Oral Acyclovir for Herpes Simplex Virus Eye Disease: Title and subTitle BreakEffect on Prevention of Epithelial Keratitis and Stromal Keratitis FREE

HERPES simplex virus (HSV) is an important cause of corneal disease and visual loss. To assess whether antiviral treatment can prevent recurrences of ocular HSV disease, we conducted a randomized clinical trial in which oral acyclovir, 400 mg twice daily for 1 year, was compared with placebo in immunocompetent individuals who had a history of an episode of ocular HSV within the prior year. We found that acyclovir-treated patients had an approximately 45% lower risk of recurrence of any type of ocular HSV disease during the 12 months of treatment, without evidence of a rebound worsening after treatment was discontinued.¹

In this report, we detail the effect of acyclovir treatment on specific types of ocular HSV disease, particularly epithelial keratitis and stromal keratitis. We also explore whether certain subgroups of patients might have a greater or less protective effect from long-term suppressive acyclovir therapy.

The study, supported through cooperative agreements with the National Eye Institute of the National Institutes of Health, was conducted by the Herpetic Eye Disease Study (HEDS) Group at 74 clinical sites. The protocol and informed consent forms were approved by institutional review boards, and all study patients gave written informed consent. Study oversight was provided by an independent data and safety monitoring committee. Details of the protocol are given in the trial's Manual of Operations² and have been published in summary form.¹

Between September 1992 and December 1996, 703 patients entered the trial, subject to the following criteria: age 12 years or older, active HSV eye disease within the previous 12 months that was inactive and untreated for at least 30 days before trial entry, and no prior keratoplasty or keratorefractive surgery of the involved eye. Three hundred fifty-seven patients were randomly assigned to receive oral acyclovir (Zovirax), 400 mg twice daily for 12 months (administered as 2 capsules, each containing 200 mg of acyclovir, provided by Glaxo Wellcome Inc, Research Triangle Park, NC), and 346 to receive placebo (capsules containing 218 mg of lactose and identical in appearance and taste to the active drug capsules). Use of study medication (acyclovir or placebo) was continued for the full 12 months regardless of whether a recurrence occurred. Topical treatment of a recurrence of ocular HSV disease was left to the discretion of the investigator.

At the end of the 12-month treatment period, patients were observed for 6 months while not receiving treatment; only data from the 12-month treatment period are reported herein. No serious adverse effects were attributable to the study medication; however, 32 patients (15 in the acyclovir group and 17 in the placebo group) discontinued treatment because of adverse effects. Among the 575 patients (82% of the 703 patients) who completed the full 12-month course of treatment, 89% of the acyclovir group and 87% of the placebo group were at least 80% compliant in taking the oral study medication; 72% and 68%, respectively, were at least 90% compliant.

The development of a recurrence of active ocular HSV disease was assessed by a HEDS-certified ophthalmologist using slitlamp biomicroscopy. Examinations were performed after months 1, 3, 6, 9, and 12 and at additional times when a patient developed new ocular symptoms. Recurrences were classified as blepharitis, conjunctivitis, epithelial keratitis, stromal keratitis (corneal stromal inflammatory infiltrate or corneal edema associated with endothelial inflammatory precipitates), or iritis.

Analyses included data from the 12-month treatment period for all randomized patients and were conducted separately for the following outcomes: any type of ocular HSV recurrence, epithelial keratitis recurrence, and stromal keratitis recurrence. The cumulative probability of a recurrence during the 12-month treatment period was calculated for each treatment group with the Kaplan-Meier product-limit method and compared by the Mantel log-rank test.³ Rate ratios were determined from proportional hazards models.⁴ For the epithelial keratitis and stromal keratitis analyses, patients remained at risk (not censored) for the specific type of recurrence when a different form of recurrence occurred.

For subgroup analyses, only subgroups with at least 50 patients were assessed. (For this reason, ethnicity was not assessed because of the limited number of patients among nonwhite ethnic groups.) Rate ratios were determined from proportional hazards models adjusted where indicated for the number of past episodes of HSV disease. Subgroup analyses for stromal keratitis recurrences were limited to patients with a history of stromal keratitis. (Because of the low incidence of stromal keratitis recurrences in patients without a history of stromal keratitis, there were no subgroups among these patients in whom a meaningful reduction in risk of stromal keratitis was possible.)

Analyses followed the intention-to-treat principle. All reported P values are 2-tailed.

