Herpes simplex virus infections of the eye and their management with acyclovir

Journal of Antimicrobial Chemotherapy (1983) 12, Suppl. B, 39-43 Herpes simplex virus infections of the eye and their management with acyclovir M. G. Falcon Eye Department, St Thomas' Hospital, London SEl TEH, England Hcrpetic kcratitis remains a prominent cause of recurrent or chronic and blinding corneal disease; areas of particular difficulty are indolent ulceration, herpetic keratouveitis, keratoplasty and problems associated with steroid therapy. Topical acyclovir has been widely demonstrated to be a safe and effective antiviral for ulcerative herpetic keratitis; furthermore its particular advantages of high efficacy, minimal toxicity and good ocular penetration, suggest that it should be the treatment of choice for patients within these other areas of particular difficulty. Introduction Herpes simplex keratitis remains one of the most important causes of blindness from corneal disease. This disease is usually produced by HSV I. There is a mass of experimental and clinical evidence indicating that the virus can remain latent in the Gasserian ganglion. For reasons that are still not clear, activation of latent virus occurs in some individuals which leads to clinical disease. This may be manifest as ulcerative (dendritic or amoeboid) keratitis which is the direct result of virus replication within the epithelium; there can also be visible signs of involvement deeper within the cornea or within the eye, producing a wide spectrum of clinical signs in the general category of keratouveitis. Such disease may be mediated by inflammatory (particularly type IV) mechanisms, or by viral replication, or by both, and it is here that the principal problems of herpetic keratitis occur. Simple epithelial disease, unless it becomes chronic, rarely produces significant loss of vision since the epithelium has good powers of regeneration, but delayed (indolent) ulceration may be very problematical; here toxicity of antiviral compounds often plays a primary role, whereas stromal disease, and secondary changes such as corneal anaesthesia and tear film disorders may also be implicated, and secondary bacterial or fungal infection may supervene, with disastrous consequences. Stromal disease, unaccompanied by ulceration, may also frequently lead to stromal opacification from scarring and vascularization. Furthermore, the ophthalmologists' attempts to maintain corneal transparency by reducing an inflammatory response in the stroma with topical steroids may encourage HSV replication; such steroid therapy must therefore be accompanied by antiviral therapy, which is not always completely effective, and which may need to continue for many weeks. A considerable proportion of patients with cornea! scarring from herpetic keratouveitis eventually undergo keratoplasty, following which there is a particular need for intensive topical immunosuppressive (steroid) therapy to prevent graft rejection; here again the effect of steroids in encouraging virus replication can cause considerable difficulties, which have hitherto been compounded by the toxic effects of antiviral therapy on the fragile epithelium of the graft. 39 0305-1453/83/12B039 +05 J02.00/0 1983 The British Journal of Antimicrobial Chemotherapy

40 M. G. Fakon The main problem areas of herpetic keratitis may thus be summarized as: latency and recurrence, for which there is as yet no practical therapy; indolent ulceration, a sequel to simple herpetic epithelial disease, where antiviral toxicity is often the principal factor; and steroid therapy (whether employed for stromal disease, or following keratoplasty) when any beneficial effect may be overweighed by the effect of encouraging virus replication, since antiviral therapy may not always be effective in controlling this potential complication. Undoubtedly there have been great advantages in the management of patients with herpetic eye disease since the introduction of idoxuridine (IDU) and more recently of adenine arabinoside (Ara A) and trifluorothymidine (F3T), but these drugs are to some extent limited by being toxic and having inadequate ocular penetration, and the problems described above still occur all too frequently. The introduction of acyclovir brings in a truly herpes virus-specific and non-toxic antiviral with good ocular penetration from topical (Poirier et al., 1982) or systemic routes, which has greatly increased the scope of therapy for this disease. The results of clinical and other investigations to assess its effect will now be reviewed. Ulcerative disease Clinical assessment of acyclovir The first clinical trial of topical acyclovir (ACV) in herpetic keratitis was carried out at Moorfields Eye Hospital in 1979 (Jones et al., 