Abstract: One hundred thirty-seven studies involving 8333 eyes met the inclusion criteria. Placebo-controlled studies were heterogeneous in comparison with idoxuridine (RR 1.74; 95% CI 1.03 to 2.91) and few in number for vidarabine (RR 1.81; 95% CI 1.09 to 3.01), interferon (RR 1.32; 95% CI 1.06 to 1.64), and debridement. Vidarabine (RR 1.13; 95% CI 1.02 to 1.25), trifluridine (RR 1.30; 95% CI 1.18 to 1.43), acyclovir (RR 1.23; 95% CI 1.14 to 1.34), and brivudine (RR 1.34; 95% CI 1.18 to 1.51) were more effective than idoxuridine. Trifluridine (RR 1.17; 95% CI 1.03 to 1.32) and acyclovir (RR 1.11; 95% CI 1.03 to 1.19) were more effective than vidarabine. No significant differences in healing emerged among trifluridine, acyclovir, brivudine, and foscarnet although few studies compared brivudine or foscarnet with other antivirals. Any potential advantage of ganciclovir compared to acyclovir was mitigated by study heterogeneity and possible publication bias. Only one study evaluated the joint use of two topical antivirals. In a limited number of studies, oral acyclovir (RR 0.92; 95% CI 0.79 to 1.07) or the combination of oral acyclovir with a topical antiviral (RR 1.36; 95% CI 0.68 to 2.74) appeared as effective as a single topical antiviral agent. Compared to topical antiviral monotherapy, the combination of an antiviral with either interferon or debridement had inconsistent effects on expediting healing and improving outcome. Placebo-controlled studies of HSV epithelial keratitis are limited to superseded interventions. Trifluridine and acyclovir are more effective than idoxuridine or vidarabine and similar in therapeutic effectiveness. Brivudine and foscarnet do not substantially differ in effectiveness from trifluridine or acyclovir. Ganciclovir is at least as effective as acyclovir. The addition of interferon to a nucleoside antiviral agent and the combination of debridement with antiviral treatment need to be further assessed to substantiate any possible advantage in healing.

Plain-language summary: This update, current to December 2014, uses a network of 137 studies of 8333 eyes to compare antiviral medicines and to find out if interferon or debridement would help. Between one and 28 studies were available to compare seven ophthalmic antiviral drugs, an antiviral taken by mouth, interferon, office procedures to remove the eye's infected surface, and other medicines. The first antivirals, idoxuridine and vidarabine, seem better than no treatment in healing HSV dendritic keratitis within two weeks. Topically applied trifluridine, acyclovir, or brivudine are better and safer than idoxuridine, cure about 90% of treated eyes within two weeks, and have no significant differences in effectiveness. The evidence is conflicting whether ganciclovir is as good as or better than acyclovir. Determining the role of antiviral pills is limited by few studies and inconsistent findings. Interferon, a natural part of the immune system that can be given as an eye drop, is active against HSV infection of the cornea. The integrated use of interferon and an antiviral drug might be slightly better than an antiviral drug by itself. Another treatment is to rub off the infected surface of the eye, but using a wiping method followed by an antiviral drug is not consistently better than just an antiviral medication. Comparisons of one ophthalmic antiviral drug to another have a moderate quality of evidence, except for the appraisal comparing ganciclovir and acyclovir where studies are inconsistent. The quality of the evidence is moderate to low when an ophthalmic antiviral drug was compared to combined antiviral and interferon treatments or to combined antiviral treatment and debridement. Evidence is scarce or poor for placebo-controlled comparisons, comparisons of antiviral treatment to interferon or to debridement, and evaluations of antiviral pills. Proper randomisation could not be assured in nearly a quarter of the studies. Patients or examiners could have known which treatment was assigned in at least half of the studies.