A Comparison of Acyclovir and Idoxuridine As Treatment for Ulcerative Herpetic Keratitis

Br J Ophthalmol: first published as 10.1136/bjo.64.10.763 on 1 October 1980. Downloaded from

British Journal of Ophthalmology, 1980, 64, 763-765

A comparison of acyclovir and idoxuridine as treatment for ulcerative herpetic keratitis

DOUGLAS J. COSTER, K. R. WILHELMUS, R. MICHAUD, AND BARRIE R. JONES From the Department of Clinical Ophthalmology, Institute of Ophthalmology, Moorfields Eye Hospital, City Road, London

SUMMARY Sixty patients were treated with either acyclovir 3% ointment or idoxuridine 1% ointment 5 times a day in a stratified randomised double-blind clinical trial. The 2 antiviral agents were equally effective.

Acyclovir (ACV, previously called Wellcome 248U The biological activity of acyclovir having been and acycloguanosine) is a compound active in confirmed in human viral disease, the next step was herpes simplex virus (HSV) infections. It has con- to compare the drug used in a more conventional siderable clinical potential because it is extremely manner to established antiviral chemotherapy. Here specific. Only cells infected with virus, and therefore we report the results of a trial comparing the effects with virus-coded thymidine kinase, phosphorylate of acyclovir and idoxuridine (IDU) ointments on the drug to a form capable of inhibiting DNA- the rate of healing of herpetic corneal ulcers. copyright. polymerase. Furthermore, it does not appear to be metabolised to inactive substances by human cells.1 Patients and methods The inhibition of viral coded DNA-polymerase is also highly specific. The potential value of the drug Sixty consenting patients presenting with ulcerative is related to its high specificity and low toxicity. herpetic keratitis were admitted to the trial. Patients Acyclovir has been demonstrated to possess potent were allocated to strata on the basis of clinical antiviral activity in vitro and in animal models of features likely to be significant in prognosis. The herpetic keratitis.2 stratification factors were the type of ulcer, that is, http://bjo.bmj.com/ Clinical studies have confirmed the activity of geographic or dendritic, the size of the ulcer, the drug in human herpetic disease. The first of whether the patient had received topical cortico- these studies involved debriding epithelial lesions steroids within the 3 weeks prior to presentation, produced by HSV and comparing the ability of and the degree of inflammatory reaction in the acyclovir to prevent lesion formation.3 When cornea and anterior chamber. Within these strata dendritic ulcers are treated with debridement alone, patients were randomly allocated to 1 of 2 treatment healing is rapid and patients become free of pain groups. One group received IDU 1% ointment 5 on September 27, 2021 by guest. Protected within 24-48 hours. However, 50% of patients so times a day until the epithelial defect had healed treated develop small foci of viral activity in the and then 3 times a day for 3 more days. The other epithelium within a week of treatment that requires group received acyclovir 3% ointment 5 times a day further debridement or antiviral chemotherapy.4 until the epithelial defect healed and then 3 times a Placebo-controlled trials designed to test an anti- day for a further 3 days. All patients received a viral agent's ability to suppress the formation of drop of atropine 1% each day until healed. Neither these microscopic lesions are capable of demon- the patient nor the ophthalmologist knew which strating a potentially useful biological activity while treatment was being used, so that the trial was subjecting a very small number of patients to a stratified, randomised, and double-blind. small amount of drug. Having begun treatment, patients were examined at the slit-lamp on alternate days. The point of Correspondence to Professor D. J. Coster, Department of healing was judged to have occurred when no Clinical Ophthalmology, Moorfields Eye Hospital, City epithelial defect was demonstrable with rose Bengal Road, London ECIV 2PD. and fluorescein staining. 763 Br J Ophthalmol: first published as 10.1136/bjo.64.10.763 on 1 October 1980. Downloaded from

