A Double-Controlled Evaluation of Acyclovir and Vidarabine for the Treatment of Herpes Simplex Epithelial Keratitis*

A DOUBLE-CONTROLLED EVALUATION OF ACYCLOVIR AND VIDARABINE FOR THE TREATMENT OF HERPES SIMPLEX EPITHELIAL KERATITIS*

BY William R. Yeakley, MD, (BY INVITATION) Peter R. Laibson, MD, Marc A. Michelson, MD (BY INVITATION) AND (BY INVITATION)JuanJ. Arentsen, MD

THE CURRENTLY AVAILABLE OCULAR ANTIVIRAL DRUGS, IDOXURIDINE, VIDARABINE, and trifluorothymadine, are effective against herpes simplex virus epithelial keratitis. All of these drugs can produce toxic side effects such as punctate keratopathy, conjunctival hyperemia, edema, scarring and punctal occlusion. They can reduce stromal wound strength and collagen content. 1,2 These antiviral drugs do not prevent superficial or deep stromal keratitis and do not eliminate viral neuronal reservoirs. The systemic toxicity of these drugs is largely the result of their detrimental effect on normal host DNA synthesis. Acyclovir, formerly called acycloguanosine [9-(2-hydroxyethoxymethyl) guanine], is a highly potent3 and specific4 antiviral drug which is ther- apeutically active against herpes simplex virus types 1 and 2 and varicella zoster virus. In vitro studies have shown that acyclovir preferentially enters herpes simplex infected cells.4 Unlike the other available antiviral drugs, acyclovir is activated only by viral-induced thymidine kinase present in herpes simplex infected epithelial cells. Normal uninfected epithelial cells are not affected by acyclovir. This specificity ofacyclovir for viral infected cells accounts for the lack of host toxicity and the potential for systemic administration. In addition, acyclovir is the only antiviral drug which does not interfere with either epithelial or stromal wound healing.5 Thus, the advantages of acyclovir over the presently available antiviral drugs include its high potency, selectivity of action, and potential as a systemic medication. *From the Cornea Service, Wills Eye Hospital, Philadelphia, PA. TR. AM. OPHTH. Soc. vol. LXXIX, 1981 Herpes Simplex Keratitis 169 The results of previous studies evaluating the therapeutic efficacy of topical 3% acyclovir ointment used five times daily in the treatment of herpes simplex keratitis in experimental animals have been variable. Acyclovir ointment was found as effective as idoxuridine ointment in several studies' 7'8 or more effective than idoxuridine ointment and vidarabine ointment."89 Acyclovir was as effective as trifluorothymidine solution in yet another report.10 In a double-masked clinical study evaluating the efficacy of topical acyclovir idoxuridine in treating human dendritic corneal ulcerations, all thirty patients treated with acyclovir healed (average 4.4 days to heal) whereas only 22 of 29 patients receiving idoxuridine healed (average 9.2 days to heal).12 A second randomized double-blind clinical trial comparing acyclovir 3% ointment and idoxuridine 1% ointment in treating ulcerative herapetic keratitis in 60 patients demonstrated no significant difference in efficacy between these two drugs. 13 No significant adverse effects oftopical acyclovir have been reported. A mild transient stinging sensation was noted immediately after application ofacyclovir ointment in 18% to 27% of patients in two reports. 12"14 Mild superficial punctate epitheliopathy was noted in approximately 16% ofpatients after 14 days ofacyclovir therapy in another study. 14 In this paper we will report our findings ofa prospective, randomized, double-masked clinical study evaluating the therapeutic efficacy and safety of 3% acyclovir ointment 3% vidarabine ointment for treatment of acute epithelial herpetic keratitis in forty patients.