1979). It was based on experience of an earlier trial of interferon (Jones, Coster & Falcon, 1976), which was designed to demonstrate any effect from topical application of the substance in reducing early recurrences following a simple debridement. This had the advantage of requiring the smallest amount of the substance under assessment to produce a significant result. ACV was highly effective in this preliminary trial with the expectedly minimal toxicity. There shortly followed a number of clinical trials in epithelial disease in which ACV was compared with another standard antiviral; several of these were described at the previous Acyclovir Symposium (King & Galasso, 1982). Coster et al. (1980) compared ACV and IDU and found no significant difference in cure rates or healing rates, and the multicentre trial of McCulley et al. (1982) has reached the same conclusions. There was less punctate epitheliopathy in those patients treated with ACV. Collum, Benedict- Smith & Hillary (1980) in a similar comparative study found that ACV cured a higher proportion of patients than IDU, and led to more rapid healing; the trial of Colin et al. (1981) supported this conclusion. A recent paper by KJauber & Ottovay (1982) comparing ACV and IDU found a superior cure rate with ACV. There was moreover a suggestion that more patients with accompanying stromal disease healed if they were treated with ACV (7 in 8 patients) than if treated with IDU (4 in 10 patients). There have been some similar suggestions in other trials, although none has reached statistical significance. Several clinical trials have compared ACV with topical Ara A in patients with epithelial disease. Tormey, McGiU & Walker (1981) and McGill, Tormey & Walker (1981) found no statistically significant difference in healing rate, nor in the course of co-existing stromal disease. Young, Patterson & Ravenscrofl (1982) found a significant difference in the healing rate, in favour of ACV. Trifluorothymidine has been shown to be at least as effective as Ara A and superior to IDU, where the disease wasrelativelymild, as in dendritic ulcers (Coster et al., 1976). It was superior to Ara A where the disease was severe, as in amoeboid ulcers (Coster,

Herpes simplex Hms infections of tbe eye 41 Jones & McGiU, 1979). The clinical trial of F3T and ACV in patients with dendritic ulcers (La Lau et al., 1982) showed that both drugs were comparable in efficacy. If valid comparisons can be made across different trials, then this result is as anticipated, indicating that ACV and F3T have some superiority over IDU and Ara A. Two investigations have been carried out to assess the value of debridement in combination with ACV therapy for ulcerative herpetic keratitis. Wilhehnus, Coster & Jones (1981) found that combined debridement and ACV therapy led to a significantly faster healing rate with ACV alone. Jensen, Nissen & Jessen (1982) on the other hand, in a trial where nearly one-third of the patients had failed to respond first to other antiviral agents, found no difference between ACV and ACV plus debridement. Either treatment schedule appeared to be effective for metaherpetic ulceration. These trials of ACV therapy in patients with ulcerative herpetic keratitis have provided an impressive body of evidence that the drug is well tolerated, safe and effective, even when other antivirals have failed. ACV is at least as effective as the other antivirals used, and there have been suggestions (as yet lacking statistical confirmation) that there may be a benefit in certain types of herpetic stromal disease. Keratouveitis Clinical trials in stromal herpetic keratitis have been notoriously difficult to execute, because of the variable nature of the disease, to which therapy should be adjusted precisely. Nevertheless, Collum, Logan & Ravenscroft (1983) have recently published a trial in which 40 patients with disciform keratitis were treated either with ACV or with ACV and 001 % betamethasone. This important trial demonstrates two principle points: firstly, that 40% of the patients treated with ACV alone were healed (i.e. there was no clinical evidence of active disease) within 50 days; secondly, that all the patients treated with ACV and steroid were healed within 41 days. Although objective comparisons are limited by the absence of other clinical trials, and by the absence of clinical details about individual patients in this trial, the healing rates appear to be better than those generally experienced previously, both in the non-steroid group and in the steroid group: clinicians attempting to control disciform keratitis without steroid have failed in a high proportion of patients, and have eventually felt bound to use steroids because of intolerable symptoms, or because of signs