Documenta Ophthalmologica 44,1 : 23-33, 1977

T R E A T M E N T OF HERPETIC K E R A T I T I S

J O H N BLAKE & M A R I O N BROWNE

(Dublin)

ABSTRACT

Idoxuridine which was first used in 1960 (Kaufman et al., 1962), has been for many years the only antiviral agent available in the treatment of herpetic keratitis. It is however no more successful than is mechanical removal of diseased epithelium (Patterson & Jones, 1967), and furthermore it may give rise to serious toxic side effects. The search for an alternative medication is therefore a pressing one.

Trifluorothymidine (F3T) has, in recent years, been shown to be more effective than IDU and to be free from significant toxicity. Both of these drugs are pyri- midine nucleosides.

Adenine Arabinoside or Arabinoside-A (Ara-A) is, by contrast, a purine nucleo- side. It is thought to exert its antiviral effect by blocking DNA polymerase and ribonucleOtide reductase.

Over a per iod of two years we u n d e r t o o k a study to de termine whether

Arabinoside-A is effect ive in the management of epithelial herpet ic kerati t is

and to assess the acceptabi l i ty and to lera t ion of the eye o in tment . As IDU

is the accepted standard of t r ea tment we were able to carry out a double-

blind compar ison of two groups, one t reated with 3% adenine arabinoside

eye o in tmen t and the o ther wi th 0.5% idoxur id ine eye o in tment . 30 pat ients

with acute or recurrent active epithelial herpet ic keratit is were studied, the

diagnosis being made on the typical findings of dendri t ic or geographic

ulcers wi th or wi thou t s t romal involvement .

Patients with disciform keratit is and those who had been t reated with an

antiviral drug within the previous 7 days were excluded.

R a n d o m assignment resulted in 17 pat ients being t reated with arabinoside-

A and 13 with IDU eye o in tmen t (Table 1). The o in tmen t was applied four

t imes a day unti l re-epithelial isat ion was comple te after which the f requency

of applicat ion was reduced to twice a day for the nex t 7 days.

If the lesion failed to improve or was worse by the seventh day, i f com-

plete re-epithelial isat ion had n o t occurred by the four teen th day, or if the

disease worsened during the per iod of t r ea tment with reduced f requency,

the t r ea tment was considered a failure and the drug al locat ion code broken.

23

io

.Ix

Tab

le 1

. C

har

acte

rist

ics

of

trea

tmen

t g

rou

ps

Pat

ien

t A

ge

Sex

D

iag

no

stic

D

ura

tio

n o

f P

revi

ous

eye

Oth

er d

isea

se

nu

mb

er

(yea

rs)

cate

go

ry

dise

ase

(day

s)

dise

ase

Ara

-A G

rou

p

1 59

M

G

eog

rap

hic

4

Her

pes

Ker

atit

is

4 35

M

D

end

riti

c S*

6

No

5 52

M

D

end

riti

c S

3 H

erpe

s K

eraf

itis

10

33

F

Den

dri

tic

M*

7 N

o 11

65

M

G

eog

rap

hic

3

Her

pes

Ker

atit

is

14

40

M

D

end

riti

c S

10

No

15

46

M

Den

dri

tic

S 14

N

o 17

50

M

D

end

riti

c M

14

N

o 19

62

F

Den

dri

tic

S 14

H

erpe

s K

erat

itis

22

45

M

D

end

riti

c M

7

No

23

58

F S

tro

mal

7

Her

pes

Ker

atit

is

27

75

F G

eog

rap

hic

4

2

No

28

19

M

Den

dri

tic

S 5

No

29

47

M

Den

dri

tic

S 4

No

31

30

F D

end

riti

c S

2 H

erpe

s K

erat

itis

32

47

M

D

end

riti

c S

3 H

erpe

s K

erat

itis

33

64

F

Den

dri

tic

S 30

N

o

IDU

Gro

up

G

eog

rap

hic

3

57

F D

end

riti

c S

0 H

erpe

s K

erat

itis

6

55

F D

end

riti

c S

2 N

o 9

7 F

Den

dri

tic

S 6

No

12

61

M

Den

dri

tic

S 21

H

erp

es K

erat

itis

13

72

F

Geo

gra

ph

ic

3 N

o 16

54

F

Geo

gra

ph

ic

56

No

18

49

F

Geo

gra

ph

ic

30

Her

pes

Ker

atit

is

20

28

M

Den

dri

tic

S 11

N

o 21

19

F

Den

dri

tic

S 14

N

o 24

45

M

D

end

riti

c S

8 N

o 26

9

M

Den

dri

tic

S 4

Her

pes

Ker

atit

is

27

29

M

Den

dri

tic

S 8

No

30

35

F D

end

riti

c M

7

Her

pes

Ker

atit

is

* S

= S

ingl

e, M

= M

ulti

ple

Fre

qu

ent

recu

rren

ces

of

bro

nch

itis

Pep

tic

ulc

erat

ion

Ton

sill

itis

an

d e

ar i

nfe

ctio

n

Co

ncu

rren

t in

flu

enza

RESULTS

Efficacy

Key variables in the context of herpetic keratitis may be regarded as of two

types, indicators of whether the condit ion was cured and indicators of speed

of action. Other variables include assessment of effectiveness against accompanying

signs and symptoms such as conjunctival injection, reduction of visual acuity, lacrimation and sensitivity.

