Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis

Kirk R. Wilhelmus

doi:10.1002/14651858.CD002898.pub4

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Figure 1

Funnel plot of acyclovir versus idoxuridine

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Figure 2

Funnel plot of ganciclovir versus acyclovir

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Figure 3

PRISMA flow diagram

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Figure 4

Methodological quality graph: review author's judgements about each methodological quality item presented as percentages across all included studies.

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Figure 5

Funnel plot of idoxuridine versus inactive control

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Figure 6

Network of interconnected clinical trials comparing topical antiviral agents in the treatment of HSV epithelial keratitis: The circled numerals are the number of comparative treatment trials included in this systematic review that compared relative corneal healing at 14 days of treatment. Data from these 52 trials that enrolled 1590 eyes with HSV epithelial keratitis were used for direct and adjusted indirect comparisons of topical antiviral agents. Twenty‐two head‐to‐head antiviral treatment comparisons, in 20 reports, were excluded from this systematic review because of methodological or presentation shortcomings, including three idoxuridine‐vidarabine trials, three idoxuridine‐trifluridine trials, six idoxuridine‐acyclovir trials, one vidarabine‐trifluridine trial, three vidarabine‐acyclovir trials, and six acyclovir‐ganciclovir trials. Trials comparing other topical antiviral agents (e.g., foscarnet), antiviral combinations (e.g., acyclovir‐vidarabine), formulations, or oral antivirals are not mapped.

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Figure 7

Network of clinical trials comparing antiviral agents, interferon, and débridement in the treatment of HSV epithelial keratitis: The circled numerals are the number of comparative treatment trials included in this systematic review that compared relative corneal healing at 14 days. Trials comparing placebo, different interferon formulations, different débridement methods, different antiviral agents, or interferon inducers are not mapped. The débridement‐antiviral combination group comprises the combination of débridement with either a nucleoside antivirals or with interferon.

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Figure 8

Comparative corneal healing rates among placebo, idoxuridine, vidarabine, trifluridine, and acyclovir: overall healing curves estimated from pooled data from 24 studies (Abe 1987; Altinisik 1987; Blake 1977; Colin 1981; Collum 1980; Collum 1985; Coster 1976; Coster 1979; Coster 1980; Denis 1983; Hart 1965; Hoang‐Xuan 1984; Høvding 1989; Jackson 1984; Klauber 1982; Kumar 1987; La Lau 1982; Luntz 1963; Markham 1977; McCulley 1982; Van Bijsterveld 1980; Wellings 1972; Yeakley 1981; Young 1982) that enrolled 1168 participants to evaluate placebo control (44 eyes), idoxuridine (278 eyes), vidarabine (262 eyes), trifluridine (201 eyes), and acyclovir (383 eyes). Compared to the healing rate with idoxuridine, the hazard ratios for healing were 1.36 (95% CI 0.81‐2.28) for vidarabine, 2.29 (95% CI 1.37‐3.83) for trifluridine, and 2.15 (95% CI 1.70‐2.72) for acyclovir among included studies.

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Figure 9

Comparative corneal healing rates between combined antiviral and interferon therapy and antiviral monotherapy: overall healing curves estimated from pooled data from seven studies (Carmassi 1993; Colin 1983; de Koning 1982; de Koning 1983; Meurs 1985; Sundmacher 1981b; Van Bijsterveld 1989) that enrolled 363 participants to evaluate antiviral monotherapy with trifluridine (48) or acyclovir (97) or brivudine (22) in comparison to trifluridine‐interferon (75) or acyclovir‐interferon (102) or brivudine‐interferon (19). The cumulative healing curve of antiviral monotherapy (Antiviral) in these trials differs slightly from that of either acyclovir or trifluridine in other studies (Figure 8).

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Figure 10

Histogram of publication year: included studies

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Figure 11

Histogram of publication year: excluded studies

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Analysis 1.1

Comparison 1 Topical antiviral agents, Outcome 1 Idoxuridine versus inactive control: 7‐day & 14‐day healing.

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Analysis 1.2

Comparison 1 Topical antiviral agents, Outcome 2 Idoxuridine versus inactive control: healing rate.

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Analysis 1.3

Comparison 1 Topical antiviral agents, Outcome 3 Vidarabine versus inactive control: 7‐day & 14‐day healing.

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Analysis 1.4

Comparison 1 Topical antiviral agents, Outcome 4 Vidarabine versus inactive control: healing rate.

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Analysis 1.5

Comparison 1 Topical antiviral agents, Outcome 5 Vidarabine versus idoxuridine: 7‐day & 14‐day healing.

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Analysis 1.6

Comparison 1 Topical antiviral agents, Outcome 6 Vidarabine versus idoxuridine: healing rate.

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Analysis 1.7

Comparison 1 Topical antiviral agents, Outcome 7 para‐Fluorophenylalanine versus idoxuridine: 7‐day & 14‐day healing.