The mean ± SD age of the 703 patients was 49 ± 18 years; 46% were female and 79% were white. In accordance with the trial's eligibility criteria, all patients had experienced at least 1 episode of ocular HSV disease during the year before study entry: 202 (29%) had experienced 1 episode, 230 (33%) had experienced 2 or 3 episodes, and 271 (39%) had experienced 4 or more episodes. There were 223 patients (32%) with a history of both epithelial keratitis and stromal keratitis, 331 (47%) with a history of epithelial keratitis but not stromal keratitis, 114 (16%) with a history of stromal keratitis but not epithelial keratitis, 28 (4%) with a history of blepharitis or conjunctivitis only, and 7 (1%) with a history of iritis only. Demographic characteristics and ocular history were well balanced between treatment groups.¹

During the 12-month treatment period, ocular HSV disease recurred in 66 (18%) of the 357 patients in the acyclovir group and in 104 (30%) of the 346 patients in the placebo group. Among the 533 patients without a recurrence, 12-month follow-up was complete for 269 (92%) of 291 patients in the acyclovir group and 216 (89%) of 242 patients in the placebo group. Table 1 lists the frequency of the type of ocular HSV in the initial recurrences in each group.

Sixteen patients in the acyclovir group and 30 in the placebo group had more than 1 recurrence during the 12 months. No patients in the acyclovir group had more than 2 recurrences, whereas 2 patients in the placebo group had 5 recurrences and 2 had 3 recurrences. In most patients, subsequent recurrences were of the same type as the initial recurrence (Table 2).

The probability of a recurrence of any type of ocular HSV disease was 19% in the acyclovir group and 32% in the placebo group (rate ratio, 0.55; 95% confidence interval, 0.41-0.75; P <.001). The epithelial keratitis recurrence rate was lower in the acyclovir group than in the placebo group (9% vs 14%; P = .03, Figure 1), being lower among both patients with and without a history of epithelial keratitis (10% vs 15% and 5% vs 12%, respectively, Table 3). The stromal keratitis recurrence rate was markedly lower in the acyclovir group than in the placebo group among patients with a history of stromal keratitis (14% vs 28%; P = .004, Figure 2). When a history of stromal keratitis was not present, the rate of stromal keratitis recurrences in the placebo group was so low (3%) that treatment could not be assessed for benefit (Table 3).

The relative treatment effect (rate ratio) of preventing an ocular recurrence was consistent in the subgroups based on the number of past episodes of ocular HSV (Table 3). Because of the increased recurrence risk with an increased number of past episodes, the absolute benefit of treatment (risk in placebo group minus risk in acyclovir group) was greater for patients with more prior episodes (9% for patients with 1 prior episode, 11% for those with 2 to 3 prior episodes, and 17% for those with 4 or more episodes). This association was present for stromal keratitis recurrences but not for epithelial keratitis recurrences (Table 3).

The overall near-50% lower risk of any type of recurrence in the acyclovir group was also generally observed in subgroups of patients based on other baseline factors (Table 4). The beneficial effect of treatment was less among patients whose last episode of ocular HSV was within 6 months of study entry (P value for interaction = .01) and among older patients (P value for interaction = .02, comparing patients 65 years or older to those younger). The treatment effect appeared greater among patients with a history of nonocular HSV disease (primarily orofacial) than among patients without such a history (P value for interaction = .03).

The benefit of treatment in reducing epithelial keratitis recurrences was present in most subgroups (Table 5). There was a suggestion of a greater treatment benefit in younger patients (P value for interaction = .06) and in those with a history of nonocular HSV disease (P value for interaction = .24).

For stromal keratitis recurrences, subgroup assessments were limited to patients with a history of stromal keratitis, because there were so few recurrences among patients without such a history. The benefit of treatment on reducing stromal keratitis recurrences was consistently seen in almost all subgroups (Table 6). The data did not suggest an association between the time of the last episode and the benefit of treatment; patients with a more recent episode of stromal keratitis appeared to benefit just as much as those with a longer duration since the last episode. There was a suggestion of a greater treatment benefit in patients younger than 65 years (P value for interaction = .14) and among those with a history of nonocular HSV disease (P value for interaction = .12).

Eye disease due to HSV is a leading cause of corneal opacification. As many as half a million people in the United States have had herpetic eye disease, and worldwide an estimated 10 million people have been affected. Important unsolved problems are how to suppress recurrences and how to reduce its sight-threatening complications.

