ACTA 0 P H T H A L M 0 L O G I C A 67 (1989) 51-54

A comparison between acyclovir and trifluorothymidine ophthalmic ointment in the treatment of epithelial dendritic keratitis

A double blind, randomized parallel group trial

Gunnar Hravding

Department of Ophthalmology (Head: Torstein I. Bertelsen), University of Bergen, Bergen, Norway

Abstract. This report presents the results of a double blind randomized study comprising 50 patients with epi- thelial herpes simplex keratitis. Twenty-five patients re- ceived 3% acyclovir ophthalmic ointment, the other 25 patients 2% trifluorothymidine (TFT) ophthalmic oint- ment. The mean duration of treatment in the 2 study groups before healing of the epithelial ulceration was ob- tained was 6.7 days and 5.9 days, respectively (no statisti- cally significant difference). Two patients (8%) in the acy- clovir group and 1 patient (4%) in the TFT group failed to heal within 14 days of treatment. No clinically significant adverse effects were recorded.

Key words: acyclovir - trifluorothymidine - epithelial dendritic keratitis - double blind randomized study.

Since the first clinical trial with acyclovir in the treatment of epithelial herpes simplex keratitis (Jones et al. 1979), several reports have shown that this drug gives a significantly more rapid healing of the dendritic ulceration than treatment with idoxuridine (IDU), and that it is at least as effective as adenine-arabinoside (ara-A) (Collum et al. 1980; McGill et al. 1981; Klauber 8c Ottovay 1982; Young et al. 1982). Trifluorothymidine (TFT) has also been found to be superior to IDU and equal or bet- ter than ara-A (Wellings et al. 1972; Coster et al. 1976; Pavan-Langston 8c Foster 1977). A study by La Lau et al. (1982) has indicated that the efficacy of acyclovir and TFT in the treatment of epithelial herpes simplex keratitis do not differ sigdkantly. To the best of my knowledge, this is the only report

published on this topic, and another clinical study comparing the healing rate obtained by acyclovir and TFT in dendritic keratitis was therefore felt in- dicated.

Material and Methods Study group The study group initially included 55 patients con- secutively treated for epithelial dendritic keratitis at our department during the study period. Five of these patients did not attend the requested follow- up visits, and the final study group thus comprised 50 patients (23 females and 27 males) aged 14-86 years. The inclusion criterium was the clinical di- agnosis of a dendritic keratitis typical of a herpes simplex infection. Exclusion criteria included treatment with corneal epithelial debridement, anti-viral agents or steroids during the previous 14 days, as well as signs of secondary bacterial infec- tion of the corneal ulcer@), significant stromal dis- ease (a slight or moderate stromal infiltration around the ulcer was allowed) or other coexisting corneal pathology.

The patients were randomly allocated to receive an ophthalmic ointment containing either acy- clovir (13 females and 12 males) or trifluorothy- midine (10 females and 15 males). The mean age in the two treatment groups was 46.3 years and 45.6 years, respectively. There were no major imbalan- ces between the groups regarding previous deni

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Table 1. The frequency of healing within 1 week of treatment according to several single pre-treatment factors.

Acyclovir

Healed 5 7 d

No. Yo P

Total No.

TFT Whole study group

Healed 5 7 d

No. No.

Healed 5 7 d Totdl Total

No. Oh P No. %I P

n.s.* = not significant. **Other ulcer types = medium sized ulcers, a combination of small and large ulcers, multiple large ulcers and ulcers with a more geographic configuration.

dritic attacks, duration of symptoms, distribution of ulcer sizes or degree of stromal infiltration or uveitis (Table 1).

Methods The study was conducted as a double blind ran- domized trial. Each patient received 2 identical, masked tubes containing either 3% acyclovir or 2% TFT ophthalmic ointment. Epithelial debride- ment was not made, and with the occasional excep- tion of 1% atropine eye drops no other ocular treatment was given. About 1 inch ribbon of oint- ment was applied 5 times a day until healing of the corneal ulcer(s) was achieved. Healing was defined as the disappearance of epithelial ulceration(s) staining with fluorescein. The patients were re- examined 1, 2,3, 5 and 7 days after the treatment was started, and thereafter if necessary every 2-4 days until healing occurred. Modifications of this observation schedule were often made in order to

ensure the correct recording of the day of healing. At the first visit a patient history was obtained, in- cluding earlier ocular or cutaneous herpetic dis- ease and the duration of the present symptoms. At each visit a pencil drawing indicating the size and shape of the corneal ulcer(s) was made. In addition, the appearance of the corneal epithelium outside the ulceration(s), the degree of stromal infiltration and signs of uveitis were recorded. All the exami- nations were made by the author. The patients’s subjective symptoms and signs of drug adverse ef- fects were also noted.

The duration of treatment in the two test groups before healing was obtained were compared using the log rank test. The Fisher exact test was used to study the possible association between single fac- tors such as ulcer size, degree of stromal infiltra- tion and signs of uveitis on the one hand, and on the other hand the frequency of healing within the first week of treatment.

