupner et al, 1969183 Fluorophenylalanine vs idoxuridine, with iodinization Matthaus et al, 1970'4 Fluorophenylalanine vs panthenol, with iodinization or cryotherapy Pietruschka, 19681' Fluorophenylalanine vs idoxuridine Yamamoto et al, 198411 Zinc sulfate vs zinc sulfate with idoxuridine Treatments sufficienily similar McGill et al, 1974187 Trifluridine solution vs trifluridine viscous solution Shiota et al, 1988188 Interferon-13 105 IU/mL vs interferon-4 101 IU/mL Sundmacher et al, 197893 Thermochemical debridement with interferon-a vs wiping debridement with interferon-a Sundmacher et al, 197894 Debridement with interferon-ao vs debridement with interferon-B Sundmacher et al, 1981166 Trifluridine with interferon-a 10 x 10' IU/ml vs trifluridine with interferon-a 30 x 106 IU/mL Sundmacher et al, 1984189 Trifluridine with interferon-at 30 x 10' IU/ml vs trifluridine with interferon-a 100 x 10' IU/mL Sundmacher et al, 1985'9° Trifluridine with interferon-a 30 x 106 IU/ml vs trifluridine with recombinant interferon-a 23 x 108 IU/mL Sundmacher et al, 1987191 Trifluridine with interferon-a vs trifluridine with interferon-,y vs trifluridine with both interferons at different concentrations Uchida, 1982167 Interferon-13 10' IU/mL vs interferon-,B 103 IU/mL

Outcome not based on epithelial healing Coster et al, 197792 Recrudescent epithelial keratitis was primary outcome (debridement with placebo or interferon-ao 11 x 106 IU/mL or interferon-a 33 x 106 IU/mL) Bianchetti and Witmer, 1964'71 Idoxuridine solution vs ointment Jones et al, 1979192 Recrudescent epithelial keratitis was primary outcome (debridement with placebo or acyclovir) Stambuk et al, 1995193 Change in peripheral blood T-lymphocytes was primary outcome (idoxuridine/acyclovir with or without thymic extract)

512 The Treatment ofHerpes Simplex Virus Epithelial Keratitis

TABLE III (CONTINUED): CLINICAL TRIALS OF HSV EPITHELIAL KERATITIS EXCLUDED FROM META-ANALYSIS

STUDY TREATMENT GROUPS Insufficient data provided* Assetto et al, 1981`94 Debridement vs idoxuridine vs cytarabine vs trifluridine vs idoxuridine with methisoprinol vs vidarabine with methisoprinol Babushkin and Malkhanov, 19931' Idoxuridine vs acyclovir Fellinger and Bartl, 1980'9 Idoxuridine with or without iodinization vs trifluridine with or without iodinization Galin et al, 197619' Idoxuridine vs poly IC (days to healing not specified) Hilsdorf and Forudastan, 1969119 Cryotherapy vs debridement Inocencio et al, 1982199 Interferon-ot vs acyclovir Jin et al, 19922° Acyclovir vs interferon inducer vs acyclovir with interferon inducer Kasparov et al, 1974201 Idoxuridine with or without poly AU vs poly AU vs placebo Kasparov et al, 1991202 Interferon-a vs acyclovir Kolomiets et al, 1986203 Immunoglobulin solutions Leopold, 1965204 Idoxuridine vs cytarabine (code not broken) Mathur and Elhence, 1984205 Physical methods with or without idoxuridine McGill et al, 1981142 Vidarabine vs acyclovir Mohan et al, 1987206 Vidarabine vs acyclovir Panda et al, 1995207 Idoxuridine vs trifluridine vs acylcovir vs bromovinyldeoxyuridine Pavan-Langston and Dohlman, 19722c8 Idoxuridine vs vidarabine Pavan-Langston and Foster, 1977159 Idoxuridine vs trifluridine Pivetti-Pezzi et al, 198529 Antiviral agent with or without thymostimulin Prost et al., 1986210 Cryotherapy with or without oral isoprinosine Scialdone et al, 1986211 Idoxuridine vs interferon-, Sellitfi et al, 1982212 Methisoprinol with or without cytarabine Shimomura et al, 1987213 Idoxuridine with or without debridement (days to healing not specified) Struck and Schafer, 1989214 Physical methods vs idoxuridine vs trifluridine vs bromovinyldeoxyuridine Tarakji et al, 1978215 Idoxuridine vs cryotherapy Topciu et al, 1992216 Antiviral therapy with or without immunostimulants Whitcher et al, 1976217 Idoxuridine vs debridement

*Only average number of days to healing in each treatment group was reported, unless otherwise noted.

(range, 0.8 to 4.1 for individual studies), and the median investigators was noted in 47 reports. sex ratio was 2.0 (25% and 75% quartiles, 1.2 and 3.3). Forty reports were limited to dendritic epithelial ker- OUTCOME ANALYSIS atitis; 29 enrolled patients with either dendritic or geographic epithelial keratitis; 2 were restricted to geograph- Outcome evaluation was judged by slit-lamp biomi- ic keratitis; and 5 provided insufficient information. Use croscopy in all trials. Fifty-five reports stated that fluores- of a cycloplegic agent was reported in 33 studies (atropine cein, with or without other measures, was the primary in 12, scopolamine in 6, homatropine in 3, cyclopentolate method to assess corneal epithelial status; 7 studies used in 1, and a nonspecified agent in 11). Seven studies primarily rose-Bengal staining. Days 7 and 14 were select- reported using a concomitant topical antibiotic (chloram- ed as times to compare treatment groups because these phenicol in 3 studies and a nonspecified agent in 4). days were regularly scheduled follow-up time points in Randomization was not apparent in the published report most clinical trials of HSV epithelial keratitis. A time point in 15 studies. Ofthe other reports, 11 studies specified the of 1 week was chosen as the primary treatment day for randomization method. Masking of patients was reported comparison because the masked review of the 41 trials to have been used in 50 reports, and masking of that provided survival graphs (Table IV) showed that the