SUBJECTS AND METHODS

PATIENTS Forty patients were treated in a double-masked fashion. Twenty-seven men and thirteen women, ranging in age from seven to eighty-one years, were entered in the study. Seventeen patients had primary herpetic keratitis and twenty-three patients had recurrent herpetic keratitis. Thirty-eight patients had typical dendritic keratitis. One patient had predominantly dendritic lesions with smaller areas of geographic ulceration, and another patient had a herpetic marginal (limbal) ulcer. Since we wanted to test the efficacy ofthe antiviral drugs in acute epithelial herpetic disease, only those patients who were symptomatic forfourteen days or less were included in the study. Usually patients with epithelial herpetic lesions and symptoms for longer than fourteen days have some stromal changes which can complicate the course of epithelial healing; such patients were not entered in the study. 170 Laibson Patients with primary or recurrent epithelial herpetic keratitis with or without stromal keratitis and/or uveitis were admitted to the study. Those patients on topical corticosteroids for stromal disease and/or uveitis co- existing with active epithelial ulcerative keratitis were included. No patient who had received other antiviral therapy one week prior to the study was admitted to the study. Additional criteria for exclusion from the study included: (1) concomitant microbial keratitis, acute trauma, or corneal graft in the affected eye; (2) a history ofherpetic keratitis clinically unresponsive to vidarabine or a history of hypersensitivity to vidarabine; (3) prior administration ofimmunomodulators (eg, BCG, levamisole, etc); (4) preg- nant women or nursing mothers; and (5) patients who had been debrided during their presenting episode of herpetic keratitis.

ANTIVIRAL DRUGS AND DOSAGE Zovirax" brand acyclovir ophthalmic ointment 3% and Vira-A brand vidarabine ophthalmic ointment 3% were supplied by Burroughs Well- come Co. The drugs were packaged in sequential order by random code number designation and were dispensed sequentially. The patients were instructed to apply a halfinch "ribbon" ofthe drug to the lower cul-de-sac of the infected eye at four hour intervals while awake for a total of five applications daily for fourteen days.

CLINICAL EVALUATION All patients were questioned regarding the number of previous attacks of herpetic keratitis and previous use of antiviral drugs and/or topical or systemic steroids. None of the patients were using any concurrent medication, such as systemic corticosteroids, that might interfere with the drug evaluation. All patients were informed ofthe double-masked nature ofthe study and were asked to return for examination on study days 2, 4, 7, 10, 15, and 21. On each visit, the clinical evaluation of the patient included: (1) best corrected visual acuity; (2) number of epithelial lesions present, as deter- mined by fluorescein staining; (3) total lesion area, as measured using the Haag-Streit 900 slit lamp; (4) diagnosis based on herpes simplex virus ocular code of McKinnon, McGill, and Jones'5; (5) graded assessment of the symptoms and signs ofinfection; and (6) documentation ofany adverse effects oftherapy. Each patient was questioned about the following symptoms: foreign body sensation, excess lacrimation, photophobia, and itch- ing. The signs of infection evaluated at each visit included; bulbar and/or palpebral injection, follicles, papillae, aqueous cells and flare, keratic precipitates, superficial punctate keratitis, and punctal occlusion. These Herpes Simplex Keratitis 171 clinical symptoms and signs were graded according to a four point scale (0-none, 1-mild, 2-moderate, and 3-severe).

LABORATORY EVALUATION Viral cultures were taken prior to starting antiviral therapy and again on the first post-treatment day (study day 15). All specimens were collected by swabbing the superior and inferior cul-de-sac of the infected eye with a calcium alginate swab moistened with transport medium (minimal essen- tial medium + 10% fetal calfserum + penicillin (100 U/ml) + streptomy- cin (100 ,ug/ml). Specimens were immediately taken in transport medium in an ice bath to the laboratory for inoculation. Rabbit corneal epithelial cells were used for culturing the virus. During a two-week incubation period, the cultures were examined daily for specific cytopathic effect and were reported as positive or negative. Corneal epithelial healing was used as the primary parameter for evaluating the efficacy ofacyclovir versus vidarabine. Healing was defined as the absence offluorescein staining or punctate staining in the area ofprevious corneal ulceration within the treatment period without recrudescence. Viral culture data and clinical signs and symptoms data were used as additional important measures of drug efficacy.

