Wilhelmus K R
Department of Ophthalmology, Baylor College of Medicine, Houston, USA.
Trans Am Ophthalmol Soc. 2000;98:505-32.
Epithelial keratitis is the most common presentation of ocular infection by herpes simplex virus (HSV). Quantitative assessment of available therapy is needed to guide evidence-based ophthalmology. This study aimed to compare the efficacy of various treatments for dendritic or geographic HSV epithelial keratitis and to evaluate the role of various clinical characteristics on epithelial healing.
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.
After excluding 48 duplicate reports, 14 nonrandomized studies, 15 studies with outdated or similar treatments, and 29 trials lacking sufficient data on healing or accessibility, 76 primary reports were identified.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.
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.
上皮性角膜炎是单纯疱疹病毒（HSV）眼部感染最常见的表现形式。需要对现有治疗方法进行定量评估，以指导循证眼科学。本研究旨在比较各种治疗方法对树枝状或地图状HSV上皮性角膜炎的疗效，并评估各种临床特征在上皮愈合中的作用。
在对文献进行系统回顾后，提取了HSV树枝状或地图状上皮性角膜炎临床试验的信息，并对每项研究的方法学质量进行评分。上皮烧灼和刮除方法被归为相对等效的物理化学疗法，给定局部抗病毒药物的溶液和软膏制剂进行合并。基于对已发表愈合曲线中最大治疗差异的盲法评估，选择治疗1周时愈合的比例作为主要结局，这一预定随访日近似于抗病毒治疗的平均愈合时间。记录14天时愈合的比例作为补充信息。采用固定效应和随机效应荟萃分析模型，通过汇总比较治疗试验的结果来获得汇总估计值。通过对疱疹性眼病研究数据集进行多变量分析，提出了关于哪些预后因素可能影响抗病毒治疗期间上皮愈合的假设。
在排除48份重复报告、14项非随机研究、15项采用过时或相似治疗方法的研究以及29项缺乏足够愈合或可及性数据的试验后，共识别出76份主要报告。这些报告涉及4251例患者，分配到28类树枝状上皮性角膜炎的93种治疗比较以及6类地图状上皮性角膜炎的9种治疗比较中。对于树枝状角膜炎，7天时碘苷比安慰剂效果更好（合并比值比[OR]，3.59；95%置信区间[CI]，1.92 - 6.70），14天时也是如此（OR，4.17；95% CI，1.33 - 13.04），但由于缺乏同质性和研究质量较低，合并分析受到限制。治疗1周时的直接比较表明，三氟尿苷或阿昔洛韦明显优于碘苷（OR分别为3.12和4.56；95% CI分别为1.55 - 6.29和2.76 - 7.52），间接比较也显示出具有临床意义的益处。在合并治疗比较中，1周时阿糖腺苷并不比碘苷显著更好（OR，1.20；95% CI，0.72 - 2.00），但在2项间接比较中效果更好（OR分别为4.22和4.78；95% CI分别为1.69 - 10.54和2.15 - 10.65）。14天时，三氟尿苷（OR，6.05；95% CI，2.50 - 14.66）、阿昔洛韦（OR，2.88；95% CI, 1.39 - 4.78）和阿糖腺苷（OR，1.24；95% CI，0.65 - 2.37）均比碘苷效果更好。地图状上皮性角膜炎的试验也表明，三氟尿苷、阿昔洛韦和阿糖腺苷比碘苷更有效。其他局部抗病毒药物，如溴乙烯脱氧尿苷、更昔洛韦和膦甲酸钠，似乎与三氟尿苷或阿昔洛韦等效。口服阿昔洛韦与局部抗病毒治疗等效，与局部治疗联合使用时并不会加速愈合。与清创术相比，抗病毒药物不会提高愈合速度，但可降低上皮性角膜炎复发的风险。物理化学治疗与抗病毒药物联合使用似乎比单独的物理化学治疗或抗病毒治疗更好，但烧灼和刮除技术的异质性以及各种治疗组合限制了有效的定量汇总效应量度。局部干扰素与抗病毒药物联合使用在7天时明显优于抗病毒治疗（OR，13.49；95% CI，7.39 - 24.61），但在14天时并非如此（OR，2.36；95% CI，0.82 - 6.79）。一些汇总估计值存在明显的异质性，表明不同研究在患者、干预措施、结局或临床试验的其他后勤方面存在差异。
关于疑似HSV上皮性角膜炎急性治疗的现有证据证明了抗病毒治疗的有效性，并显示了治疗后树枝状上皮性角膜炎的对数-逻辑斯蒂愈合曲线。局部三氟尿苷、阿昔洛韦和阿糖腺苷比碘苷显著更有效，但对于树枝状上皮性角膜炎，它们的相对有效性相似。去除感染角膜上皮的物理化学方法是有效的，但需要辅助杀病毒药物以避免上皮性角膜炎复发。清创术与抗病毒治疗联合使用是否比单独的抗病毒化疗更有益似乎很有可能，但仍不确定。局部干扰素与抗病毒药物联合使用可显著加速上皮愈合。未来HSV上皮性角膜炎急性治疗的试验必须旨在获得足够的统计效力以评估主要结局，并应考虑病变大小和其他特征对治疗反应的影响。