764 Douglas J. Coster, K. R. Wilhelmus, R. Michaud, and Barrie R. Jones Results curves is likely to have occurred by change (P>0 05). When the geographic ulcers are excluded from the Sixty patients were admitted to the trial. Fifty-four analysis the difference between the groups is even had dendritic and 6 had geographic (amoeboid) less (Fig. 3). ulcers. Thirty received IDU and 30 received acyclovir. The distribution of patients is set out in Table 1. 100% One patient treated with acyclovir failed to present r 0 -A regularly for follow-up, though he responded ULCERS A favourably in that his geographic ulcer had healed HEALED ACV IDU when he returned 10 days after beginning therapy. 80 N = 29 N = 30 He is not included in the analysis. There were no treatment failures, nor were there any untoward reactions that necessitated withdrawal of therapy. One patient developed an allergic reac- 60 tion that subsided on withdrawing the atropine drops. The results were evaluated on the basis of the 40 number of days it took the ulcers to heal in each group. The distribution of healing times for patients in both treatment groups is set out in Fig. 1. A cumulative frequency curve indicating the pattern 20 of healing in each group is displayed in Fig. 2. Clearly the patterns are very similar, and a logrank analysis indicates that the difference between the I II - - _____j 5 10 15 25 DAYS Fig. 2 Cumulative frequency graph of the time taken copyright. Table 1 Distribution o patients with dendritic or to heal of59 herpetic corneal ulcers (54 dendritic, geographic ulcers to treatment group to receive S geographic) treated with acyclovir (ACV) or idoxuridine (IDU) or acyclovir (ACV) S-iodo-2' deoxyuridine (IDU).

IDU ACV l o r Geographic 4 2* Small dendritic 14* 14* ULCERS Large dendritic 12 14 HEALED ACV IDU http://bjo.bmj.com/ Total 30 30 80 N =28 N =26 Patients with marked inflammatory reaction in the corneal stroma and anterior chamber. 60

NO on September 27, 2021 by guest. Protected ULCERS 40

20 I

5 10 15 20 25 . . . DAYS 5 10 15 DAYS Fig. 1 Histogram ofhealing times ofherpetic ulcers Fig. 3 Cumulative frequency graph ofthe time taken treated with acyclovir (ACV) and 5-iodo-2' to heal of54 dendritic ulcers treated with acyclovir deoxyuridine (IDU). (ACV) or S-iodo-2' deoxyuridine (IDU). Br J Ophthalmol: first published as 10.1136/bjo.64.10.763 on 1 October 1980. Downloaded from

A comparison ofacyclovir and idoxuridine as treatment for ulcerative herpetic keratitis 765

Discussion to represent a different level of challenge and are capable of demonstrating a difference between The results of this trial establish that acyclovir is an antiviral agents that cannot be appreciated when effective antiviral agent for treating ulcerative only dendritic ulcers are studied.5 Herpetic corneal herpetic keratitis, since it is at least as active as ulcers which have failed to heal with IDU or IDU. debridement are another difficult problem with It is to be expected that such a trial will yield a which to challenge a prospective new topical null result. The majority of ulcers are dendritic antiviral agent. Stromal keratitis is also a form of rather than geographic. IDU is so effective for herpetic eye disease often resistant to current dendritic ulcers, with 100% of patients being therapy. An important challenge is to conduct trials healed within 14 days, that there is little chance of directed at evaluating this new antiviral agent in another antiviral agent bringing about a significant these sight-threatening conditions. Because of its improvement on what is achieved with IDU. This remarkably low toxicity and high specificity, is not to say that a null result is insignificant, but it acyclovir is a drug with exciting therapeutic poten- demands that trials be well designed, carefully con- tial. ducted, and the data be analysed in an appropriate manner. References A further limitation of trials evaluating antiviral agents as treatment for dendritic ulcers is that they 1 Schaeffer HJ, de Miranda P, Elion GB, Bauer JD, Collins do not provide any information on chronic toxicity, P. 9-(Hydroxyethoxymethyl) guanine activity against as the treatment viruses in the herpes group. Nature 1978; 272: 583-5. majority of patients complete the 2 Falcon MG, Jones BR. Acycloguanosine: antiviral programme in less than 2 weeks. This is a major activity in the rabbit cornea. Br J Ophthalmol 1979; 63: limitation, since it is the toxicity of antivirals that 422-4. limits their clinical usefulness. 3 Coster DJ, Jones BR, Falcon MG. Role of debridement Since it is established that acyclovir is as effective in the treatment of herpetic keratitis. Trans Ophthalmol Soc UK 1977; 97: 314-7. as IDU in the treatment of ulcerative herpetic 4 Jones BR, Coster DJ, Fison PN, Thompson GM, Cobo copyright. keratitis, the next step is to evaluate the drug in LM, Falcon MG. Efficacy of acycloguanosine (Wellcome situations in which currently employed therapeutic 248U) against herpes simplex corneal ulcers. Lancet 1979; measures are less than universally satisfactory. i: 243-4. 5 Coster DJ, Jones BR, McGill JI. Treatment of amoeboid Geographic ulcers are generally more difficult to herpetic ulcers with adenine arabinoside or trifluoro- treat than dendritic ulcers. They have been shown thymidine. Br J Ophthalmol 1979; 63: 418-21. http://bjo.bmj.com/ on September 27, 2021 by guest. Protected