RESULTS Nineteen patients were treated with acyclovir and twenty-one received vidarabine. All patients used the medication as directed, and no patient was lost to follow-up prior to complete corneal re-epithelialization. The two groups ofpatients were similar with regard to sex and age distribution (Table I). In their acyclovir group, 15 patients were symptomatic for seven days or less prior to beginning the double-masked trial, and four patients had symptoms for 8 to 14 days before entering the study. In the vidarabine group, 18 patients were symptomatic for seven days or less,

TABLE I: PATIENT STUDY GROUP TREATMENT NO. OF SEX AGE (yrs) GROUP PATIENTS MALE FEMALE RANGE MEAN ACV 19 12 7 19-77 55 Ara-A 21 15 6 7-81 44 Total 40 27 13 7-81 49 ACV = Acyclovir Ara-A = Vidarabine 172 Laibson

TABLE II: DRUG EFFICACY THERAPY HEALED FAILED TO HEAL TOTAL ACV 19 0 19 Ara-A 20 1 21 Total 39 1 40 and three patients had symptoms for 8 to 14 days. The mean initial corneal ulcer size was 5.02 mm2 for the acyclovir group and 3.62 mm2 for the vidarabine group. Seventeen ofthe 19 patients who were treated with acyclovir presented with typical dendritic lesions. One patient had both dendritic and geographic lesions, and one patient had a herpetic marginal (limbal) ulcer. All 21 patients who received vidarabine had typical dendritic ulcers at entry into the study. There were no treatment failures among the 19 patients who received acyclovir and one treatment failure among the 21 patients treated with vidarabine (Table II). A treatment failure was defined as a patient who used the drug properly but (1) the lesion increased in size by treatment day 4, (2) the lesion had not decreased in size by day 7, or (3) the lesion had failed to completely heal by day 14. The one failure receiving vidarabine had a dendritic ulcer which showed no decrease in size by the seventh day of therapy. The one patient with a herpetic marginal ulcer was treated with acyclovir and took two days to heal. The patient with combined dendritic and geographic ulcerations also received acyclovir and required ten days to re-epithelialize. The nineteen patients treated with acyclovir took an average of 4.42 days to heal (range 2 to 10 days) while the twenty patients on vidarabine healed in an average of 4.45 days (range 2 to 8 days), as shown in Table III. The cumulative rate of healing for both treatment groups appears in Figure 1. There was no statistically significant difference between the two groups in terms of healing rate. In the acyclovir group, three patients presented with stromal keratitis as well as epithelial herpetic lesions. In two ofthese patients, the stromal

TABLE III: CORNEAL HEALING TIMES MEAN INITIAL NO NO DAYS TO HEAL* LESION AREA THERAPY EVAL HEALED MEAN RANGE (mm2) ACV 19 19 4.42 2-10 5.02 Ara-A 21 20 4.45 2-8 3.62 *Excluding Failures 173 100

60 %~~~~~~~~~

p 5 0 | f Acyclovir T f ll ---- Vidarabine T r H 30

E J

D 20

2 4 6 8 10 12 14 16 18 20 22 STUDY DAY

FIGURE 1 Cumulative percentage of patients healed on acyclovir and vidarabine at each study day. 174 Laibson