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Percent not healed

weeks of treatment in more than 90% of the pa- tients receiving acyclovir or TFT ophthalmic oint- ment. This frequency of healing compared well with previous reports of therapeutic trials with these medications, and confirmed that the fre- quency af healing obtained with acyclovir or TFT is significantly higher than that to be expected during IDU treatment (Wellings et al. 1972; Pavan- Langston & Foster 1977; Collum et al. 1980; Jensen et al. 1982; Klauber & Ottovay 1982; La Lau et al. 1982). The present frequency of healing was also at least as high as that previously reported during ara-A treatment (Coster et al. 1976; McGill et al. 1981; Young et al. 1982). In accordance with the findings reported by La Lau et al. (1982), our re- sults showed that the efficacy of acyclovir and TFT in the treatment of epithelial dendritic keratitis is very similar. Several single pre-treatment factors (duration of symptoms before treatment, degree of stromal infiltration, signs of uveitis and a history of previous dendritic keratitis) were not found to be significantly correlated to the successifailure of the treatment. It should be remembered, however, that none of our patients had a significant degree of stromal involvement or uveitis.

In conclusion, our results confirmed that the ef- ficacy of acyclovir and TFT ophthalmic ointment in the treatment of epithelial herpes simplex ker- atitis is very similar, that both drugs are highly ef- fective and well tolerated, and that they at present obviously are the drugs of choice in the treatment of this disease.

80-

60-

40-

2 0 -

- Acyclovir TFT _---

Results

The mean duration of treatment before healing was obtained was slightly shorter in the patients receiving TFT (mean 5.9 days, SE 0.65 days) than in those treated with acyclovir (mean 6.7 days, SE 0.81 day), but this difference was not statistically signifi- cant (Fig. 1). The approximate confidence interval for the mean difference in healing time in the 2 groups was -1.4-+2.8 days. One patient in the TFT group and 2 patients in the acyclovir group failed to heal within 14 days. Thus, during this treatment period 96% of those receiving TFT and 92% of those treated with acyclovir were healed (no statistically significant difference).

An analysis of the possible influence of several single pre-treatment factors on the frequency of healing within the first week of treatment is shown in Table 1. If regarded separately, neither the dura- tion of symptoms before treatment was started, a history of previous herpes simplex keratitis, the size of the ulcer(s), nor the degree of stromal idil- tration or uveitis were in this respect shown to be of statistical significance.

Apart from a slight epithelial punctate kerato- pathy in a few patients in both treatment groups, no drug adverse effects were observed.

Discussion

In the present study, complete healing of the epi- thelial dendritic ulceration was obtained within 2

References

Collum L M T, Benedict-Smith A & Hillary I B (1980): Randomized double-blind trial of acyclovir and idoxu- ridine in dendritic corneal ulceration. Br J Ophthal- mol64: 766-769.

Coster D J, McKinnon J R, McGill J, Jones B R & Fraun- felder F T (1976): Clinical evaluation of adenine arabi- noside and trifluorothymidine in the treatment of cor- neal ulcers caused by herpes simplex virus. J Infect Dis- ease 133: A173-177.

Jensen K B, Nissen S H & Jessen F (1982): Acyclovir in the treatment of herpetic keratitis. Acta Ophthalmol (Co- penh) 60: 557-563.

Jones B R, Fison P N, Cob0 L M, Coster D J, Thompson G M & Falcon M G (1979): Efficacy of acycloguanosine (Wellcome 248u) against herpes-simplex corneal ul- cers. Lancet 1: 243-244.

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Klauber A & Ottovay E (1982): Acyclovir and idox- iuridine treatment of herpes simplex keratitis - a double blind clinical study. Acta Ophthalmol (Co- penh) 60: 838-844.

La Lau C, Oosterhuis J A, Versteeg J, van Rij G, Renardel de Lavalette J G C, Craandijk A A & Lamers W P M A (1982): Acyclovir and trifluorothymidine in herpetic keratitis: a multicenter trial. Br J Ophthalmol 66: 506-508.

McGill J, Tormey P & Walker C B (1981): Comparative trial of acyclovir and adenine arabinoside in the treat- ment of herpes simplex corneal ulcers. Br J Ophthal- mol 65: 610-613.

Pavan-Langston D & Foster C S (1977): Trifluorothy- midine and idoxuridine therapy of ocular herpes. Am J Ophthalmol84: 819-825.

Wellings P C, Awdry P N, Bors F H, Jones B R, Brown D C & Kauftnan H E (1972): Clinical evaluation of trifluoro- thymidine in the treatment of herpes simplex corneal ulcers. Am J Ophthalmol 73: 932-942.

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Received on June 29th, 1988.

Author's address: Gunnar H~vding, MD, Department of Ophthalmology, N-5022 Haukeland sykehus, Norway.

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