Herpetic Eye Disease Study Acyclovir Prevention Trial, a randomized double-masked placebo-controlled multicenter trial in 703 immunocompetent patients who had had ocular HSV disease within the preceding year: cumulative probability of a recurrence of any type of ocular HSV disease over the 12-month treatment period was 19% on acyclovir versus 32% on placebo (P<0.001), and among the 337 patients with a history of stromal keratitis, recurrent stromal keratitis was 14% versus 28% (P=0.005); nonocular, primarily orofacial, recurrence was also lower at 19% versus 36% (P<0.001), and there was no rebound in the rate of HSV disease in the 6 months after treatment stopped. A further analysis of the same trial gave rate ratios of 0.62 (95% CI 0.39 to 0.97) for preventing epithelial keratitis and 0.57 (95% CI 0.36 to 0.89) for preventing stromal keratitis, with the absolute benefit greatest in patients with the most prior episodes, and the authors report that the benefit in preventing stromal keratitis was seen solely among patients with a history of stromal keratitis.

Randomized double-blind trial in 60 patients with simple dendritic corneal ulceration comparing acyclovir 400 mg tablets 5 times daily against acyclovir ophthalmic ointment 5 times daily: 88.9% healed on the oral drug versus 96.6% on the ointment, a difference that was not significant, with a median healing time of 5 days in both groups and trough tear concentrations within or above the range of mean in vitro ID50 levels for HSV-1. A Cochrane review of 137 studies in 8333 eyes reports that in a limited number of studies oral acyclovir alone (RR 0.92, 95% CI 0.79 to 1.07) or combined with a topical antiviral (RR 1.36, 95% CI 0.68 to 2.74) appeared as effective as a single topical antiviral agent.

Herpetic Eye Disease Study, a randomized double-masked placebo-controlled multicenter trial in 104 patients with HSV stromal keratitis without accompanying epithelial keratitis, all of whom also received topical prednisolone phosphate and trifluridine: median time to treatment failure was 84 days (95% CI 69 to 93) on acyclovir versus 62 days (95% CI 57 to 90) on placebo, and by 16 weeks 75% versus 74% had failed, neither difference significant. The authors concluded there was no statistically or clinically significant beneficial effect on time to treatment failure, proportion failing, proportion resolving, time to resolution, or 6-month best-corrected visual acuity, while also reporting that visual acuity improved over 6 months in more patients on acyclovir than on placebo.

Randomized, double-masked, acyclovir-controlled parallel-group multicenter trial across 87 centers, 454 patients with V1 ophthalmic zoster in the intent-to-treat population. One or more ocular manifestations occurred in 142 of 245 (58.0%) on famciclovir 500 mg three times daily versus 114 of 196 (58.2%) on acyclovir 800 mg five times daily, odds ratio 0.99 (95% CI 0.68 to 1.45), with no significant difference in severe or non-severe manifestations, in the prevalence of individual ocular manifestations, or in visual acuity loss. The comparator was acyclovir, not placebo, so the trial establishes similar efficacy rather than a treatment effect size. Timing is the actionable variable: a review of herpes zoster antivirals states that acyclovir, valacyclovir and famciclovir started within 72 hours of acute rash onset significantly shorten acute pain, viral shedding, rash, and acute and late-onset anterior segment complications, and that valacyclovir and famciclovir also reduce the incidence and severity of postherpetic neuralgia, but that none of these agents prevents it.

Non-randomized prospective interventional study of 29 eyes with PCR-confirmed CMV anterior segment infection (23 anterior uveitis, 6 endotheliitis) treated with the 0.15% gel 5 times daily: at 6 weeks 26 of 29 eyes had undetectable aqueous CMV titre and no anterior chamber activity, the 2 eyes that worsened were non-compliant, but mean aqueous ganciclovir concentration was 17.4 plus or minus 30.6 ng/mL, which the authors state is below the 50% inhibitory dose for CMV replication. A systematic review and meta-analysis of 23 studies reported good clinical response of acute CMV anterior uveitis to topical 0.15% gel in 90% (95% CI 74 to 100%), comparable to oral valganciclovir at 95% (95% CI 88 to 100%), but found that chronic anterior uveitis and endotheliitis required escalated concentration and frequency, with endotheliitis series using topical 0.5% to 2% ganciclovir rather than 0.15%, and that recurrence after stopping maintenance was common.