TABLE IV: PATIENTS DEVELOPING SECONDARY INVOLVEMENT ON ACV HSV CODE SYMPTOMS SECONDARY INVOLVEMENT PATIENT AT ENTRY (DAYS) TYPE DAYS F M DURR 10 Stromal Ker 2 N R DURR 5 Stromal Ker 2 C D DU 14 Stromal Ker 2 J H DU 7 Stromal Ker 4 DURR = Recurrent Dendritic Ulcer DU = Primary Dendritic Ulcer keratitis resolved by study day 10, and in the third patient, the stromal changes were improved but not completely resolved by the time the patient's dendritic lesion was healed. Two patients in the acyclovir group presented with disciform keratitis in addition to the epithelial lesions. The disciform changes resolved by day 10 and day 15 in these two patients. In the vidarabine group there was one patient who had herpetic stromal keratitis and uveitis as well as dendritic ulcers upon entry into the study. The ulcer healed by day 2 and the keratouveitis resolved by day 7. Two additional patients in the vidarabine group, one with stromal keratitis and the other with uveitis when admitted to the study, still had these changes present (although improved) on day 21. Superficial stromal haze beneath the dendritic ulcer developed during the treatment period in four patients on acyclovir and in four patients on vidarabine (Tables IV and V). In addition, herpetic uveitis developed in one patient and disciform keratitis in another patient during treatment with vidarabine. Diffuse superficial punctate epitheliopathy was noted in one patient on acyclovir on study day 9 (5 days following corneal re-epithelialization) and resolved within two days after the drug was discontinued. No other adverse effects were noted in either drug treatment group during the course of therapy.

TABLE V: PATIENTS DEVELOPING SECONDARY INVOLVEMENT ON ARA-A HSV CODE SYMPTOMS SECONDARY INVOLVEMENT PATIENT AT ENTRY (DAYS) TYPE DAYS F P DURR 1 Stromal Ker 21 P C DU 5 Stromal Ker 7 L C DURR 1 Uveitis 4 W R DURR 2 Disciform 2 J L DU 9 Stromal Ker 4 D P DU 5 Stromal Ker 4 DURR = Recurrent Dendritic Ulcer DU = Primary Dendritic Ulcer Herpes Simplex Keratitis 175 The corneal healing results were analyzed in terms ofpresenting condi- tion (primary vs recurrent disease), duration of symptoms (less than 7 days vs 7 to 14 days), and ophthalmic corticosteroid use (within two weeks before the study vs longer than two weeks before the study). No significant difference in rate of corneal healing attributable to these factors was found. The resolution of symptoms in patients receiving acyclovir and vidarabine paralleled the course of corneal re-epithelialization, and there were no significant differences between the two treatment groups. Thirteen of 40 (32.5%) pre-treatment conjunctival viral cultures were positive. This low yield of positive pre-treatment cultures was attributed to the culture technique. Specimens were obtained from the conjunctival fornices rather than from the edges of the corneal ulcerations. Directly culturing the ulcerative lesions was not done since this might have affected the rate of corneal healing. All post-treatment viral cultures were negative with the exception of one patient on vidarabine who had a positive culture on study day 15.

DISCUSSION Acyclovir is an acyclic purine nucleoside analogue with highly potent and specific activity against herpes simplex virus types 1 and 2. Although in vitro studies3 have shown acyclovir is a more potent antiherpetic drug than those currently in use, the present study indicates both acyclovir and vidarabine are equally effective when used topically in the treatment of epithelial herpetic keratitis. Significant side effects were not encountered with either drug over the 14 day therapy period. Wilhelmus, Coster, and Jones14 found superficial punctate epitheliopathy in 16% of patients, usually occurring 14 days after starting acyclovir treatment. McGill (personal communication) found a 20% incidence of superficial punctate keratopathy in patients treated with topical acyclovir in his recent trial comparing acyclovir and vidarabine in treating herpes simplex and herpes zoster keratitis. In the present study, we found a 5% incidence of this adverse reaction among the patients receiving acyclovir. This side effect disappears within a few days after discon- tinuation of acyclovir. As yet, no one has shown whether the superficial punctate keratopathy is an adverse effect of acyclovir or is due to the ointment vehicle. Our study shows that topical acyclovir is efficacious in treating superficial herpetic keratitis. Neither topical acyclovir nor topical vidarabine is able to prevent the development of deeper secondary stromal changes in 176 Laibson herpetic keratitis. Ideally, we need a systemically active, non-toxic antiviral drug effective in situations in which current antiviral therapy is limited (eg, the t9erapy of deep herpetic stromal disease and the prevention of recurrent herpetic disease). Pavan-Langston, Park, and Lass'6 have shown that systemic acyclovir results in a significant reduction in recovery of latent herpes simplex virus from the trigeminal ganglia in mice following ocular infection. Trousdale, Dunkel, and Nesburn, 17 using the rabbit ocular model, have shown that topical acyclovir treatment does not prevent the establishment oflatent herpes simplex virus infection and that intravenous acyclovir therapy in rabbits with latent herpes infection reduces recoverable herpes simplex virus in the central nervous system, but does not eradicate existing latent herpetic infection. Further studies are needed to investigate the efficacy of topical and systemic acyclovir in patients with deep stromal herpetic keratitis and to evaluate this drug's ability to prevent recurrent herpetic disease. Because of its low toxicity and high specificity, acyclovir appears to have potential for systemic use.