Key variables

Many different observations and measurements were recorded as indices of efficacy - these included serial drawings of lesions, serial measurements of lesions, estimates of percentage healing and classification of lesions at each visit as 'cleared' , ' improved' , 'unchanged' or 'worsened' . We found that complete epithelial healing occurred in 14 of the 17 patient s treated with arabinoside-A i.e. 82% as opposed to 9 out of the 13 patients treated with IDU (69%). Furthermore all those patients whose healing was incomplete

had shown evidence of improvement which could be at tr ibuted to t reatment with one exception; this was patient number 3 who was under t reatment with IDU and showed worsening of his geographic lesions on the 10th day.

Rapidity of action was assessed in two ways: (1) The mean duration of

t reatment at the time that complete healing was achieved was 11.7 days in the case of Arabinoside-A and 10 days in the case of IDU. (2) The per- centage healing at each visit was also estimated. The means were taken and plot ted graphically; here the Arabinoside-A group seems to have fared better whether one takes into account all the patients in the series or the

cured patients only (Figure 1).

Other variables

The degree of conjunctival injection was recorded as 'none ' (0), 'minimal ' (1), 'modera te ' (2), and 'marked ' (3). Table 2 shows that only 2 patients in the Ara-A group had persisting conjunctival injection on the 21st day, and likewise only 2 patients in the IDU group, apart from patient 3 whose treatment was discontinued.

About half of the patients in the Ara-A treated group had normal visual

acuity throughout (Table 3). Of those with initial impairment a trend towards normal values was apparent in every pat ient treated with Arabino-

25

o

Pe

rce

nta

ge

H

ea

lin

g

J~

II

II

II

o

o

r-

Pe

rce

nta

ge

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ea

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g

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00

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00

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0~

0

00

00

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00

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00

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Table 3(a). Visual acuity (denominators determined in Snellen Test): Ara-A

Patient Day: number 0 3 5 7 10 14 21

1 9 9 6 6 6 4 60 12 12 12 5 24 18 18 18 18

10 6 6 6 6 11 24 12 9 9 14 5 5 5 5 15 9 9 9 9 17 18 18 6 6 19 18 18 9 9 9 9 22 6 6 6 6 6 23 6 6 6 6 6 25 CF 36 36 12 12 28 6 6 6 6 6 29 9 6 6 6 6 31 6 6 6 6 6 32 9 9 9 - - 33 12 9 9 9 9

LP = projection of light; PL = perception of light.

Table 3(b). Visual acuity (denominators determined in Snellen Test): IDU

Patient Day: number 0 3 5 7 10 14 21

3 . . . .

6 6 6 6 6 6 9 6 6 6 6 6 6 6

12 36 12 6 6 6 13 LP PL PL PL 16 CF CF 60 36 18 CF CF CF CF 20 5 5 5 5 5 5 21 5 5 5 5 5 5 24 6 6 6 6 6 26 6 6 6 6 6 27 12 12 12 9 6 30 ~ HM HM HM HM HM HM

LP = projection of light; PL = perception of light.

28

side-A. Likewise in the IDU group about half had normal visual acuity

throughout. In the other half however the trend towards normal was less

evident than in the Ara-A group. The degree of initial impairment however can be seen to have been more severe in this group. Table 4 shows that almost all patients initially had some degree of lacrimation, photophobia

and sensitivity but that on the 21st day only two in the Ara-A group and

three in the IDU group still had symptoms.

Age and sex are variables which were unequally distributed between the

two treatment groups and which might influence the effectiveness of

treatment. The size and type of lesion may also affect the efficacy of

healing. Size of lesions has been recorded in different ways e.g. 'length

of longest dendrite' or surface area in the case of geographic lesions. For

the purposes of this table all geographic lesions are classified as large, and

dendritic lesions with a total length exceeding 5 mm are similarly classified.

Dendrites the length of which, including branches if any, is 5 mm or less are

classified as small.