513 Wilhelmnus

TABLE IV: SURVIVAL CURVE ANALYSIS OF CLINICAL TRIALS OF DENDRITIC EPITHELIAL KERATITIS DAY OF MAXIMAL CURVE SEPARATION

DAY OF NIIAL CURVE SEPARATION NO. TRIALS STUDY

2 3 Sundmacher et al, 19789 Wilhelmus et al, 198175 Yeakley et al, 1981'69 3 5 Wilhelmus et al, 19815I Sundmacher and Neumann-Haefelin, 19765 Stindmacher et al, 1976' Sundmacher et al, 1984"'1 Sundmacher et al, 1985'9° 4 .5 Coster et al, 197669 Coster et al, 1980"W Hoang-Xuan et al, 1984133 Suindmacher et al, 1981166 Sundmacher et al, 198158 5 6 Colin et al, 19831" Denis et al, 1983211 Graupner and Mtiller, 1968125 McCulley et al, 1982261 Stundmacher et al, 197894 Sundmacher et at, 1987'9 6 6 Collum et al, 198013 de Koning et al, 1983O Hung et al, 19842211 Meurs and van Bijsterveld, 1985'47 Power et al, 1991161 van Bijsterveld et al, 1989"' Blake and Brown, 1977 1 Colin, 1984221 Collumn et al, 1985' de Koning et al, 1982'1 Hoh et al, 199622 Jackson et al, 1984 ' Parlato et al, 1985223 8 3 Colin et al, 1981224 Markham et al, 197772 Altinisik, 1987- 9 3 H0vding, 1989225 Klauber and Ottovay, 1982226 Young et al, 1982 6 10 2 Jensen et al, 1982227 WAellings et al, 1972 4 11 1 La Lau et al, 1982'37 maximum separation of the healing curves for different single-agent treatment, no conclusion regarding treat- treatments occurred at a mode of 7 days, a mean of 6 ± 2 ment efficacy could validly be drawn from the aggregate days, and a median of 6 days (25% and 75% quartiles of 4 information (Table V) other than about one half of and 7 days, respectively). Sixty-five reports included data patients who were treated with trifluridine, acyclovir, or for proportions of eyes healed at 7 days. vidarabine healed within 1 week of antiviral therapy. Sixty-two reports presented data pertaining to the All potentially relevant treatment comparisons were average number of days that passed for healing to occur; analyzed. Treatment groups were combined for the follow- these estimates did not account for withdrawals, losses to ing: photoinactivation and carbolization;54 cryotherapy and follow-up, and failures and did not apply to healing curves carbolization;55 ganciclovir 0.05% and 0.15% gels;56 thermo- that were not normally distributed. The inappropriateness mechanical debridement and thermomechanical debride- of using an aggregate of absolute rather than relative ment with interferon-alpha 6.25 x 104 IU/mL, a dosage treatment effects was evident in a preliminary summary of probably too low to exert clinical effects;57 and trifluridine the set of trials included in this meta-analysis. For trials with interferon-alpha at either 1 x 10 IU/mL or at 30 x 106 reporting the average day of resolution and for reports IU/mL.58 Some placebo-controlled trials used the vehicle of providing sufficient data to allow this estimation for the corresponding study drug for the placebo control, but

514 The Treatmewnt of Herpes Simplex Vinrs Epithelial Keratitis

TABLE V. AVERAGE DAYS TO RESOLUTION OF HSV EPITHELLAL KERATITIS IN TRIALS OF DENDRITIC EPITHELIAL KERATITIS USING A SINGLE ANTIVIRAL AGENT

ANTIVIRAL AGENT NO. TRIALS MEAN ± SD MEDIAN (25% AND 75% QUARTILES)

Idoxuiridine 25 8.9 ± 2.4 8.2 (7.2, 10.1) Vlidarabine 12 7.5 ± 2.2 7.0 (5.8, 8.8) Trifluiridine 13 7.2 ± 2.2 6.4 (5.9, 7.6) Acyclovir 27 7.0 ± 2.2 6.8 (5.9, 7.8) other agents also classified as a placebo in this review fluridine, and acyclovir were considered equivalent, the included neomycin,5960 albumin,6' nonspecific gamma glob- pooled OR for the trials that compared these agents to ulin62 and several low-dose interferon preparations.","',' idoxuridine was 3.21 (95% CI, 1.77, 5.81) at 7 days by a random-effects model. DATA SYNTHESIS The combination ofa physical or chemical method vith an antiviral agent appeared better than either modality Treatment comparisons were analyzed according to type alone (Fig 4). The combination of topical interferon with of therapeutic modality. Table VI presents all comparisons a topical antiviral agent was significantly more effective of single antiviral agents or placebo. Table VII provides than the corresponding antiviral agent alone (Fig 5). The data from trials with at least 1 treatment arm that used a few studies evaluating combined therapy with 2 antiviral physical or chemical method to remove infected corneal agents did not find a significant effect over single-agent epithelium. Table VIII gives similar information for trials treatment. that evaluated interferon. Table IX gives data for the Two trials were restricted to geographic epithelial remaining treatment comparisons that were evaluated in keratitis.1066 These data, when combined with data from 6 only 1 trial each. other trials that provided sufficient data on the subgroup Relative effect measures of treatment comparisons of patients with geographic keratitis, lacked precision in for HSV epithelial keratitis are summarized in Table X. comparing different treatments (Table XII). One trial that Idoxuridine appeared to be significantly better than place- showed trifluridine to be superior to vidarabine for geo- bo (Fig 2). Figure 3 compares individual antiviral agents graphic epithelial keratitis has apparently not been con- to idoxuridine. Direct and indirect comparisons of firmed.66 vidarabine, trifluridine, and acyclovir compared to idox- Study quality scores varied considerably. Reports list- uridine showed that the pooled estimates of treatment ing a biostatistician as a coauthor or in the credits were effect for each of these agents showed a trend toward more likely to have a higher score (median, 61.5; 25% and faster healing (Table XI), but these comparisons were lim- 75% quartiles, 55 and 69) than reports without a listed ited by heterogeneity of the studies. When vidarabine tri- biostatistical consultant (median, 46.5; 25% and 75%

TABLE VI: TRIALS COMPARING A SINGLE TOPICAL ANTIVIRAL AGENT TO PLACEBO OR TO ANOTHER SINGLE TOPICAL AGENT

ODDS RATIO (95% CL) STUDY STUDY NO. DAY 7 DAY 14 STUDY QUALITY LOCALE SCORE

Idoxuridine vs Placebo Burns, 1963221 N America 38 4.18 (0.76, 23.06) NA 33 Luntz and MacCallum, 1963" Europe 22 0.69 (0.13, 3.72) 5.71 (0.52, 62.7) 24.5 Patterson et al, 1963229 Europe 23 9.00 (1.29, 63.0) NA 48 Patterson et al, 1963229 Europe 32 21.1 (3.28, 136.2) NA 48 Patterson et al, 1963229 Europe 30 30.00 (3.03, 1214) NA 48 Jepson, 196421 N America 24 7.86 (0.75, 82.13) NA 44 Laibson and Leopold, 196423' N America 100 3.81 (1.63, 8.91) NA 54.5 Davidson and Evans, 196462 Europe 50 1.96 (0.62, 6.19) NA 29 Hart et al, 1965' Australia 32 15.40 (2.49, 95.1) NA 54 Markham et al, 197772 Europe 41 0.94 (0.20, 4.41) 3.75 (1.02, 13.80) 71 Vidarabine vs Placebo Markham et al, 197772 Europe 43 3.08 (0.78, 12.12) 5.40 (1.42, 20.52) 71