REFERENCES 1. Langston R, Pavan-Langston D, Dohlman C: Antiviral medication and corneal wound healing. Arch Ophthalmol 92:509, 1974. 2. Foster CS, Pavan-Langston D: Corneal wound healing and antiviral medication. Arch Ophthalmol 95:2062, 1977. 3. Schaeffer HJ, Beauchamp L, deMiranda P, et al: 9-(2-hydroxyethoxymethyl)quanine activity against viruses of the herpes group. Nature 272:583, 1978. 4. Elion GB, Furman PA, Fyfe JA, et al: Selectivity of action of an anti-herpetic agent, 9-(2-hydroxyethoxymethyl)quanine. Proc Natl Acad Sci USA 74:5716, 1977. 5. Lass JH, Pavan-Langston D, Park NH: Aciclovir and corneal wound healing. Am J Ophthalmol 88:102, 1979. 6. Kaufman HE, Varnell ED, Centifanto YM, et al: Effect of 9-(2-hydroxyethoxymethyl)quanine on herpes virus-induced keratitis and iritis in rabbits. Antimicrob Agents Chemother 14:842, 1978. 7. Shiota H, Inoue S, and Yamane S: Efficacy ofacycloguanosine against herpetic ulcers in rabbit cornea. Br J. Ophthalmol 63:425, 1979. 8. Bauer DJ, Collins P, Tucker WE Jr, et al: Treatment of experimental herpes simplex keratitis with acycloguanosine. Br J Ophthalmol 63:429, 1979. 9. Pavan-Langston D, Campbell R, Lass J: Acyclic antimetabolite therapy ofexperimental herpes simplex keratitis. Am J Ophthalmol 86:618, 1978. 10. Paven:Langston D: Current trends in therapy of ocular herpes: experimental and clinical studies. Gauri K. (ed): Advances in Ophthalmology, vol 38, Basel, Karger, 1979, p 82. 11. Jones BR, Coster DJ, Fison PN, et al: Efficacy of acycloguanosine (Wellcome 248U) against herpes-simplex corneal ulcers. Lancet 1:243, 1979. 12. Collum, LMT, Benedict-Smith A, Hillary IB: Randomised double-blind trial of acyclovir and idoxuridine in dendritic corneal ulceration, Br J Ophthalmol 64:766, 1980. 13. Coster DJ, Wilhelmus KR, Michaud R, et al: A comparison ofacyclovir and idoxuridine as treatment for ulcerative herpetic keratitis. BrJ Ophthalmol 64:763, 1980. Herpes Simplex Keratitis 177

14. Wilhelmus KR, Coster DJ, Jones BR: Acyclovir and debridement in the treatment of ulcerative herpetic keratitis. Am J Ophthalmol 91:323, 1981. 15. McKinnon Jr, McGill J, Jones BR: Summary code for ocular herpes simplex. Br J Ophthalmol 59:539, 1975. 16. Pavan-Langston D, Park NH, Lass JH: Herpetic ganglionic latency: acyclovir and vidarabine therapy. Arch Ophthalmol 97:1508, 1979. 17. Trousdale MD, Dunkel EC, Nesbum AB: Effect ofacyclovir on acute and latent herpes simplex virus infections in the rabbit. Invest Ophthalmol Vis Sci 19:1336, 1980.