Acyclovir is an antiviral drug that selectively targets virus-infected tissues.⁵ Shown to be effective in treating and preventing genital⁶ and orofacial herpes,⁷ oral acyclovir has been evaluated in the therapy and prophylaxis of HSV eye disease in a series of clinical trials known collectively as HEDS. Most recently, HEDS studied whether the long-term use of oral acyclovir would reduce the risk of recurrent HSV eye disease.¹

This trial of 703 patients demonstrated that oral acyclovir safely and effectively suppresses recurrences of HSV eye disease during a 12-month treatment period. Acyclovir reduced the risk of all forms of recurrent HSV eye disease by about half. Treatment had a beneficial effect both on ocular surface recurrences, such as blepharitis, conjunctivitis, and epithelial keratitis, and on deeper forms, such as stromal keratitis and keratouveitis. The benefit of acyclovir in preventing epithelial keratitis was seen both in patients who had experienced epithelial keratitis in the past and in those who had not. The beneficial effect on preventing stromal keratitis was limited to those patients with a history of stromal keratitis, for whom benefit was strong, because the untreated risk of stromal keratitis was minimal in the absence of a history of prior stromal keratitis. Upon discontinuation of treatment, there was no evidence of either sustained benefit or rebound during the ensuing 6 months.¹

The twice-daily regimen used in this study was convenient and well tolerated by most patients.¹ Continued, rather than intermittent, dosing is probably needed for a full suppressive effect. Adverse reactions associated with oral acyclovir use were generally mild and self-limited. The excellent compliance with medication use during this study made it difficult to determine whether a lower dose would be effective. Poor compliance did not explain recurrences during acyclovir treatment.¹

Oral acyclovir can prevent stromal keratitis but does not appear to contribute to the resolution of established herpetic stromal inflammation.⁸ These findings suggest that stromal keratitis may begin with a viral process that evolves into an immune-mediated reaction.^{9 - 12} Further investigation into the molecular virology of HSV corneal disease is warranted.

We undertook subgroup analyses to determine whether certain patients should be targeted for treatment. The data show that acyclovir's benefit extends to patients whose last episode occurred up to 1 year before. Other than the effect on stromal keratitis in patients with prior stromal keratitis, no subgroup differences in treatment effect were found that are likely to be clinically meaningful. Although certain subgroups had a larger treatment effect and others had little or no treatment effect, none of these differences have a clear biologic basis or support from prior studies. In view of the multiple subgroups that were explored, there is a strong likelihood that these subgroup differences were due to chance. The intriguing finding that people who have had orofacial herpes seemed to have a greater benefit from oral acyclovir might also be due to chance. These patients, however, have an additional reason for taking oral acyclovir, because acyclovir reduces recurrences of nonocular herpes.

In summary, oral acyclovir has a strong beneficial effect on all types of recurrences of herpetic eye disease. Our results can be generalized to teenagers and adults who have experienced an episode of ocular HSV disease within the prior year. Treatment decisions need to consider the visual impact and costs—direct and indirect—of the types of herpetic eye disease. For epithelial keratitis and other HSV infections of the ocular surface, the prolonged use of oral acyclovir must be weighed against the generally excellent results achieved with short-term topical antiviral therapy. In contrast, patients who have had stromal keratitis may have the greatest opportunity for benefit. These individuals are at the greatest risk for developing stromal keratitis, the form of herpetic eye disease associated with loss of visual acuity. The clear benefit of oral acyclovir in preventing stromal keratitis among patients with a history of prior stromal keratitis identifies these patients as an important target population for suppressive therapy. Thus, although preventive antiviral therapy could be offered to all patients who are at risk of a recurrence, targeting younger people with prior stromal disease might be the most cost-effective way to reduce the national and global burden of visual loss caused by HSV.

Accepted for publication January 27, 2000.

This study was supported by cooperative agreements EY09686, EY09687, EY09691, EY09692, EY09693, EY09694, EY09695, EY09696, and EY09697 with the National Eye Institute, National Institutes of Health, Bethesda, Md. Glaxo Wellcome Inc supplied the study medications.

The members of the investigator group who signed authorship responsibility, financial disclosure, and copyright transfer statements for the group are as follows: Roy W. Beck, MD, PhD (writing committee), Penny A. Asbell, MD, Elisabeth J. Cohen, MD, Chandler R. Dawson, MD, Robert A. Hyndiuk, MD, Dan B. Jones, MD, Herbert E. Kaufman, MD (writing committee), Kevin E. Kip, PhD (writing committee), Natalie Kurinij, PhD, Pamela S. Moke, MSPH, R. Doyle Stulting, MD, PhD, Joel Sugar, MD, Kirk R. Wilhelmus, MD, MPH (writing committee).

The following individuals participated in the conduct of the trial.