515 Wilhelmus

TABLE VI (CONTINUED): TRIALS COMPARING A SINGLE TOPICAL ANTIVIRAL AGENT TO PLACEBO OR TO ANOTHER SINGLE TOPICAL AGENT

ODDS RATIO (95% CL) STUDY STUDY NO. DAY 7 DAY 14 STUDY QUALITY LOCALE SCORE Vidarabine vs Idoxuridine Pavan-Langston and Buchanan, 197615' N America 169 0.88 (0.48, 1.62) 1.07 (0.49, 2.37) 66 Blake and Brown, 197767 Europe 30 2.14 (0.49, 9.36) 2.25 (0.32, 15.97) 65.5 Markham et al, 197772 Europe 44 3.27 (0.83, 12.81) 1.44 (0.37, 5.67) 71 Trifluridine vs Idoxuridine Wellings et al, 1972 7 Europe/N America 78 5.07 (1.93, 13.31) 8.04 (2.10, 30.85) 72.5 Laibson et al, 19772 N America 33 NA 11.00 (0.54, 223) 46.5 Sugar et al, 1980' N America 61 1.78 (0.62, 5.06) 3.75 (1.01, 13.97) 58 Trifluridine vs Vidarabine Coster et al, 197669 Europe 102 1.16 (0.45, 2.99) 4.82 (0.52, 44.7) 47.5 Travers and Patterson, 1978' Europe 100 0.48 (0.16, 1.43) NA 32.5 van Bijsterveld and Post, 198078 Europe 56 0.62 (0.20, 1.89) 0.50 (0.13, 1.95) 67.5 Trifluridine vs Bromovinyldeoxyuridine Power et al, 1991163 Europe 60 2.26 (0.80, 6.36) 3.22 (0.32, 32.9) 64.5 Trifluridine vs Foscarnet Behrens-Baumann, 19922" Europe 20 NA 1.00 (0.05, 18.57) 60 Acyclovir vs Idoxuridine Collum et al, 1980"' Europe 60 116.0 (13.05, 1031) 27.0 (1.49, 488) 57 Coster et al, 198068 Europe 56 3.71 (0.89, 15.48) 0.47 (0.04, 5.43) 63.5 Colin et al, 1981?"4 Europe 46 2.88 (0.82, 10.10) 0.38 (0.01, 9.82) 55.5 Klauber and Ottovay, 19822"6 Europe 38 4.67 (1.19, 18.35) 3.33 (0.72, 15.37) 66.5 McCulley et al, 19822' N America 64 1.54 (0.56, 4.18) 0.86 (0.22, 3.33) 69 Kitano et al, 19832" Asia 109 NA 3.49 (1.05, 11.61) 45 Abe and Hara, 198723 Asia 27 5.50 (0.88, 34.5) 30.3 (1.40, 654) 26.5 Altinisik, 1987-- Asia 19 8.00 (0.71, 90.0) 4.50 (0.37, 54.2) 36 Maychuk and Kazachenko, 1988"3 Asia 102 NA 4.07 (1.27, 13.02) 25.5 Acyclovir vs lododeoxycytidine Colin, 1984221 Europe 32 2.25 (0.54, 9.45) 7.48 (0.35, 157.8) 59 Acyclovir vs Vidarabine Pavan-Langston et al, 19811' N America 41 0.28 (0.03, 2.98) 2.00 (0.17, 23.96) 56.5 Yeakley et al, 1981 169 N America 40 0.89 (0.11, 7.06) 2.85 (0.11, 74.3) 60 Young et al, 198276 Europe 79 0.96 (0.38, 2.46) 1.03 (0.32, 3.27) 67 Denis et al, 1983218 Europe 23 0.07 (0.01, 0.73) 1.63 (0.09, 29.78) 35.5 Jackson et al, 1984wl N America 66 2.68 (0.87, 8.27) 4.13 (0.44, 39.14) 71 Gen6e and Maith, 1987239 Europe 28 NA 2.75 (0.52, 14.44) 37 Acyclovir vs Trifluridine La Lau et al, 198213' Europe 59 1.82 (0.63, 5.24) 2.08 (0.59, 7.34) 62.5 Hoang-Xuan et al, 1984'" Europe 31 0.30 (0.06, 1.47) 0.42 (0.04, 4.53) 24.5 H0vding, 1989'2 Europe 50 1.00 (0.29, 3.44) 0.31 (0.03, 3.16) 75 Acyclovir vs Ganciclovir Hoh et al, 1996222 Europe 46 0.25 (0.06, 1.11) 0.17 (0.01, 3.69) 42.5 Colin et at, 1997' Africa 59 1.05 (0.35, 3.18) 0.54 (0.14, 1.99) 23 Colin et al, 19975 Europe 35 1.41 (0.37, 5.32) 0.48 (0.09, 2.43) 23

CL, confidence limits; IDU, idoxuridine; NA, not available.

516 The Treatment ofHerpes Simplex Virus Epithelial Keratitis

TABLE VII: TRIALS USING A PHYSIOCHEMICAL METHOD IN ONE OF THE COMPARISON GROUPS OF THE TREATMENT OF HSV EPITHELIAL KERATITIS

ODDS RATIO (95% CL) STUDY ANTMRAL PHYSIOCHEMICAL STUDY NO. DAY 7 DAY 14 STUDY AGENT METHOD LOCALE SCORE QUALITY Physical Treatment vs Placebo Davidson and Evans, 196462 Gamma Iodinization Europe 50 1.96 (0.62, 6.19) NA 29 globulin Sundmacher et al, 197663 Low-dose Thermo- Europe 55 1.35 (0.42, 4.36) 2.02 (0.40, 10.27) 57.5 interferon mechanical debridement Antiviral Agent vs Physicochemical Method Davidson and Evans, 196462 IDU lodinization Europe 50 1.00 (0.33, 3.03) NA 29 MacKenzie, 1964' IDU Carbolization Europe 80 NA 0.05 (0.01, 0.37) 6 Patterson and Jones, 1967'49 IDU Carbolization Europe 77 0.78 (0.22, 2.82) NA 18 Patterson and Jones, 1967141 IDU Carbolization Europe 28 1.60 (0.09, 28.57) NA 18 Fulhorst et al, 19725 IDU Cryotherapy or carbolization Europe 59 0.12 (0.04, 0.38) NA 29.5 Austin and Walker, 1974241 IDU Iodinization Europe 41 NA 0.57 (0.10, 3.38) 12.5 O'Day et al, 1975w IDU Photo-inactivation Europe 17 NA 1.14 (0.06, 21.87) 18 Bartholomew et al, 197754 IDU Photo-inactivation or carbolization Europe 21 NA 0.90 (0.12, 7.03) 24.5 Kato et al, 197923 IDU Wiping debridement Asia 27 0.95 (0, 1.32) NE 23 Parlato et al, 1985' Trifluridine Wiping debridement N America 22 4.17 (0.66, 26.29) 45.57 (2.01, 1034) 61.5 Physicochemical/Antiviral Combination vs Physicochemical Method Fulhorst et al, 197255 IDU Cryotherapy or carbolization Europe 64 2.16 (0.58, 8.07) NA 29.5 Sundmacher and Neumann-Haefelin, 19765' Interferon- Thermo- alpha mechanical debridement Europe 40 6.00 (0.61, 59.4) 1.00 (NE) 70.5 Uchida et al, 19814 Interferon- Wiping beta debridement Asia 37 2.80 (0.65, 12.06) NA 41.5 Uchida et al, 19814 IDU Wiping debridement Asia 34 1.28 (0.32, 5.13) NA 41.5 Hung et al, 1984°° Oral Wiping acyclovir debridement Europe 29 5.50 (1.06, 28.42) NA 65 Parlato et al, 1985223 Trifluridine Wiping debridement N America 20 1.67 (0.27, 10.33) 39.3 (1.72, 897) 61.5

