22 Herpes simplex keratitis

Background

Herpetic keratitis is an important public health issue with deep social and economic repercussions. In the United States alone, herpes simplex virus (HSV) eye disease affects approximately 400 000 to 500 000 people, with an estimated 48 000 episodes of active HSV eye disease annually.1,2

HSV has been identified as the single most frequent cause of corneal opacities in developed countries.3 Each episode can bring inflammation, structural damage and corneal scarring that eventually leads to opacities of the cornea and blindness. It is a leading cause for corneal grafting.4 The survival rate for corneal grafts performed for HSV keratitis ranges from 14% to 61%.5, 6

Treatment options

Over the past three decades, much has been written about the treatment and prophylaxis of herpes simplex virus ocular infection. Unfortunately, much of this has been based on clinical impression or uncontrolled, potentially biased trials. Even if the conclusions from these reports are valid, they cannot be accepted as proven evidence unless confirmed by randomised controlled trials that provide solid scientific backing to the conclusions derived.

Question

In patients with dendritic, epithelial herpetic keratitis, which antivirals have been shown to be the most effective?

The evidence

The earliest trials comparing different antiviral agents showed that trifluorothymidine (F3T, trifluridine) was more

effective than idoxuridine (IDU) in the treatment of dendritic and amoeboid (geographic) ulcers (P <0·005).7 Other authors

showed that F3T was more effective than traditional debridement, but that debridement combined with F3T was not superior to F3T alone,8 and that topical adenine arabinoside

(Ara-A, vidarabine) was equally effective in treating dendritic herpetic ulcers when compared to topical F3T.9

At the end of the 1970s, a new drug, aciclovir (ACV), was introduced for the treatment of herpetic disease. This drug, in theory, would be more selective against infected cells and therefore less toxic to the corneal epithelium.10 The first controlled trials proved that topical ACV was an effective antiviral agent for treating ulcerative herpetic keratitis, and that it was at least as active as Ara-A, IDU, or F3T11–25 (Tables 22.1 and 22.2). A recent systematic review of controlled clinical trials concluded that currently available and investigational antiviral agents (excluding IDU) are all effective and nearly equivalent.29 One study,23 however, also found a significantly lower rate of superficial punctuate epitheliopathy with ACV when compared to IDU (P = 0·0096). Others have shown that ACV produces a

significantly more rapid healing rate when combined with minimal debridement than ACV alone (P <0·025),30

although this has not been corroborated by others.31

A double-blind RCT of 60 patients showed topical ACV to be superior to IDU in healing times and rates in dendritic corneal ulceration26,27 (Tables 22.1 and 22.2). A later trial also demonstrated that oral ACV (400 mg five times a day) is as effective as locally applied aciclovir (3% ophthalmic ointment five times a day) in the management of herpes simplex dendritic corneal ulceration, and thus oral medication appears to be an acceptable alternative for patients unable or unwilling to use local treatment for their disease.32 In many countries, however, the higher cost of oral medication remains an important issue in selecting the antiviral of choice.

The search continues for newer, more effective antiviral agents that are better tolerated. Recently, ganciclovir has been introduced for the treatment of herpes simplex keratitis. Ganciclovir is an antiviral agent, structurally related to aciclovir, with an antiviral broad spectrum of activity, which includes cytomegalovirus, Epstein-Barr virus, adenovirus, herpes zoster and herpes simplex. A recent report of two RCTs comparing ACV ointment with ganciclovir gel for the treatment of dendritic and geographic ulceration32 showed ganciclovir gel 0·05% and 0·15% to have equal efficacy to topical ACV in the treatment of

ulcerative herpes simplex keratitis (Tables 22.1 and 22.2). Additionally, they found local tolerance to be significantly superior with ganciclovir, with fewer complaints of discomfort (stinging, burning) or blurred vision after application (trial 1: P = 0·05, trial 2: P = 0·045). Another report also failed to find any statistically significant difference in rate of healing of herpes simplex dendritic keratitis, treated with either ACV 3% ointment, or ganciclovir 0·15% gel.33 Other antivirals will probably find their place in the current treatment arsenal. Valaciclovir, a pro-drug of aciclovir, appears promising although long-term studies of efficacy are still lacking.

