Prevention of Herpes Simplex Virus Eye Disease
January 1, 1999
Prevention of Herpes Simplex Virus Eye Disease
By Joan Unger, RN, MS, ARNP-C
Summary—The primary culprit in infection-related visual loss is herpes simplex virus (HSV), with 500,000 cases in the United States annually. It is known that oral acyclovir may decrease recurrent orofacial and genital HSV. The question is, will it act the same in ocular HSV disease? In this large, randomized, multicenter study, 703 patients received placebo or 200 mg of oral acyclovir twice daily for 12 months. Investigators determined oral acyclovir reduced the incidence of ocular HSV eye disease recurrence during the treatment period by nearly 50%. Patients with a history of ocular HSV disease in the past 12 months were most likely to benefit.
Experts report HSV is a leading cause of infection-related vision loss, with 500,000 cases in the United States each year.1 Although the patient often is asymptomatic and the infection usually self-limited, recurrent ocular HSV can result in corneal neovascularization with scarring resulting in poor vision. Other complications include necrotizing interstitial keratitis, stromal keratitis, recurrent uveitis, iritis, or secondary glaucoma. Severe scarring may require corneal transplant.1,2
Studies had established that oral acyclovir reduced recurrent orofacial and genital HSV disease, but scientists were unsure whether prophylactic treatment would prevent recurrences of ocular HSV disease. Some animal studies found prophylactic systemic acyclovir helpful, but others did not.
Clinical confirmation through a large, well-designed study in humans was lacking. The Herpetic Eye Disease Study Group, composed of researchers at 74 clinical sites around the United States, conducted a randomized, placebo-controlled trial to establish whether twice-daily treatment with 400 mg of oral acyclovir for one year in immunocompetent subjects with a history of ocular HSV within the preceding year would prevent ocular recurrences.3
Study Methodology
Criteria for the 703 study-eligible patients included the following:
• age 12 or older;
• history of ocular HSV disease in preceding 12 months;
• and disease inactive and untreated for 30 days before study began.
Exclusion criteria included the following:
• patients receiving antiviral or immunosuppressive therapy;
• history of immune dysfunction;
• renal insufficiency;
• keratoplasty or keratorefractive surgery;
• and allergy or adverse reaction to acyclovir.
Sexually active patients of reproductive age agreed to use contraception during the 12-month treatment period and the following three months.
Patients were assigned to two treatment groups in approximately equal numbers, using computer-generated random numbers for each of eight geographic regions. Subjects in the treatment group received 200 mg of acyclovir orally twice a day for 12 months. The control group took a placebo capsule twice a day that appeared identical to the study medication. Compliance with the treatment regimen was assessed by counting capsules remaining in returned medication bottles or estimated from medication records and patient self-reports.
An experienced ophthalmologist used slit-lamp biomicroscopy to determine whether active ocular HSV disease had recurred in study subjects. Examinations were done at one, three, six, nine, and 12 months into the study and after months 13, 15, and 18 for post-treatment observation. Classification of recurrences included infections of:
• the ocular surface (blepharitis, conjunctivitis, epithelial keratitis);
• stromal keratitis (corneal stromal inflammatory infiltrate or corneal edema associated with endothelial inflammatory precipitates);
• and iritis alone.
Nonocular HSV infection was recorded based on patients’ reports and classified as:
• orofacial;
• genital;
• or other cutaneous site.
Study Results
Of the 703 subjects enrolled in the study, 357 were in the acyclovir group, and 346 were in the placebo group. Baseline characteristics of the two groups were similar. During the 12-month trial and six-month follow-up, acyclovir patients completed 88% of specified visits, and placebo subjects completed 86%.
Of the 575 subjects (82%) who completed the 12-month treatment, 89% of the acyclovir group and 87% of the placebo subjects reported at least 80% compliance in taking the study medication. A 90% compliance rate was reported for 72% of acyclovir subjects and 68% placebo subjects.
Researchers discovered the compliance rates were similar for patients who developed recurrent ocular HSV disease during the treatment period and those who did not.
Patients who did not have recurrent ocular HSV disease during the study totaled 486, and follow-up was incomplete for 64 of these (13%). Patients experienced no serious adverse effects from treatment. However, 15 acyclovir patients and 17 placebo patients discontinued treatment as a result of medication side effects, including gastrointestinal effect, rash, anxiety, dizziness, fatigue, hair loss, headache, memory loss, sexual dysfunction, tinnitus, and/or weight gain.
The cumulative probability of recurrence of ocular HSV disease was significantly lower in the acyclovir group (19%) than in the placebo group (32%). Study results were similar whether patients enrolled at a university-affiliated or community-based clinical center. However, investigators found the number of previous episodes of ocular HSV disease was strongly associated with probability of recurrence in both treatment groups. Forty-six patients had more than one recurrence during the trial period, 16 in the acyclovir group (4%), and 30 in the placebo group (9%).
Interestingly, acyclovir reduced the risk of recurrent stromal keratitis only among the 337 patients who reported at least one prior episode of the condition. No significant differences existed between the two groups in recurrences of ocular HSV disease during the six-month observation period after the 12-month treatment phase.
Researchers found that oral acyclovir reduced the incidence of ocular recurrence during the treatment period by nearly 50%. A similar reduction in the rate of orofacial HSV recurrence also was noted. Side effects were minimal. However, the benefit did not continue when treatment was stopped, although no acute rebound effect occurred.3
Implications for Practice
Results of this study are of interest to advanced practice nurses who may have patients presenting with recurrent episodes of ocular HSV disease. The researchers stated the following conclusions:
• Long-term treatment with acyclovir was helpful in preventing recurrent ocular and orofacial HSV disease in patients with a previous history of the ocular HSV disease.
• The form recurrent ocular HSV takes is closely associated with the form that occurred in previous episodes.
• Patients with a prior history of stromal keratitis, which can produce corneal scarring and loss of vision, likely will obtain the most benefit from long-term acyclovir.
• The benefit to patients with blepharitis, conjunctivitis, and epithelial keratitis (superficial forms of ocular HSV) is not as certain. These forms usually respond to short-term topical antiviral therapy and result in little permanent eye damage.
• The researchers suggest that study results are most applicable to immunocompetent patients who had an episode of ocular HSV disease during the year before treatment.
References
1. Hejkal T. Herpes eye infections: Basics. In: Dambro M, Griffith, eds. Griffith’s 5 Minute Clinical Consult. (Computer program.) Baltimore: Williams & Wilkins; 1997.
2. Simon A, Pavan-Langston D. Long-term oral acyclovir Therapy: Effect on recurrent infections herpes simplex keratitis in patients with and without grafts. Ophthalmology 1996;103:1399-1405.
3. The Herpetic Eye Disease Study Group. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. NEJM 1998;339:300-306.
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