Combination vs Antiviral Agent Fulhorst et al, 19725 IDU Cryotherapy or carbolization Europe 57 18.32 (4.70, 71.5) NA 29.5 Daniel and Karseras, 1972w44 IDU Ultraviolet light Europe 54 4.27 (1.17, 15.59) 2.70 (0.76, 9.55) 26.5 Wilhelmus et al, 198175 Acyclovir Wiping debridement Europe 50 2.09 (0.18, 24.62) 1.00 (NE) 55.5 Jensen et al, 198227 Acyclovir Wiping debridement Europe 43 0.66 (0.18, 2.42) 0.75 (0.23, 2.50) 53.5 Parlato et al, 1985m Trifluridine Wiping debridement N. America 26 0.40 (0.08, 2.02) 1.00 (NE) 61.5 Richter and Matthes, 198679 BVDU Wiping debridement Europe 57 0.89 (0.26, 3.07) 1.00 (NE) 39.5 Altinisik, 19877 Acyclovir Wiping debridement Asia 18 1.67 (0.25, 11.07) 2.68 (0.10, 75.1) 36 CL, confidence limits; IDU, idoxuridine; NA, data not available; NE, not estimable

517 Wilhelmus

TABLE VIII: TRIALS EVALUATING INTERFERON IN THE THERAPY OF HERPES SIMPLEX VIRUS EPITHELIAL KERATITIS

ODDS RATIO (95% CL) STUDY ANTIVIRAL INTERFERON STUDY NO. DAY 7 DAY 14 STUDY AGENT TYPE LOCALE SCORE QUALITY

Interferon vs Placebo Uchida et al, 1981' None Beta Asia 9 0.75 (0.03, 17.51) 4.50 (0.25, 80.6) 48 Uchida et al, 1981' None' Beta Asia 68 1.91 (0.72, 5.08) NA 39.5 Yamazaki, 19846 None Beta Asia 74 1.18 (0.47, 2.97) 2.09 (0.69, 6.29) 40 Yamazaki, 198461 None' Beta Asia 36 15.00 (2.54, 88.70) 25.38 (1.30, 495) 40 Antiviral/Interferon Combination vs Antiviral Agent Sundmacher et al, 198158 Trifluridine Alpha Europe 70 6.00 (1.00, 35.91) NE 60.5 de Koning et al, 1982'25 Trifluridine Alpha Europe 53 68.2 (11.37, 410) 7.00 (0.34, 142.5) 51.5 Colin et al, 1983"1 Acyclovir Alpha Europe 45 16.33 (0.84, 316) NE 51 de Koning et al, 1982'5 Acyclovir Alpha Europe 51 14.25 (3.60, 56.4) 3.00 (0.12, 77.2) 59.5 Meurs and van Bijsterveld, 1985146 Acyclovir Alpha Europe 93 8.24 (3.12, 21.71) 3.27 (0.13, 82.4) 44.5 Maychuk and Kazachenko, 1988' Acyclovir Alpha Asia 75 NA 1.26 (0.26, 6.05) 25.5 van Bijsterveld et al, 198910' BVDU Alpha Europe 41 26.00 (2.92, 231) NE 63.5 Carmassi et al, 1993245 Acyclovir NS Europe 10 7.86 (0.28, 217) 2.67 (0.16, 45.1) 17.5

Interferon vs Antiviral Agent Kitano et al, 1983'3 IDU Beta Asia 55 0.89 (0.18, 4.39) 0.78 (0.12, 5.10) 45 Vannini et al, 1986241 IDU Beta Europe 20 3.32 (0.12, 91.6) 30.3 (1.39, 661) 45 Carmassi et al, 1993245 Acyclovir NS Europe 10 NE 7.86 (0.28, 217) 17.5 Interferon Inducer vs Antiviral Agent Guerra et al, 1979'" IDU Poly IC Europe 20 0.58 (0.07, 4.55) 0.11 (0.05, 0.84) 47

BVDU, bromovinyldeoxyuridine; IDU, idoxuridine; CL, confidence limits; NA, not available; NE, not estimable; NS, not stated. 'Low-dose interferon group classified as placebo group.

TABLE IX: TRIALS EVALUATING COMBINATION CHEMOTHERAPY OR ORAL ANTIVIRAL AGENTS FOR HSV EPITHELIAL KERATITIS

ODDS RATIO (95% CL) STUDY STUDY NO. DAY 7 DAY 14 STUDY QUALITY LOCALE SCORE Idoxuridine/Oxyphenbutazone Combination vs Idoxuridine Norn, 19732' Europe 29 0.48 (0.10, 2.30) NA 55 AcyclovirNidarabine Combination vs Acyclovir Colin et al, 1987245 Europe 32 9.00 (0.94, 86.5) 2.12 (0.12, 84.4) 58 Acyclovir/Debridement vs Idoxuridine/Debridement Serifoglu and Karakurt, 1987249 Asia 25 2.75 (0.40, 18.88) 1.00 (NE) 40 Acyclovir/Epidermal Growth Factor Combination vs Acyclovir Cellini et al, 19942 Europe 40 1.00 (NE) 1.00 (NE) 68 Idoxuridine/Oral Acyclovir Combination vs Idoxuridine Srinivas, 1993"' Asia 40 NA 41.0 (2.18, 770) 20.5 Trifluridine/Oral Acyclovir Combination vs Trifluridine HEDS Group, 1997W N America 287 1.43 (0.87, 2.34) 1.07 (0.50, 2.31) 79.5 The Treatment of Herpes Simplex Virus Epithelial Keratitis

TABLE LX (CONTINUED): TRIALS EVALUATING COMBINATION CHENIOTHERAPY OR ORAL ANTIVIRAL AGENTS FOR HSV EPITHELIAL KERATITIS

ODDS RATIO (95% CL) STUDY STUDY NO. DAY 7 DAY 14 STUDY QUALITY LOCALE SCORE

Oral Acyclovir vs Acyclovir Collum et al, 1986"fi Europe 56 0.76 (0.23, 2.47) 0.29 (0.03, 2.93) 54.5 Oral Isoprinosine vs Placebo Haut et al, 1983252 Europe 26 8.25 (0.82, 82.7) 2.50 (0.49, 12.64) 34.5 CL, confidence limits; NA, not available; NE, not estimable.