Comment

Aciclovir has become the standard treatment for herpetic ulcerative keratitis throughout the world. Topically, it has been proven to be at least as effective as Ara-A or F3T, as well as being better tolerated. In cases where the patient is not able to use topical preparations, oral ACV is an equivalent option. New drugs such as ganciclovir have been shown to be as efficient as ACV although few randomised trials comparing their results are available.

Question

Is there evidence supporting the use of aciclovir, or any other antiviral, in treating the geographic form of epithelial herpetic ulceration?

The evidence

There is less written in the literature about the treatment of geographic or amoeboid ulcers when compared to the more common dendritic ulceration, and few trials have studied this form of keratitis as a separate entity. Treatment of geographic ulcers has been more difficult, perhaps because of the frequent association of steroid use prior to the start of antivirals, and thus success in the treatment of these lesions would seem a more sensitive therapeutic test to differentiate the effect of different antivirals that prove to be highly active in treating less challenging dendritic ulcers. In several reports, results in treating geographic ulcers were extracted from larger series treating dendritic ulcers, and included small numbers of patients from which a statistically significant conclusion could not be determined.

A RCT that included 30 patients found topical F3T to be more effective than Ara-A in dealing with amoeboid ulcers (logrank P = 0·05).34 A more recent trial treated 51 patients in a dual-centre, double-blind comparison of topical ACV and Ara-A in geographic ulcers35 and found both drugs to be effective and of equal potency in the management of geographic herpetic ulcerations.

Comment

Since few trials have addressed the treatment of geographic ulcers independently, more trials are warranted in order to establish if ACV, or any other antiviral agent, is preferable for treating these patients.

Question

In patients with stromal herpetic keratitis, what evidence is there for combining corticosteroids with antivirals for treatment, and does the use of steroids carry a higher rate of recurrence?

The evidence

It is believed that stromal keratitis, particularly the disciform variety, is largely an immunological condition.36

With this presumption, antiviral treatment should be more effective if combined with steroids. An early trial showed that aciclovir combined with steroids is more effective than ACV alone, and that ACV without concomitant use of steroids does not provide effective control of disciform keratitis.37 This randomised trial of 40 patients, however, included patients who were using topical steroids prior to randomisation, and thus was potentially biased by selecting patients with steroid dependent keratitis. The same authors performed a similar trial, but in 30 patients who never had used steroids in the past.38 Even in these patients, a combination of aciclovir and steroids proved to be superior to ACV alone in the treatment of disciform keratitis. Using the Mantel Cox test, patients receiving ACV and steroids were shown to heal significantly more quickly than those receiving ACV alone, suggesting that it is necessary to use corticosteroids to promote healing in disciform keratitis.

Additionally, this study found no significant statistical differences in recurrence rates when comparing patients who had and had not received steroids.

The effect of topical steroids has been recently addressed by a multi-centre RCT, the Herpetic Eye Disease Study (HEDS). A randomised, double masked, placebo controlled clinical trial was designed, in which patients with active herpes simplex stromal keratitis who had not received any corticosteroids for at least 10 days before enrolment were treated with topical F3T and either topical prednisolone or placebo over 10 weeks.39 The planned sample size was 178 patients. However, enrolment was stopped at 106 patients, after the primary objective, determination of the time to treatment failure, was satisfied, and a statistically significant difference in the primary outcome between the treatment groups had been established. The median time to treatment failure was 98 days for the steroid group (95% CI, 81 to > 120 days) and 17 days for the placebo group (95% CI, 14–27 days). This difference proved to be highly significant in favour of the steroid group (P <0·001). The time from randomisation to resolution of active herpes keratitis was also significantly shorter for the steroid group (steroid group: median, 26 days; 95% CI, 14–49 days; placebo group: median, 72 days; 95% CI, 44–123 days, P <0·001). Additionally, there was no statistically significant difference in recurrence rates between the two treatment groups (P = 0·9).