indicating a risk of permanent damage to the eye such as endothelial decompensation or raised intraocular tension. The steroid group also fared particularly well: a 100% healing rate within 41 days in 20 patients with disciform keratitis is exceptional, and there were apparently no problems following withdrawal of steroid therapy. It is tempting to conclude that these good results are due to the presence within the cornea and anterior chamber of therapeutic levels of ACV: for whether or not disciform keratitis is partly mediated by viral replication, it is undoubtedly desirable that there should be an effective level of antiviral within the eye during steroid therapy. The failure of other antivirals to enter the eye may account for the apparent worsening of some cases of disciform keratitis on steroid therapy: the worsening clinical signs may have been brought about by viral replication encouraged by the steroid therapy under inadequate antiviral prophylaxis. Shimeld's demonstration (Shimeld et al., 1982) that there is virus in the cornea of herpetic patients even after 6 months of inactivity, indicates very nicely the dangers which could arise from unprotected steroid therapy. Wilhehnus, Falcon & Jones (1981) treated 20 patients who had presumed herpetic iridocyclitis either with ACV or with IDU. All those in the ACV group resolved within 8 weeks, whereas 4 out of the

42 M. G. Falcon 10 in the IDU group worsened and required steroid therapy. The numbers are small and the conclusions are thus uncertain. It is clear, however, that ACV should be the antiviral of choice in this condition (regardless of the precise pathogenesis) because of its good ocular penetration: the principles discussed in the context of stromal disease still hold. Keratoplasty Keratoplasty is the only feasible treatment for severe visual loss due to corneal scarring from herpetic keratitis, and it may also be used ocasionally for therapeutic purposes, where medical means of controlling active disease have failed. Although several surveys have demonstrated certain favourable prognostic factors and other unfavourable prognostic factors, it is generally agreed that the prognosis for keratoplasty in herpes is nevertheless uncertain, because of the possibilities of recurrence of ulcerative herpetic disease, or keratouveitis or rejection. As discussed earlier, a full regimen of topical steroid is essential postoperatively for prophylaxis against rejection. Opinions have varied hitherto concerning the routine use of antiviral prophylaxis: if used, it was associated with a high incidence of toxic epitheliopathy and even persistent ulceration; if not used, there was an increased risk of recurrence of viral replication. The availability of ACV has been welcomed by clinicians as a satisfactory solution to this dilemma. It can be used quite safely in the postoperative period without disturbing the epithelium of the graft: this will lead to a major improvement in the prospects for keratoplasty in herpetic patients. A question as yet unanswered, is - when should the antiviral therapy be curtailed, and - should it be reduced suddenly or gradually? It is possible that the latter course may lead to an increased incidence of ACV-resistant strains of HSV, just as these can be produced in vitro by exposure to the drug. Careful monitoring of patients receiving such a treatment regime should provide an answer. Conclusion Clinical studies to date have demonstrated that ACV is a safe and effective antiviral for therapy of ulcerative herpetic keratitis. There are indications that it may have some superiority over IDU, Ara A and F3T. The combination of good efficacy, minimal toxicity and good ocular penetration indicates that ACV should be the drug of choice in the problem areas of indolent herpetic ulceration, in stromal disease as antiviral cover for steroid therapy, and likewise in keratoplasty as antiviral prophylaxis for steroid therapy. It is anticipated that ACV will have a considerable impact in lessening these difficulties. Further clinical studies are underway which will assess these roles for ACV more precisely. Concern over the readiness with which HSV may become resistant to ACV is fortunately reduced by the fact that these resistant strains are of reduced virulence, in proportion to their failure to induce thymidine kinase (Gordon et al., 1983). References Colin, J., Tournoux, A., Chastel, C. & Renard, G. (1981). Superficial herpes simplex keratitis. Double-blind comparative trial of acyclovir and idoxuridine. La Nouvelle Prase Medicate 10, 2969-75. Collum, L. M. T., Benedict-Smith, A. & Hillary, I. B. (1980). Randomised double-blind trial of acyclovir and idoxuridine in dendritic corneal ulceration. British Journal of Ophthalmology 64, 766-9.