DISCUSSION DR WALTER J. STARK. It is my pleasure to discuss the paper presented by Doctor Laibson on the treatment of herpes simplex keratitis using a new antiviral agent, acyclovir. The three drugs currently available for treatment of herpes simplex keratitis are: idoxuridine (IDU), vidarabine (Vira-A), and trifluorothymidine (TFT). Al- though these drugs are all effective in the treatment of herpes simplex dendritic keratitis, there may be some differences in their efficacy for the treatment of geographic corneal ulcers, especially those associated with the use of topical corticosteroids. However, as pointed out by Doctor Laibson, these medicines all have potential toxic side-effects, especially with prolonged use or abuse. Acyclovir (ACV) not only has a potent antiviral action' against herpes simplex virus types I and II and varicella zoster virus, but-as pointed out by Doctor Laibson-acyclovir also has a selective toxic action against the virus itself, as opposed to the non-infected host cell. This high antiviral specificity and low degree of host toxicity make acyclovir an especially promising drug for ocular herpes. In this double-masked clinical trail presented by Doctor Laibson, he and his co-workers have compared acyclovir to Vira-A in the treatment of ulcerative herpes simplex keratitis, and they have found no clinically-significant difference in the healing time ofthe ulcer, the development ofstromal keratitis, or toxicity of the two drugs. Doctor Laibson's results parallel the overall results of acyclovir clinical trials sponsored by the Burroughs Wellcome Company (Stephen Hutcherson, Personal Communication). In those studies 96% (142 of 148) eyes responded favorably to acyclovir. Evidence of toxicity, which has been minimal, includes mild erythema in a few patients; but it is difficult to determine whether this is from thV drug or the disease. One case of punctal occlusion with use of topical acyclovir has been reported. From the results of this study and other clinical trials in which we have also participated, it appears that dendritic herpetic keratitis responds equally well to acyclovir, trifluorothymidine, and Vira-A, and possibly even IDU. In the present study and others sponsored by Burroughs Wellcome, healing was defined as the absence of fluorescein staining in the area of previous corneal ulceration. Although this is an adequate definition for an experienced observer such as Doctor Laibson, there may remain areas of punctate or localized staining 178 Laibson with fluorescein in areas of poor re-epithelialization despite eradication of the herpes virus. For this reason, we prefer to use 1% rose bengal dye to monitor epithelial healing. The rose bengal dye stains the damaged or devitalized epithelium, whereas the fluorescein stains the bare stroma. In dendritic keratitis the virus-infected cell takes on rose bengal stain and is called a "balloon cell" or "swollen cell" (slide). Rose bengal also can demonstrate extension of the dendrite onto the conjunctiva (slide), and helps distinguish trophic or non-infected ulcers versus the infected geographic herpetic ulcers (slide). In this and other comparative clinical trials of drugs, debridement of the infected epithelium is not permitted. In fact, the viral cultures, as mentioned by Doctor Laibson, must be taken from the conjunctiva so as not to debride the virally-infected cells. Prior studies, however, have demonstrated the effectiveness of gentle debridement of epithelial herpes, and debridement plus medication usually results in more-rapid healing ofan epithelial dendrite than with any antiviral medication alone. However, if no antiviral medications are used after debridement, focal dendritic lesions recur in about 60% of cases within 7 days. Therefore, for practical purposes the recommended therapy for dendritic keratitis today in the non-study situation is gentle debridement of the area with a cotton- tipped applicator to remove the loosened and diseased corneal epithelium at the ulcer edge (slide). This is followed by application of the chosen antiviral medication, five times daily. A recent study by Wilhelmus and co-workers (Am J Ophthalmol 91: 323-327, 1981) has demonstrated that debridement followed by topical acyclovir therapy produced a significantly more-rapid healing rate than did acyclovir alone. In that study, 6 patients developed herpes simplex kerato-uveitis within 6 months of therapy. Five of these six had not been treated with epithelial debridement. The authors speculated that use of debridement might reduce the amount of viral antigen getting into the stroma, thus helping prevent kerato-uveitis. The major problems with ocular herpes are recurrent