Other RCTs have addressed the results of using different antivirals. A trial involving 30 patients, all with dilute betamethasone, reported that there is no significant difference either in the time to heal or rate of healing between ACV and Ara-A when combined with corticosteroids in treatment of disciform keratitis. However, they found a significantly lower rate of superficial punctuate keratopathy with ACV (P = 0·02), suggesting ACV is a more appropriate drug because of its low toxicity.40

A randomised trial of 39 patients published in 1990 compared topical and systemic aciclovir in the management of herpetic disciform keratitis, in patients receiving topical prednisolone 0·05%.41 No statistically significant difference was demonstrated in resolution times for the clinical signs studied, or in time required for complete healing. Additionally, no difference was found in recurrence rates over a three-year follow-up. The authors concluded that oral ACV treatment is an effective alternative to ophthalmic ointment in the management of herpetic disciform keratitis.

The benefits of using oral ACV in herpes simplex stromal keratitis have recently been studied by the HEDS. In a randomised, double masked, placebo controlled trial of 104 patients, either oral ACV (400 mg five times daily) or placebo was used, along with a standard regimen of topical prednisolone and F3T to treat patients with active HSV stromal keratitis, without concomitant epithelial keratitis,

treated with steroids.42 Sample size was chosen so that a 5%, one-tailed test would have an 80% chance of detecting a doubling of the median time to treatment failure. This study found no statistically significant difference overall in time to treatment failure between the aciclovir treated group and the placebo treated group (P = 0·46). Oral ACV did not significantly delay the time to treatment failure, decrease the proportion of patients who failed treatment, increase the proportion of patients whose keratitis resolved, decrease the time to resolution, or increase best corrected visual acuity. Thus, oral ACV given in addition to standard treatment (topical antiviral and steroid) provided additional benefits of such a small magnitude that no statistical and clinical significance could be determined.

Comment

It can be concluded that the treatment of stromal herpetic keratitis should involve an antiviral agent as well as a steroid, and the usefulness of ACV, either topical or oral, has already been determined. Studies have proven the importance of steroids in promoting healing, and their safety in terms of recurrences. Combining topical plus oral antivirals, however, does not provide an additional level of protection.

Question

What evidence is there for the use of prophylactic aciclovir to prevent recurrent herpes simplex keratitis?

The evidence

In 1967, a randomised controlled trial that studied the effect of IDU or placebo and their ability to prevent dendritic keratitis recurrence in patients receiving steroids, established the importance of topical antivirals in reducing the rate of recurrence of HSV epithelial keratitis during corticosteroid treatment of HSV disciform keratitis.43 In 1978, a similar trial demonstrated the importance of topical antivirals (F3T) in reducing the rate of recurrence of HSV epithelial keratitis during steroid treatment of HSV keratouveitis.44 A recent study of the risk factors for HSV epithelial keratitis recurrence during treatment of stromal keratitis or iridocyclitis45 recruited 260 patients who were all receiving topical F3T for active stromal keratitis and/or iridocyclitis without epithelial keratitis. Patients were examined for HSV epithelial keratitis during 16 weeks and were enrolled in one of three parallel trials. One trial compared the effects of a 10-week course of topical placebo with a tapering dosage of topical steroids. Another compared a 10-week course of oral ACV with oral placebo

in patients receiving topical prednisolone phosphate (and F3T) for stromal keratitis, and the third trial compared oral ACV with oral placebo in patients receiving topical prednisolone phosphate for iridocyclitis. In all these trials, patients were also receiving topical F3T. Overall, epithelial keratitis developed in 4·6% of the patients, and no statistically significant differences in the occurrence of HSV epithelial keratitis between any of the groups were found. Thus, adding oral ACV to a standard topical antiviral treatment with F3T did not provide additional benefits, nor did steroids provide additional risks when under antiviral treatment.