Regional Centers and Clinical Sites

LSU Eye Center, Louisiana State University Medical Center, New Orleans: regional principal investigator: B. A. Barron; regional coordinators: K. Edwards, S. J. Massare, M. S. McGovern, D. Williams; site investigators: S. J. Capps, D. M. Dragon, C. T. Fitzmorris, E. E. Graul, Jr, M. S. Insler, H. E. Kaufman, A. D. Lacoste, C. S. McCaa, R. E. Selser, Jr, N. J. Wagner, J. A. Yokubaitis. Cullen Eye Institute, Baylor College of Medicine, Houston, Tex: regional principal investigator: K. R. Wilhelmus; regional coordinators: L. A. Todaro, S. J. Woodside; site investigators: C. B. Bowman, J. Chodosh, R. M. Gilliam, J. D. Goosey, D. B. Jones, C. Kirkland, Jr, R. P. Lehmann, A. Y. Matoba, R. E. Pitts, P. D. Scott, S. L. Smith, T. C. Wolf, R. W. Yee. Francis I. Proctor Foundation, University of California, San Francisco: regional principal investigator: C. R. Dawson; regional coordinators: S. Banuvar, S. Y. Osaki; regional center investigator: F. Cohen; site investigators: G. P. Barth, R. Biswell, E. Cunningham, D. R. DeMartini, D. Gritz, W. Hodge, D. S. Holsclaw, D. G. Hwang, C. M. Knox, T. Lietman, T. P. Margolis, I. R. Schwab, L. Schwartz, M. Sherman, B. Silverstein, D. W. Vastine, M. Volpicelli, J. P. Whitcher, S. Wilson, I. G. Wong. Emory Eye Center, Emory University, Atlanta, Ga: regional principal investigator: R. D. Stulting; regional coordinator: L. G. DuBois; site investigators: R. Baldassare, B. A. Bertram, H. Chopra, S. D. Croll, R. C. DiIorio, J. R. Gussler, S. M. Hamilton, G. R. John, J. W. McCann, J. C. Meyer, P. G. Mitchell, D. A. Palay, R. J. Ramirez, R. E. Reed, R. N. Serros, L. R. Taub, K. P. Thompson, K. A. Walter. UIC Eye Center, University of Illinois at Chicago: regional principal investigator: J. Sugar; regional coordinator: R. Rodiek; site investigators: C. S. Bouchard, R. Dennis, R. S. Feder, M. J. Hennessey, D. M. Lubeck, S. D. McLeod, D. Meisler, D. D. Morimoto, P. K. Morimoto, J. B. Rubenstein, H. H. Tessler. The Eye Institute, Medical College of Wisconsin, Milwaukee: regional principal investigator: R. A. Hyndiuk; regional coordinator: C. Samson; site investigators: N. P. Barney, F. S. Brightbill, J. D. DeCarlo, E. S. Fogel, S. P. Gainey, S. B. Koenig, D. J. Kontra, D. B. Krebs, D. R. Lewellen, S. M. Patalano, P. R. Rice, M. C. Sanderson, K. P. Wienkers, M. M. Yeomans. Wills Eye Hospital, Philadelphia, Pa: regional principal investigator: E. J. Cohen; regional coordinators: S. C. Marshall; I. M. Rodriguez, P. Phipps; site investigators: A. J. Altman, R. J. Bailey, K. L. Fung, S. B. Hannush, K. F. Heffler, H. J. Ingraham, J. J. Kesselring, V. O. Kowal, P. R. Laibson, N. F. Martin, M. A. Naidoff, S. E. Orlin, I. M. Raber, C. R. Rapuano, R. S. Rubinfeld, M. E. Sulewski. The Department of Ophthalmology, Mount Sinai Medical Center, New York, NY: regional principal investigator: P. A. Asbell; regional coordinators: N. Justin, R. C. Azueta, M. Arroyo, S. Celanges, D. M. Annunziato, S. Epstein; site investigators: B. A. Barker, E. R. Brocks, N. H. Choo, W. H. Constad, G. D'Aversa, M. J. Dunn, B. D. Gorman, M. R. Leopold, M. J. Newton, V. E. Perez-Arroyo, W. J. Schwartz, G. Sternberg, I. J. Udell.

Central Units

National Coordinating Center: Jaeb Center for Health Research, Inc, Tampa, Fla (1994-1999): R. W. Beck (director), P. S. Moke, R. C. Blair, S. R. Cole, R. Gal, H. A. Gillespie, K. Kip, L. A. Lester, M. L. Mhamdi, E. S. Tan; University of California, San Francisco (1992-1994): W. W. Hauck (director), L. Gee, J. E. Hidayat. National Eye Institute: N. Kurinij. Data and Safety Monitoring Committee (if no dates listed, the individual was a member of the committee for the entire study): S. I. Bangdiwala (chairman), W. E. Barlow, J. W. Chandler (1992-1994), M. A. Lemp (1994-1996), A. B. Nesburn (1992-1995), D. L. Patrick (1994-1998), J. E. Sutphin, Jr (1995-1998), S. B. Watson (1992-1993).

Reprints: Roy W. Beck, MD, PhD, Jaeb Center for Health Research, 3010 E 138th Ave, Suite 9, Tampa, FL 33613 (e-mail: rbeck@jaeb.com).