TABLE X: SUMMARY RELATIVE TREATMENT EFFECTS AT 1 WEEK AFTER TRIAL ENTRY FOR DIRECTLY COMPARED TREATMENTS OF HERPES SIMPLEX VIRUS EPITHELIAL KERATITIS

TREATMENTS COMPARED NO. TRIALS ODDS RATIO° TEST FOR (95% CL) HOMOGENEIIY Antiviral-placebo comparisons Idoxuridine vs placebo 10 4.05 (2.60, 6.30) 0.03 Vidarabine vs placebo 1 3.08 (0.78, 12.12) Single antiviral agent comparisons Vidarabine vs idoxuridine 3 1.20 (0.72, 2.00) 0.16 Trifluridine vs idoxuridine 2 3.12 (1.55, 6.29) 0.15 Trifluridine vs vidarabine 3 0.74 (0.41, 1.34) 0.46 Trifluridine vs bromovinyldeoxyiridine 1 2.26 (0.80, 6.36) Acyclovir vs idoxuridine 4.56 (2.76, 7.52) 0.03 Acyclovir vs vidarabine 5 0.91 (0.51, 1.64) 0.06 Acyclovir vs trifluridinie 3 1.01 (0.50, 2.01) 0.18 Acyclovir vs ganciclovir 3 0.78 (0.38, 1.60) 0.20 Acyclovir/vidarabine vs acvclovir 1 9.00(0.94, 86.5) Oral acyclovir vs acyclovir 1 0.76 (0.23, 2.47) Oral acyclovir/trifluiridine vs trifluridine 1 1.43 (0.87, 2.34) Physicochemical comparisons Physical method vs placebo 2 1.63 (0.72, 3.71) 0.65 Anitiviral agent vs physicochemical method 6 0.53 (0.30, 0.92) 0.01 Phvsicochemical/antiviral combination vs pbysicocbemical metbod 6 2.50 (1.33, 4.69) 0.76 Pbysicocheinicallantiviral combination vs antiviral agenit 7 2.01 (1.21, 3.34) (.001 Interferon comparisons Interferon vs placebo 4 2.01 (1.12, 3.63) 0.09 Interferon/antiviral combination vs antiviral agenit 7 13.49 (7.39, 24.61) 0.49 Interferon vs antiviral agent 3 1.18 (0.29, 4.75) 0.48 CL, confidence limits. °Using a fixed-effects model; pooled odds ratios using randoom-effects miiodels are reported elsewhere in this report if significant leterogenieitv \as founld. quartiles, 29.5 and 59.5; P=.0001, Wilcoxon rank-sum size of the epithelial defect on healing and showed that test). The trial quality score improved slightly over time larger lesions resolved more slowly.7i77 Three trials found (r2 = 0.068, P=.028; Fig 6). Power to detect a statistically that epithelial keratitis that had been symptomatic for significant difference between treatments exceeded 80% more than 1 week healed more slowly.7 -777 One trial in only 12 (16%) of the studies. reported that epithelial keratitis that was peripherally located took longer to heal.75 Three trials noted that PREDICTIVE FACTORS epithelial lesions associated with underlying stromal keratitis had slower healing. 5'77371 Eleven trials found a statistically significant effect of the No significant difference was found between the 2

519 Wilhelmus

Favors Placebo Favors Idoxuridine Favors Idoxuridine Favors Vidarabine Burns, 1963 -Pavan-Langston and Buchanan, 1976 Blake and Brown, 1977 *4------Luntz and MacCallum, 1963 Markham et al, 1977 * -Patterson et al, 1963 Favors Trifluridine Wellings et al, 1972 * -Patterson et al, 1963 Sugar et al, 1980 Patterson et al, 1963 Favors Acyclovir Collum et al, 1980 .-'.. Jepson, 1964 Coster et al, 1980 * -Laibson and Leopold, 1964 Colin et al, 1981 Davidson and Evans, 1964 @ -Klauber and Ottovay, 1982 McCulley et al, 1983 Hart el al, 1965 Abe and Hara, 1987 -11 -Markham et al, 1977 - -- Altinisik, 1987

- COMBINED +- -COMBINED 1 1111111i 1 1111114 111111______0.01 0.1 1 10 100 0.01 0.1 1 10 100 Odds Ratio Odds Ratio FIGURE 2 FIGURE 3 Odds ratios and corresponding 95% confidence intervals from 10 trials Trial results comparing individual antiviral agents to idoxuridine, with comparing topical idoxuridine solution or ointment to placebo, with pooled odds ratio estimated by a random-effects model. pooled odds ratio estimated by a random-effects model.

TABLE XI: DIRECT AND INDIRECT COMPARISONS OF SINGLE-AGENT ANTIVIRAL TRiALS AT 7 DAYS, USING IDOXURIDINE AS THE REFERENT

TREATMENTS COMPARED COMPARISON TYPE NO. TRIALS ODDS RATIO RISK DIFFERENCE (INTERMEDIATE COMPARATOR) (95% CL) (95% CL)

Vidarabine vs idoxuridine Direct 3 1.20 (0.72, 2.00) 0.05 (-0.08, 0.17) Indirect (trifluridine) 5 4.22 (1.69, 10.54) 0.33 (0.14, 0.52) Indirect (acyclovir) 12 5.01 (2.33, 10.77) 0.36 (0.23, 0.49) Trifluridine vs idoxuridine Direct 2 3.12 (1.55, 6.29) 0.28 (0.12, 0.43) Indirect (vidarabine) 6 0.89 (0.09, 8.63) 0.00 (-0.16, 0.16) Indirect (acyclovir) 10 4.51 (1.90, 10.71) 0.34 (0.17, 0.51) Acyclovir vs idoxuridine Direct 7 4.56 (2.76, 7.52) 0.34 (0.25, 0.44) Indirect (vidarabine) 8 1.09 (0.50, 2.38) 1.85 (1.69, 2.02) Indirect (trifluridine) 9 3.15 (1.18, 8.40) 0.28 (0.05, 0.51)

CL, confidence limits.

interventions in the Herpetic Eye Disease Epithelial (Table XIV). Increasingly longer lesions resolved more Keratitis Trial.53 Figure 7 presents the overall healing pro- slowly, and dendrites with a portion located within 2 mm file of this entire patient cohort treated with topical tri- of the limbus took longer to heal. A nonlinear association fluridine with or without oral acyclovir. Based on the rela- was found between the duration of symptoms, area of the tively larger log-likelihoods, smaller Akaike information epithelial lesion, and healing rate (Table XV). Longer den- criteria [-2log-likelihood + 2(p + 1 + k), where p = num- drites that had a longer duration healed more slowly, but ber of parameters and k = 0 for exponential distribution, smaller dendrites of a longer duration seemed to resolve 2 for generalized gamma distribution, and 1 for other dis- more rapidly. Finally, these data suggested the new find- tributions], and plots of the Cox-Snell and deviance resid- ing that previous ocular herpetic disease affects the heal- uals, the log-logistic distribution provides a suitable para- ing response. Despite antiviral therapy, patients with a metric model to fit these data (Table XIII). The approxi- previous episode of HSV eye disease, especially if recent, mate cumulative probability of comeal epithelial healing took significantly longer to resolve. can be estimated by [(7/t)4 + 1]-', with mean and median healing times of approximately 7 days. DISCUSSION Of several historical and baseline characteristics, multivariate analysis suggested that lesion size and duration Several ophthalmological textbooks and survey articles have were significantly associated with slower reepithelialization effectively summarized the clinical research on herpetic