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Analysis 1.8

Comparison 1 Topical antiviral agents, Outcome 8 Trifluridine versus idoxuridine: 7‐day & 14‐day healing.

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Analysis 1.9

Comparison 1 Topical antiviral agents, Outcome 9 Trifluridine versus idoxuridine: healing rate.

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Analysis 1.10

Comparison 1 Topical antiviral agents, Outcome 10 Acyclovir versus idoxuridine: 7‐day & 14‐day healing.

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Analysis 1.11

Comparison 1 Topical antiviral agents, Outcome 11 Acyclovir versus idoxuridine: healing rate.

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Analysis 1.12

Comparison 1 Topical antiviral agents, Outcome 12 Brivudine versus idoxuridine: 7‐day & 14‐day healing.

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Analysis 1.13

Comparison 1 Topical antiviral agents, Outcome 13 Trifluridine versus vidarabine: 7‐day & 14‐day healing.

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Analysis 1.14

Comparison 1 Topical antiviral agents, Outcome 14 Trifluridine versus vidarabine: healing rate.

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Analysis 1.15

Comparison 1 Topical antiviral agents, Outcome 15 Acyclovir versus vidarabine: 7‐day & 14‐day healing.

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Analysis 1.16

Comparison 1 Topical antiviral agents, Outcome 16 Acyclovir versus vidarabine: healing rate.

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Analysis 1.17

Comparison 1 Topical antiviral agents, Outcome 17 Acyclovir versus trifluridine: 7‐day & 14‐day healing.

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Analysis 1.18

Comparison 1 Topical antiviral agents, Outcome 18 Acyclovir versus trifluridine: healing rate.

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Analysis 1.19

Comparison 1 Topical antiviral agents, Outcome 19 Brivudine versus trifluridine: 7‐day & 14‐day healing.

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Analysis 1.20

Comparison 1 Topical antiviral agents, Outcome 20 Brivudine versus trifluridine: healing rate.

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Analysis 1.21

Comparison 1 Topical antiviral agents, Outcome 21 Brivudine versus acyclovir: 7‐day & 14‐day healing.

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Analysis 1.22

Comparison 1 Topical antiviral agents, Outcome 22 Ganciclovir versus acyclovir: 7‐day & 14‐day healing.

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Analysis 1.23

Comparison 1 Topical antiviral agents, Outcome 23 Foscarnet versus trifluridine: 7‐day & 14‐day healing.

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Analysis 1.24

Comparison 1 Topical antiviral agents, Outcome 24 Acyclovir/vidarabine versus acyclovir: 7‐day & 14‐day healing.

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Analysis 1.25

Comparison 1 Topical antiviral agents, Outcome 25 Trifluridine (aqueous) versus trifluridine (viscous).

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Analysis 1.26

Comparison 1 Topical antiviral agents, Outcome 26 Ganciclovir 0.15% versus ganciclovir 0.05%.

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Analysis 2.1

Comparison 2 Oral antiviral agents, Outcome 1 Oral antiviral versus topical antiviral.

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Analysis 2.2

Comparison 2 Oral antiviral agents, Outcome 2 Oral/topical antivirals versus topical antiviral.

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Analysis 3.1

Comparison 3 Topical interferon formulations, Outcome 1 Interferon versus inactive control, without or with débridement.

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Analysis 3.2

Comparison 3 Topical interferon formulations, Outcome 2 Interferon dosages.

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Analysis 3.3

Comparison 3 Topical interferon formulations, Outcome 3 Interferon‐α with débridement versus interferon‐β with débridement.

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Analysis 3.4

Comparison 3 Topical interferon formulations, Outcome 4 Natural interferon‐α with trifluridine versus recombinant interferon‐α with trifluridine.

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Analysis 3.5

Comparison 3 Topical interferon formulations, Outcome 5 Interferon versus nucleoside antiviral.

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Analysis 3.6

Comparison 3 Topical interferon formulations, Outcome 6 Interferon inducer versus nucleoside antiviral.

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Analysis 3.7

Comparison 3 Topical interferon formulations, Outcome 7 Interferon/nucleoside antiviral versus nucleoside antiviral: 7‐day & 14‐day healing.

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Analysis 3.8

Comparison 3 Topical interferon formulations, Outcome 8 Interferon/nucleoside antiviral versus nucleoside antiviral: healing rate.

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Analysis 4.1

Comparison 4 Methods of physicochemical débridement, Outcome 1 Débridement versus control.

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Analysis 4.2

Comparison 4 Methods of physicochemical débridement, Outcome 2 Topical antiviral agent versus débridement.

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Analysis 4.3

Comparison 4 Methods of physicochemical débridement, Outcome 3 Different débridement methods, with interferon.

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Analysis 4.4

Comparison 4 Methods of physicochemical débridement, Outcome 4 Débridement with antiviral or interferon versus débridement.