Herpes simplex Tims infections of the eye 43 Colhun, L. M. T, Logan, P. & Ravenscroft, T. (1983). Acyclovir (Zovirax) in herpetic disciform keratitis. British Journal of Ophthalmology 67, 115-18. Coster, D. J., Jones, B. R. & McGilL J. (1979). Treatment of amoeboid herpetic ulcers with adenine arabinoside or trifluorothymidine. British Journal of Ophthalmology 63, 418-21. Coster, D. J., McKinnon, J. R., McGill, J., Jones, B. R. & Fraunfelder, F. T. (1976). Clinical evaluation of adenine arabinoside and trifluorothymidine in the treatment of corneal ulcers caused by herpes simplex virus. Journal of Infectious Disease 133, A173-7. Coster, D. J., Wilhelmus, K. R., Michaud, R. & Jones, B. R. (1980). A comparison of acyclovir and idoxuridine as treatment for ulcerative herpetic keratitis. British Journal of Ophthalmology 64, 763-5. Gordon, Y. J., Armstrong, J. A., Brown, S. I. & Becker, Y. (1983). The role of herpes virus type I thymidine kinase in experimental ocular infections. American Journal of Ophthalmology 95, 175-81. Jensen, K. B., Nissen, S. H. & Jessen, F. (1982). Acyclovir in the treatment of herpetic keratitis. Ada Ophthabnologica 60, 557-563. Jones, B. R., Coster, D. J. & Falcon, M. G. (1976). Topical therapy of ulcerative herpetic keratitis with human interferon. Lancet fa, 128. Jones, B. R., Coster, D. J., Fison, P. N., Thompson, G. M., Cobo, L. M. & Falcon, M. G. (1979). Efficacy of acycloguanosine (Wellcome 248U) against herpes simplex corneal ulcers. Lancet i, 243^4. King, D. H. & Galasso, G. (1982). Proceedings of a Symposium on acyclovir. American Journal of Medicine 73, 1A. Klauber, A. & Ottovay, E. (1982). Acyclovir and idoxuridine treatment of herpes simplex keratitis - a double-blind clinical study. Acta Opthabnologica 60, 838-44. La Lau, C, Oosterhuis, J. A., Versteeg, J., Van Rij, G., Renardel de Lavalette, J. G. C, Craandijk, A. & Lamers, W. P. M. A. (1982). Acyclovir and trifluorothymidine in herpetic keratitis: a multicentre trial. British Journal of Ophthalmology 66, 506-8. McCulley, J. P., Binder, P. S., Kaufman, H. E., O'Day, D. M. & Poirier, R. H. (1982). A doubleblind, multicenter clinical trial of acyclovir vs idoxuridine for treatment of epithelial herpes simplex keratitis. Ophthalmology 89, 1195-200. McGill, J., Tormey, P. & Walker, C. B. (1981). Comparative trial of acyclovir and adenine arabinoside in the treatment of herpes simplex corneal ulcers. British Journal of Opthalmology 65, 610-13. Poirier, R. H., Kingham, J. D., de Miranda, P. & Annel, M. (1982). Intraocular antiviral penetration. Archives of Opthalmology 100, 1964-7. Shimeld, C, Tullo, A. B., Easty, D. L. & Thomsitt, J. (1982). Isolation of herpes simplex virus from the cornea in chronic stromal keratitis. British Journal of Ophthalmology 66, 643-7. Tormey, P., McGilL J. & Walker, C. (1981). Use of acyclovir in herpes simplex corneal ulcers. Transactions of the Opthalmological Society of the U.K. 101, 6-8. Wilhelmus, K. R., Coster, D. J.&Jones, B. R. (1981). Acyclovir and debridement in the treatment of ulcerative herpetic keratitis. American Journal of Opthalmology 91, 323-7. Wilhelmus, K. R., Falcon, M. G. & Jones, B. R. (1981). Herpetic iridocylitis. International Ophthalmology 4, 143-50. Young, B. J., Patterson, A. & Ravenscroft, T. (1982). A randomised double-blind clinical trial of acyclovir (Zovirax) and adenine arabinoside in herpes simplex corneal ulceration. British Journal of Ophthalmology 66, 361-3.