520 The Treatment ofHerpes Simplex Virus Epithelial Keratitis

Favors Physical Method Favors Combination Favors Antiviral Favors Antiviral-interteron Fulhorst et al, 1972 -;------4------* -Sundmacher and Neumann-Haetelin, 1976 -Sundmacher et al, 1981 -Uchida et al, 1981 * -Uchida et al, 1981 de Koning et al, 1982 -.--*--- -Hung et al, 1984 Colin et al, 1983 ;--'------*Parlato et al, 1985 -5- COMBINED - - -de Koning et al, 1983 Favors Antiviral Agent Favors Combination e - Fulhorst et al, 1972 * -Meurs and van Bijsterveld, 1985 @ -Daniel and Karseras, 1972 --- [email protected]* -Wilhelmus et al, 1981 * -van Bijsterveld et al, 1989 Jensen et al, 1982 Parlato et al, 1985 Carmassi et al, 1993 Richter and Matthes, 1986 e* -Altinisik, 1987 -.4.-+ COMBINED -4- +COMBINED 1L ± 1W U 11lla LL± 1 L.L JJ JJ.1L W L _ 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Odds Ratio Odds Ratio FIGURE 4 FIGURE 5 Individual and combined results from trials comparing a combination of Individual and combined results from trials comparing either interferon mechanical debridement or chemical cauterization with topical antiviral or an interferon-antiviral combination to corresponding antiviral agent. therapy to corresponding physicochemical method or antiviral agent.

TABLE XII: CLINICAL TRLALS EVALUATING TREATMENT FOR GEOGRAPHIC EPITHELIAL KERATITIS

ODDS RATIO (95% CL) STUDY STUDY NO. DAY 7 DAY 14 STUDY QUALITY LOCALE SCORE

Idoxuridine vs Physical Treatment Patterson and Jones, 1967'49 Europe 24 5.50 (0.91, 33.2) NA 18 Vidarabine vs Idoxuridine Blake and Brown, 197767 Europe 22 2.00 (0.36,11.23) 1.50 (0.08, 27.6) 65.5 Pavan-Langston and Buchanan, 19761's N America 14 0.12 (0.01, 1.58) 0.22 (0.01, 6.31) 66 Trifluridine vs Idoxuridine Sugar et al, 19801 N America 17 2.10 (0.25, 17.59) 6.00 (0.72, 49.8) 58 Trifluridine vs Vidarabine Coster et al, 1979' Europe 30 1.57 (0.36, 6.88) 13.50 (1.42,128.3) 59.5 Acyclovir vs Idoxuridine McCulley et al, 1982219 N America 12 21.0 (0.96, 459) 1.80 (0.12,26.2) 69 Maychuk and Kazachenko, 19882 Asia 43 NA 2.35 (0.53, 10.52) 25.5 Acyclovir vs Vidarabine Collum et al, 1985 Europe 51 2.84 (0.91, 8.86) 0.47 (0.12,1.85) 62.5 Acyclovir/Interferon vs Acyclovir Maychuk and Kazachenko, 19882 Asia 37 NA 1.70 (0.25, 11.59) 25.5 CL, confidence limits. eye disease that has accrued over the past century. A nar- tion are inadvisable if larger biased studies overwhelm the rative review, however, may give equal weight to studies results of smaller well-designed trials. A systematic when assessing each trial's overall result or introduce con- overview that uses all relevant, accessible clinical trials as founding by inappropriately adding data from individual the units of analysis can stochastically identify patterns of patients enrolled in different studies. Tallying and addi- agreement and aid in developing valid recommendations

521 Wilhelmus

Highest - S se ~~~~0 1.00 - a 0 ..~~~6. *S;-* 0.75 -

o * 0* **0 0 Average- *g . 03*; I 0.50 - * 0 cn

0 0 0 0.25 - 0~~~~~~~~~

Lowest - 0~~~~ 0.00 - 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 1963 1997 Report Year

FIGURE 6 FIGURE 7 Correlation between year of published trial and overall methodological Kaplan-Meier survival estimate with 95% pointwise confidence band of quality of each study. 287 patients with dendritic epithelial keratitis who had no stromal keratitis and who were treated with topical trifluridine, with or without oral acyclovir, in the Epithelial Keratitis Trial of the Herpetic Eye Disease Study.

TABLE XIII: RESULTS OF FITTING PARAMETRIC MODELS TO THE HEDS EPITHELIAL KERATITIS TRIAL DATASET

AKAIKE INFORMATION CRITERION MODEL* ORAL PLACEBO AND TOPICAL ORAL ACYCLOVIR AND BOTH TREATMENT TRIFLURIDINE GROUP TOPICAL TRIFLURIDINE GROUP GROUPS

Exponential 318.2 356.2 672.8 Weibull 259.4 277.8 534.8 Gompertz 301.3 330.6 629.1 Log-logistic 194.2 196.4 388.4 Log-normal 204.8 211.3 413.7 Generalized gamma 208.9 180.6 351.9 HEDS, Hepetic Eye Disease Study. 'The exponential, WVeibull, and Gompertz distributions were implemented as proportional hazard rates, while the log-logistic, log-normal, and generalized gamma distributions were parameterized as accelerated failure times.

from available evidence."'8, Meta-analysis, an "analysis of of treatments.83 Information missing or incompletely analyses,"82 uses statistical procedures to integrate individ- reported in journal articles precluded using other meas- ual studies. This quantitative approach can effectively ures of corneal healing, such as amount of reepithelializa- improve precision in combined measures of effect. tion per day. Limited data were also available for other This overview aimed to compare therapeutic options outcomes, including incidence of recrudescent epithelial for HSV epithelial keratitis. A key decision made before keratitis during acute follow-up, incidence of recurrent undertaking the literature review was defining the epithelial keratitis or subsequent stromal keratitis during primary outcome measure. HSV epithelial keratitis is gen- prolonged follow-up, development of corneal scarring, erally an acute disease that resolves within a few days or change in visual acuity, incidence of toxic or allergic ocu- weeks. While healing curves provide information on all lar surface reactions or other adverse effects, or the emer- enrolled patients, only about one half of trials of HSV gence of resistant viral strains. epithelial keratitis provided these data. To combine studies directly and indirectly, resolution within 1 week and PHYSICOCHEMICAL THERAPY resolution within 2 weeks were selected as end points commonly reported by many trials. Epithelial healing at 7 Various physical, chemical, and antiviral agents for HSV days was chosen as the principal outcome because most epithelial keratitis have been introduced over the past 100 trials included a 1-week follow-up visit and the greatest years. Cauterization methods were widely employed for treatment differences occurred at this time. dendritic epithelial keratitis during the first half of the Odds ratios were used to evaluate the relative effect 20th century. Because the techniques of randomization

522 The Treatment ofHerpes Simplex Virus Epithelial Keratitis

TABLE XIV: RELATIVE EFFECTS OF PATIENT CHARACTERISTICS, OPHTHALMIC HISTORY, AND CORNEAL STATUS ON DELAYED (> 10 DAYS) RESOLUTION OF HSV EPITHELIAL KERATITIS*