The Herpetic Eye Disease Study (HEDS) has recently addressed the subject of efficacy of oral ACV prophylaxis in preventing stromal keratitis or iritis in patients with HSV epithelial keratitis treated with a topical antiviral agent.46 This prospective, randomised, double masked, placebocontrolled study enrolled patients with active epithelial keratitis who were treated with topical F3T or Ara-A and were randomised to a three-week course of oral ACV, 400 mg five times a day or placebo, and were followed up for one year. Although the sample size needed was calculated at 502 patients, recruitment was stopped at 287, because of lack of evidence of benefit in the group that had been treated with oral ACV. The cumulative probability of developing stromal keratitis or iritis for the 12 month follow-up period (after stopping topical or oral antivirals) was 12% in the ACV group and 11% in the placebo group; the comparison of Kaplan–Meier curves by the log-rank test showed no statistically significant difference (P = 0·92). There was no evidence of a beneficial effect of the treatment in any group based on whether epithelial keratitis, stromal keratitis, or iritis had occurred in the past or based on the duration of symptoms of epithelial keratitis at the time of trial enrolment. However, the development of stromal keratitis or iritis was more common in patients with a history of HSV eye disease before the episode of epithelial keratitis (P = 0·01).

Another problem ophthalmologists face when treating herpes keratitis is recurrences in patients who will be receiving topical steroids for prolonged periods, such as in steroid dependent stromal keratitis or in patients who have had a penetrating keratoplasty (PK). A recent RCT reported for the first time the effect of postoperative oral ACV on the survival of corneal grafts.4,47 This compared the risk of recurrence in 14 eyes that underwent PK and received postoperative aciclovir (800–1000 mg/day for 12–15 months) with nine eyes that underwent PK but did not receive ACV. Both groups received topical prednisolone 1% four times daily after surgery, tapered over three months. With a follow up of 16·5 months, they showed that postoperative oral ACV significantly reduces the risk of HSK

recurrence following PK (rate of recurrence: 0% in the ACV group, and 44% in the control group, P <0·05 by x2).

Comment

The evidence shows that adding oral antivirals to a standard treatment that includes topical antivirals does not provide additional protection from HSV recurrences, whether epithelial or stromal. Nevertheless, recurrences are more frequent in patients with a history of prior herpetic episodes, and it seems logical to target prophylaxis at these high risk groups. In patients who have undergone corneal grafts, aciclovir prophylaxis has proven to be important in preventing recurrences. Since few randomised controlled studies have tackled this issue, it is still to be determined how long this prophylactic treatment needs to be in order to provide long lasting protection.

Implications for practice

Aciclovir has an established role in the treatment of HSV keratitis, whether in its topical or oral form. Its efficacy has been proven against “first generation” drugs (IDU, Ara-A, F3T). Newer drugs surely will continue to be developed, such as ganciclovir, and these will need to be compared with ACV not only in terms of their clinical effectiveness in dendritic, disciform, and other types of keratitis, but also for their tolerance and toxicity. In stromal keratitis, the combination of an antiviral agent such as aciclovir with a topical steroid has been shown to be both safe and effective.

Implications for research

In spite of these results, there are many issues that still need to be addressed with regard to HSV keratitis treatment and prophylaxis. Most trials have focused on epithelial dendritic keratitis and stromal disciform keratitis. There are few reports that have been directed at studying the treatment of geographic corneal ulcers, and no randomised trial has been performed to study the effect of oral antivirals on necrotising stromal keratitis, although data extracted from broader trials appear to be promising.41 Another issue that must be studied more carefully is that of drug induced toxicity, particularly when one is about to give prophylactic treatment for extended periods. Few trials have provided substantial evidence about drug related toxicity with the use of various topical antivirals. Some ancillary information has been gathered from larger series that have studied other variables, but to date, no randomised trial has focused entirely on toxicity.

The dosage and duration of treatment required for prophylactic antiviral medication has so far been determined empirically. Although recent reports back the need for prophylactic medication, no trial has addressed the

optimal dosage, frequency and duration of treatment. Future trials will probably help define the optimal protocols for prophylactic treatment.

References

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