Following a systematic review of the literature, information from clinical trials of HSV dendritic or geographic epithelial
keratitis was extracted, and the methodological quality of each study was scored. Methods of epithelial
cauterization and
curettage were grouped as relatively equivalent physicochemical
therapy, and
solution and
ointment formulations of a given topical
antiviral agent were combined. The proportion healed with 1 week of
therapy, a scheduled follow-up day that approximated the average time of resolution with
antiviral therapy, was selected as the primary outcome based on a masked evaluation of maximum treatment differences in published healing curves. The proportion healed at 14 days was recorded as supplemental information. Fixed-effects and random-effects meta-analysis models were used to obtain summary estimates by pooling results from comparative treatment trials. Hypotheses about which prognostic factors might affect epithelial healing during
antiviral therapy were developed by multivariate analysis of the Herpetic
Eye Disease Study dataset.
RESULTS: After excluding 48 duplicate reports, 14 nonrandomized studies, 15 studies with outdated or similar treatments, and 29 trials lacking sufficient data on healing or accessibility, 76 primary reports were identified. These reports involved 4,251 patients allocated to 93 treatment comparisons of dendritic epithelial
keratitis in 28 categories and 9 comparisons of geographic epithelial
keratitis in 6 categories. For
dendritic keratitis,
idoxuridine was better than placebo at 7 days (combined odds ratio [OR], 3.59; 95% confidence interval [CI], 1.92-6.70), and at 14 days (OR, 4.17; 95% CI, 1.33-13.04), but pooling was limited by lack of homogeneity and low study quality. Direct comparisons at 1 week of treatment showed that
trifluridine or
acyclovir was significantly better than
idoxuridine (OR, 3.12 and 4.56; 95% CI, 1.55-6.29 and 2.76-7.52, respectively), and indirect comparisons were also consistent with a clinically significant benefit.
Vidarabine was not significantly better than
idoxuridine in pooled treatment comparisons at 1 week (OR, 1.20; 95% CI, 0.72-2.00) but was better in 2 indirect comparisons (OR, 4.22 and 4.78; 95% CI, 1.69-10.54 and 2.15-10.65, respectively). At 14 days,
trifluridine (OR, 6.05; 95% CI, 2.50-14.66),
acyclovir (OR, 2.88; 95% CI, 1.39-4.78), and
vidarabine (OR, 1.24; 95% CI, 0.65-2.37) were each better than
idoxuridine. Trials of geographic epithelial
keratitis also suggested that
trifluridine,
acyclovir, and
vidarabine were more effective that
idoxuridine. Other topical
antiviral agents, such as bromovinyldeoxuridine,
ganciclovir, and
foscarnet, appeared equivalent to
trifluridine or
acyclovir. Oral
acyclovir was equivalent to topical
antiviral therapy and did not hasten healing when used in combination with topical treatment.
Antiviral agents did not increase the speed of healing when compared to
debridement but reduced the risk of recrudescent epithelial
keratitis. The combination of physicochemical treatment with an
antiviral agent seemed to be better than either physicochemical or
antiviral treatment alone, but the heterogeneous
cauterization and
curettage techniques and the various treatment combinations limited valid quantitative summary effect measures. The combination of topical
interferon with an
antiviral agent was significantly better than
antiviral therapy at 7 days (OR, 13.49; 95% CI, 7.39-24.61) but not at 14 days (OR, 2.36; 95% CI, 0.82-6.79). Finding apparent heterogeneity for some pooled estimates suggested that dissimilarities in patients, interventions, outcomes, or other logistical aspects of clinical trials occur across studies.
CONCLUSIONS: The available evidence on the acute treatment of presumed HSV epithelial
keratitis demonstrates the effectiveness of
antiviral treatment and shows the log-logistic healing curve of treated dendritic epithelial
keratitis. Topical
trifluridine,
acyclovir, and
vidarabine were significantly more effective than
idoxuridine but similar in relative effectiveness for dendritic epithelial
keratitis. Physicochemical methods of removing infected corneal epithelium are effective, but adjunctive virucidal agents are needed to avert recrudescent epithelial
keratitis. Whether
debridement in combination with
antiviral therapy is more beneficial than
antiviral chemotherapy alone appears likely but remains inconclusive. The combination of topical
interferon with an
antiviral agent significantly speeds epithelial healing. Future trials of the acute treatment of HSV epithelial
keratitis must aim to achieve adequate statistical power for assessing the primary outcome and should consider the effect of lesion size and other characteristics on treatment response.