FACTOR UNADJUSTED ODDS RATIO ADJUSTED ODDS RATIO (95% CL) (95% CL) N = 271 N = 268 Demographic factors Age > 48 yr 1.00 (0.98,1.02) Male sex 0.94 (0.46, 1.94) White ethnicity 0.95 (0.45, 2.00) Ophthalmic history Prior HSV eye disease 3.58 (1.50, 8.63) Prior HSV epithelial keratitis 3.53 (1.48, 8.39) Prior HSV stromal keratitis 2.81 (0.91, 8.69) Time since last ocular HSV episode No prior episode 1.00 (referent) 1.00 (referent) More than 2 yr 2.36 (0.86, 6.49) 2.25 (0.79, 6.40) Within 2 yr 4.92 (1.91, 12.70) 6.17 (2.28, 16.70) Prior HSV nonocular disease 0.76 (0.36, 1.57) Epithelial keratitis Duration of symptoms 1-2 days 1.00 (referent) 1.00 (refereint) 3-4 days 2.33 (1.01, 5.40) 2.70 (1.11, 6.60) 5-7 days 0.95 (0.34, 2.61) 0.80 (0.27, 2.39) Maximal axis of epithelial lesion 1.18 (0.99, 1.41) 1.16 (0.95, 1.41) Area (log) of epithelial lesion 1.53 (0.97, 2.42) Multiple dendrites 1.27 (0.60, 2.7(0) Peripheral dendrite 2.26 (0.90, 5.69) 2.49 (0.90, 6.88) CL, confidence limits. *As found by univariable and multivariable stepwise logistic regression in the herpetic eye disease study. and masking did not emerge in clinical ophthalmic the enhancement ofcorneal inflammation or scarring, and research until the development of antiviral chemotherapy, the occurrence of recrudescent epithelial keratitis if valid comparisons between different physicochemical antiviral therapy is not also given." methods are limited. The relative effects of iodinization, carbolization, and other chemical or mechanical means of ANTIVIRAL THERAPY removing infected corneal epithelium remain uncertain. For convenience and power, all physical and chemical Since the introduction ofidoxuridine in 1962, topical oph- methods were assumed to be equivalent and were thalmic antiviral agents have emerged as the preferred grouped together. Differences among these methods, treatment of HSV epithelial keratitis. Topical idoxuridine however, could limit their comparability and result in dis- solution or ointment was initially compared to placebo, cordant combinations. For example, the extent ofphysico- but most subsequent trials compared different nucleoside chemical deepithelialization varied from wiping loosened, infected epithelial cells by minimal debridement to ther- TABLE XV: ODDS RATIOS (AND 95% CL) OF EFFECTS OF DURATION AND momechanical or cryomechanical curettage and chemical SIZE OF DENDRITIC LESION ON DELAYED (>10 DAYS) HEALING OF HSV cauterization that ablated a large zone of epithelium sur- EPITHELIAL KERATITIS* rounding the dendrite. Minimal wiping debridement DURATION OF SYMPTOMS AREA OF EPITHELIAL LESION without antiviral cotreatment was often followed by < 2 MM2 > 2 MM2 recrudescent epithelial keratitis, while more aggressive 1 - 2 days 1.00 (referent) 1.40 (0.38, 5.16) physicochemical methods apparently removed all infected 3 - 4 days 2.80 (0.89, 8.82) 2.70 (0.79, 9.27) epithelial cells. An unproved benefit of debridement was 5 - 7 days 0.45 (0.08, 2.41) 2.67 (0.70, 10.20) a reduced risk of subsequent HSV stromal keratitis.7584 Reported reasons why physicochemical debridement CL, confidence limllits. 'Among 271 patients enrolled in the epithelial keratitis trial of the her- is no longer widely used are the time and effort needed petic eye disease study. for the procedure, the risk of damaging Bowman's layer,

523 Wilhelmus

TABLE XVI: SUMMARY OF INDIRECT AND DIRECT META-ANALMC RESULTS FOR ANTIVIRAL TREATMENT EFFECTS

TREATMENT COMPARISON INTERMEDIATE NO. TRIALS INDIRECT ODDS RATIO DIRECT ODDS RATIO (95% CL) (95% CL) Vidarabine vs idoxuridine Trifluridine 5 4.22 (1.69,10.5) 1.20 (0.72, 2.00) Acyclovir 12 5.01 (2.33,10.8) Trifluridine vs idoxuridine Vidarabine 6 0.89 (0.09, 8.63) 3.12 (1.55,6.29) Acyclovir 10 4.51 (1.90,10.7) Acyclovir vs idoxuridine Vidarabine 8 1.09 (0.50, 2.38) 4.56 (2.76, 7.52) Trifluridine 9 3.15 (1.18, 8.40) CL, confidence limits. antiviral agents. relative treatment effect. Findings ofthe indirect analyses Idoxuridine was significantly better than placebo, for several antiviral comparisons differed from the direct- although a summary effect could not be reliably estimat- ly estimated summary relative risks (Table XVI). While all ed. Variable formulations and dosages of idoxuridine like- patients in this systematic review had clinical signs of HSV ly contributed to heterogeneity among placebo-controlled epithelial keratitis, differences among the study popula- trials. Among trials comparing idoxuridine to placebo, an tions apparently modified treatment effects and made unusual pattern emerged in the chronological sequence of indirect estimates unreliable. Direct comparisons were trial results: the lower border of the 95% CI separated preferred as more valid estimates, and indirect treatment from the line of no difference, in favor of idoxuridine, but comparisons must be interpreted cautiously. then returned to no difference with a concomitant nar- Sufficient data were also not available to adequately rowing ofthe CI . This atypical situation86 could be due to assess topical bromovinyldeoxyuridine, topical ganciclovir, chance, since these trials were relatively small, but treat- or oral acyclovir, although these agents appeared equivalent ment formulation and study quality varied among these to topical trifluridine or topical acyclovir. The addition of a trials. However, a drift toward a reduced effect of idoxuri- second agent such as topical vidarabine or oral acyclovir to dine was also suggested when the CIs from the placebo- topical antiviral therapy did not significantly improve controlled trials were replotted in the order from the epithelial healing. No topical or oral antiviral agent reduced widest to the narrowest. the incidence ofrecurrent epithelial or stromal keratitis fol- Idoxuridine and other agents have not been ade- lowing treatment of dendritic epithelial keratitis.`388 quately compared to the physicochemical methods used Interferon did not initially appear to be effective in in the preantiviral era. The use of antiviral therapy follow- HSV keratitis in rabbits89 or in humans,90 but the improved ing minimal debridement prevents recrudescent epithe- availability of sufficient concentrations enabled a benefi- lial keratitis during the subsequent 2 weeks, but any heal- cial protective effect to be shown.91 This overview demon- ing advantage of combined physical and antiviral treat- strated that interferon monotherapy had a slight benefi- ment is uncertain.87 cial effect on dendritic epithelial keratitis, but not better Most clinical trials of the antiviral treatment of HSV than that of other antiviral agents, and was useful with epithelial keratitis have compared antiviral agents, but no debridement.5'7639i'9 A compelling and consistent observa- single treatment was used as a standard referent. Direct tion of this meta-analysis was the significantly improved pooling ofstudies with similar treatment arms and indirect treatment success produced by a combination of a topical treatment comparisons were, therefore, used to evaluate interferon and a topical nucleoside antiviral agent such as this array of studies. Compared to idoxuridine, the topical trifluridine or acyclovir. Previous literature surveys have application ofvidarabine, trifluridine, or acyclovir general- also noted the apparent benefit of interferon-antiviral ly resulted in a significantly greater proportion of patients treatment.9"9 With innovations in interferon production, healing within 1 week of treatment; however, ORs were combined interferon-nucleoside therapy may emerge as inconsistent and relatively imprecise. Among these 3 an improvement over currently available treatment for antiviral agents, no treatment emerged as significantly bet- HSV epithelial keratitis. ter for the therapy of dendritic epithelial keratitis. Indirect meta-analysis offers an opportunity to com- PREDICTIVE FACTORS pare treatments that are not directly compared in clinical trials.52 However, to estimate a summary effect, different Several studies noted that larger epithelial lesions healed patient groups must not interact with the strength of the more slowly. The treatment of geographic epithelial ker-