epithelial disease and corneal stromal inflammation and scarring. Doctor Laibson has pointed out that no study to date has shown the effectiveness oftopically-applied antiviral agents in the prevention of viral recurrence and stromal inflammation. In fact, Doctor Laibson and others have shown that there is a 25% chance of a second attack of ocular herpes within five years of the initial episode; and that if there is a second attack, there is a 45% chance ofa third attack. Therefore, it appears that there is a great need for a medication that prevents herpes simplex keratitis from recurring. The site of the reservoir that provides the source of recurrent herpes simplex virus of the eye appears to be in the trigeminal-nerve ganglion, and periodic nonspecific stimuli seem able to trigger reactivation of the virus. The virus then travels down the nerve, to erupt at the peripheral site of innervation, leading to recurrent keratitis (slide). Destruction ofthe latent virus in the ganglion site is not yet possible in man. However, because of the apparently low degree of host toxicity of acyclovir and the high degree of antiviral specificity, this drug may provide a systemic treatment to eradicate the virus infection within the trigeminal-nerve ganglion itself. Acyclovir has been used systemically for the treatment of non-ocular viral Herpes Simplex Keratitis 179 infections. Preliminary data from these studies, involving the systemic use of acyclovir for generalized herpes simplex and generalized varicella virus infections in immunosuppressed (leukemic) patients, indicate that the drug is safe and effective. For the eye, studies involving the systemic use of acyclovir for herpes simplex keratitis and recurrent keratitis are currently being planned. In the laboratory animal, Pavan-Langston and co-workers (Arch Ophthalmol 97:1508-1510, 1979) demonstrated the therapeutic efficacy of systemically-administered acyclovir in reducing the establishment of latent herpes simplex infection in the trigeminal- nerve ganglion in the mouse, and they also demonstrated a reduction in laboratory recovery of the latent virus when it had become established. However, others have not been able to confirm this efficacy of systemic use of acyclovir in the treatment of established latent herpes-simplex infection in the trigeminal- nerve ganglion. Further studies are definitely needed in this important area of virus research, because recurrent herpes-simplex keratitis is one of the leading causes of corneal blindness in man. Doctor Laibson is to be congratulated for his work and his presentation, and we encourage him to continue this productive and important line of research. DR WILLIAM F. HUGHES. It is disappointing that a specific antiviral drug such as acyclovir is no less toxic to the cornea than a more non-specific drug such as vidarabine which also damages normal cells. Also, this study emphasizes the value of clinical trials in spite of theoretical considerations. DR DAN B. JONES. I would like to add a few comments about the current status of acyclovir for therapy of other viral infections. As you heard, the drug is active in vitro against varicella-zoster virus. Unfortunately, unlike other agents, acyclovir appears to be poorly active in vitro against cytomegalovirus. Preliminary trials in Great Britain with intravenous acyclovir in herpes zoster suggest that the com- pound reduces the time ofdevelopment ofnew lesions and the time for crustation of lesions. Unfortunately, intravenous acyclovir did not reduce the incidence or severity of ophthalmic complications among 15 patients with trigeminal zoster. The drug also did not significantly alter the incidence ofpostherpetic neuralgia in this group. Acyclovir is being developed as an oral formulation and hopefully will be used in clinical trials for herpes simplex stromal keratitis as well as other forms ofvaricella-zoster infection. With regard to the therapy ofherpes simplex epithelial keratitis, it is important to distinguish minimal wiping debridement used by the Moorfields group from standard debridement employed by practitioners in this country. Doctor Stark's slide indicated a 60% recurrence rate of epithelial keratitis following debridement, but this was indeed the minimal wiping technique. The standard method ofremoving a relatively wide area ofepithelium with a blunt spatula is equally effective as antiviral therapy in simple dendritic keratitis. The Moorfields group found that patients with epithelial keratitis are more comfortable following gentle removal of the diseased epithelium by rolling a cotton swab over the cornea. This technique is followed by standard application of an antiviral agent.