To simplify matters duration of the disease before entering the trial has

been classified as 'less than 14 days' or '14 days or more'. In this analysis

the results of both forms of treatment were combined in an attempt to

identify factors that may have influenced efficacy (Table 5).

Sex. a much higher proportion of men achieved complete healing than was

the case with women. The difference however was not significant (at 5% level) and the average time taken to achieve complete healing was slightly

longer among men than among women so it is unlikely that the unequal dis-

tr ibution of the sexes between the treatment groups affected the outcome. Age: the 21 patients wh0 achieved 100% healing had a lower mean age (41.4 years) than the 9 who did not (53 years) but the difference is mainly

accounted for by the four patients under 20 in the former category. These

four patients were unevenly distributed between the treatment groups, only one being in the Ara-A group and this may have conferred aminor advantage on the IDU group.

Size of lesions: as might be expected, a higher proportion of small lesions

healed completely than did large lesions and the latter also took longer to

heal completely. This longer time to heal differed significantly from the

more rapid healing of the smaller lesions (P is less than 0.05 by Wilcoxon's rank test). This difference introduces a bias against the Ara-A group in

which there was a higher proportion of large lesions (59%) than in the IDU group (46%).

Duration o f disease: before treatment might also be expected to have

some effect upon rate of healing during treatment but the figures here lend little support to this. There is indeed a higher proportion of complete

29

0

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u')

0 ~ 0

O M �9

0

0 0 0 0 0 0 0 ~ 0 ~ 0 0 0 0 0

Z ~

~ O ~ 0 0 0 0 0 0 0 0 0 0 0 0 0

Z o

El

0

II

II

b ~

0

II

3 0

o

o

(D

r~

F~

O~3 �9

C

t~

0 . , , 3 ,

M ~ e"

I O ~ 0 0 0 0 ~ 0 0 0

Z �9

I O 0 ~ 0 0 0 0 0 0 0

~J

II

"O O

II

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O

II

31

Table 5. Analysis of several variables in relation to indices of efficacy

Complete Healing of herpetic ulcer(s) Incomplete Mean day on which 100%

healing achieved

2.

3.

4.

5.

Sex Male 14 2 10 Female 7 7 9

Age (mean) 41.4 years 53.1 years

Size of lesion(s) Large 9 7 13 Sm all 12 2 7

Duration of disease ( 14 days 16 5 9.3 )/14 days 5 4 11

Type of lesion(s) Single Dendritic 16 2 10 Multiple Dendritic 2 2 6 Geographic 3 4 15 Stromal 1 NA

p ( 0.05

healing among patients who were treated early but the difference falls far

short of the statistical significance and the mean time taken to heal was

quite similar ir~ the two groups.

It should be noted that these last two variables are probably not indepen-

dent of each other; all the lesions that had been present for 20 days or more

were large when treatment was started.

Type o f lesion: all but two of the single dendritic lesions healed com-

pletely in a mean time of 10 days. Only half of the 4 multiple dendritic

lesions healed completely. Fewer than half of the 7 geographic lesions healed completely and the

mean healing time for these three subjects was 15 days. In the one patient with predominantly stromal disease only 70% healing

occurred and the 100% was not achieved.

Previous herpetic disease: about 40% of each treatment group had had herpetic keratitis previously. About 40% (3 out of 7) of the patients whose lesions failed to heal during treatment had had the disease before. Prognosis in the present attack does not seem to be affected by previous attacks. Adverse experiences: two patients in the Ara-A group developed mild

punctate keratitis on day 10 and 5 of treatment respectively. In both cases

32

the condition cleared spontaneously on discontinuing medication.

One patient on IDU had a dramatic flare-up representing a drug sensiti-

sation reaction.

SUMMARY

Although there were slightly more large lesions in the Ara-A group than in

the IDU group the Ara-A group fared somewhat better. 82% were cured

compared with 69% in the IDU group and the only patient whose condition

worsened during treatment was a member of this latter group.

This study suggests therefore that from the standpoint of efficacy, Arab-

inoside-A shows up slightly more favourably than IDU.

This study was undertaken as part of a multi-centre trial.

Our thanks are due to Dr. J.A.L. Gorringe, Director, International Clinical

Research, Parke-Davis, for providing the medication used and for his invalu- able help in the statistical evaluation of our results.

REFERENCES

�9 ! . .

Kaufman, H.E., E.L. Martola & C. Dohlman. Use of 5-1odo-2 -deoxyundme (IDU) in treatment of herpes simplex keratitis. Arch. Ophthal. 68:235-239 (1962).

Patterson, A. & B.R. Jones. The management of ocular herpes. Trans. Ophthal. Soc. U.K. 87:59-84 (1967).

Authors' address: Eye and Ear Hospital and St. Vincent's Hospital Dublin Ireland

33