524 The Treatment ofHerpes Simplex Virus Epithelial Keratitis atitis, therefore, might present a more challenging way to studies provided healing curves without corresponding evaluate antiviral therapy. Geographic epithelial keratitis lifetables. Many studies unfortunately reported mean but is less common than dendritic keratitis, accounting for not median healing times and, if sufficient data were not only 5% of HSV epithelial keratitis in a population-based included, were not usable for this overview. The assess- study99 and 6% of patients in this meta-analysis; only 2 tri- ment of healing required subjective assessments by study als were restricted to geographic epithelial keratitis. Even investigators, but all studies used slit-lamp biomicroscopy. when these data were combined with treatment results for Fluorescein or rose-Bengal staining determined the day of this subcategory of epithelial disease reported by other resolution in over 80% ofincluded trials, although 1 group studies, the optimal therapy of geographic epithelial ker- of investigators°1""" reported both the time to initial reep- atitis cannot be determined from the available evidence. ithelialization and the day of reestablishment of a normal Except for lesion size, there were insufficient numbers of corneal surface. trials for each treatment comparison to productively The methodological quality varied among the trials undertake meta-regression. Even when grouping antiviral but gradually improved over time. Methodologically poor agents, no clear-cut stratification proved useful. Except studies can incorrectly overestimate treatment effect,'02 for lesion size, the effects of prognostic variables on reep- and other sources of confounding could bias the summa- ithelialization time were derived from retrospective sub- ry measures. Randomization presumably reduced bias group analyses. Their roles in corneal epithelial healing within most trials, but the method of treatment allocation remain to be evaluated from a priori hypotheses. The was unclear in many studies. The different placebos, the prognostic importance of suspected risk factors should be variable treatment dosages and formulations, and the considered in the design of future trials of HSV epithelial inconsistent use of cycloplegic and other adjunctive keratitis when developing eligibility criteria, planning agents could also confound the summary measures of baseline measurements, crafting randomized allocation, treatment effect. and performing stratified comparisons. Heterogeneity of some trials' findings limited pooling of selected treatment comparisons. A significant lack of VALIDITY homogeneity was noted among trials comparing idoxuridine and placebo, idoxuridine and acyclovir, vidarabine Potential weaknesses of a meta-analytic evaluation are the and acyclovir, physicochemical-antiviral combinations, incorporation of systematic errors from included studies and interferon and placebo. The Mantel-Haenszel ORs and the introduction of selection and information biases. based on a fixed-effects model are presented as weighted Limitations of this study include dissimilarities in treat- averages of individual study results for qualitative assessment dosage, formulation, or method; in eligibility criteria ment, and pooled effect measures in a random-effects of study participants; and in outcome assessment of model are reported for heterogeneous studies.103 corneal healing, for the grouped reports. Significance lev- els are tenuous and should be interpreted qualitatively. INTERPRETATION Publication bias is a concern, because not all reported trials provided extractable outcome information, and other The analyses in this systematic review aimed to provide a trials may have gone unpublished or unfound. Multiple critical, quantitative overview of previous clinical research search strategies attempted to detect all relevant studies and to yield, where possible, summary effect measures pertaining to HSV epithelial keratitis. Duplicated research with increased statistical power by combining multiple data were avoided, but selection bias could affect the meta- small clinical trials. Generalizing these findings depends analysis if unpublished data were not found. Efforts to upon the representiveness of the study population. Men avoid the inadvertent inclusion of overlapping publications were enrolled twice as often as women in most clinical tri- and to reduce the possible exclusion of unidentified trials als of HSV epithelial keratitis. Other studies have also sug- sought to enhance the validity of the summary estimates. gested that males are more likely to be treated for HSV Including nonrandomized concurrent studies may have epithelial keratitis,"53"884 but females may have been selec- biased the effect estimates, since assumptions concerning tively excluded from studies oftopical antiviral chemother- the selection and comparability of the treatment groups apy. Availability, cost, toxicity, and other considerations and the appropriateness of the statistical models for these must also be considered in determining optimal therapy trials could not be validly established. for an individual patient with HSV epithelial keratitis. Information bias was addressed by using a standard An important reason for undertaking this overview format to abstract information from journal articles and was the lack of sufficient power in most clinical trials of other sources and by applying a uniform outcome measure HSV epithelial keratitis. Most studies were too small to for all studies. Extrapolations were necessary because many prove either significant differences or equivalence

525 \Vilhelrnuis between treatments, aind improper use of significance tematic meta-analysis, and a large trial remain controver- testing in study interpretations could account for reported sial. s'i"' A large-scale randomized clinical trial comparing all null results. Most trials of HSV dendritic epithelial kerati- marketed antiviral agents has not been undertaken. Based tis showing no significant difference between treatments on tlhis systematic review, currently available antiviral agents were inconclusive because of inadequate sample sizes. A are effective and nearly equivalent, but the minority of trials in this meta-analysis achieved adequate combination of an antiviral nucleoside and interferon statistical power to ensuire a significant finding, and none seems to speed healing. A nucleoside-interferon preparation provided pretrial estimates of sample size based on may emerge as an improvement over a single agent or as an prospective alpha error allocation or anticipated epithelial alternative treatment for clinically resistant cases. This healing rates. After ensuring uniformity of effect meas- overview of the acute treatment of HSV epithelial keratitis ures among comparable studies, study results were aver- offers a valid basis for evidence-based ophthalmic therapeu- aged by weighting each by the inverse of its variance. tics and provides a foundation for further clinical research Since the pooled data from published trials suggest that into this common ocular disease. current antiviral agents achieve 80% to 90% healing within 2 weeks, subsequent trials comparing nearly equivalent REFERENCES treatments should plan to enroll sufficient numbers of 1. \Villelmnus KR. The epidemiology of ocular infections. In: Jaeger patients. 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