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Analysis 4.5

Comparison 4 Methods of physicochemical débridement, Outcome 5 Débridement with different antivirals.

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Analysis 4.6

Comparison 4 Methods of physicochemical débridement, Outcome 6 Débridement with antiviral versus antiviral: 7‐day & 14‐day healing.

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Analysis 4.7

Comparison 4 Methods of physicochemical débridement, Outcome 7 Débridement with antiviral versus antiviral: healing rate.

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Analysis 5.1

Comparison 5 Adjunctive agents: growth factors, non‐steroidal anti‐inflammatory drugs, immunomodulators, Outcome 1 Acyclovir/epidermal growth factor versus acyclovir.

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Analysis 5.2

Comparison 5 Adjunctive agents: growth factors, non‐steroidal anti‐inflammatory drugs, immunomodulators, Outcome 2 Panthenol versus para‐fluorophenylalanine, with débridement.

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Analysis 5.3

Comparison 5 Adjunctive agents: growth factors, non‐steroidal anti‐inflammatory drugs, immunomodulators, Outcome 3 Idoxuridine/oxyphenbutazone versus idoxuridine/placebo.

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Analysis 5.4

Comparison 5 Adjunctive agents: growth factors, non‐steroidal anti‐inflammatory drugs, immunomodulators, Outcome 4 Oral isoprinosine versus inactive control.

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Summary of findings for the main comparison. Summary of findings: relative healing rate for selected antiviral agents and combination interventions

Therapy of herpes simplex virus epithelial keratitis
Patient population: trial participants with dendritic or geographic epithelial keratitis Outcomes: healing rate throughout 15 or more days following trial enrolment
Treatment comparisons	Hazard ratio (95% Confidence Interval)	No. of participants (studies)
Idoxuridine vs. inactive control	2.02 (1.16‐3.49)	95 (3)
Vidarabine vs. inactive control	2.47 (1.14‐5.33)	43 (1)
Vidarabine vs. idoxuridine	1.36 (0.81‐2.28)	74 (2)
Trifluridine vs. idoxuridine	2.29 (1.37‐3.83)	78 (1)
Acyclovir vs. idoxuridine	2.15 (1.70‐2.72)	355 (8)
Trifluridine vs. vidarabine	1.31 (0.96‐1.79)	188 (3)
Acyclovir vs. vidarabine	1.13 (0.86‐1.47)	259 (5)
Acyclovir vs. trifluridine	0.92 (0.65‐1.32)	140 (3)
Brivudine vs. trifluridine	0.60 (0.35‐1.02)	60 (1)
Interferon + antiviral vs. antiviral	2.84 (2.13‐3.79)	229 (5)
Débridement + antiviral vs. antiviral	1.76 (1.32‐2.35)	248 (6)

Summary of findings for the main comparison. Summary of findings: relative healing rate for selected antiviral agents and combination interventions

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Summary of findings 2. Summary of findings: relative healing outcome with topical antiviral therapy

Topical antiviral therapy of herpes simplex virus epithelial keratitis
Patient population: trial participants with dendritic or geographic epithelial keratitis Outcomes: corneal epithelial healing after 7 days and after 14 days
Treatment comparisons	*Illustrative comparative healing percentages (95% CI)**		Relative risk (95% Cl)**	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed healing	Corresponding healing
	Treatment A	Treatment B
Idoxuridine (B) vs. inactive control (A)	7 days				Moderate^1,2	Different substances used as inactive control
	25%	57% (43%‐75%)	2.26 (1.71‐3.00)	392 (10)
	14 days
	45%	59% (36%‐97%)	1.31 (0.80‐2.15)	63 (2)
Vidarabine (B) vs. idoxuridine (A)	7 days				Moderate⁴	Combined direct and indirect comparisons indicate vidarabine more effective than idoxuridine; neither antiviral commercially marketed
	40%	44% (34%‐56%)	1.10 (0.85‐1.42)	243 (3)
	14 days
	77%	80% (71%‐90%)	1.04 (0.92‐1.18)	243 (3)
Trifluridine (B) vs. idoxuridine (A)	7 days				Moderate^1,2	Adjusted indirect comparison shows similar results
	20%	49% (34%‐71%)	2.52 (1.74‐3.63)	223 (4)
	14 days
	64%	89% (76%‐100%)	1.38 (1.19‐1.60)	256 (5)
Acyclovir (B) vs. idoxuridine (A)	7 days				Moderate^1,2,5	Adjusted indirect comparison shows similar results
	33%	64% (54%‐77%)	1.96 (1.64‐2.34)	468 (9)
	14 days
	68%	84% (78%‐90%)	1.23 (1.14‐1.32)	606 (11)
Brivudine (B) vs. idoxuridine (A)	7 days				Moderate⁴	Few studies, with slow healing of idoxuridine‐treated eyes, but indirect analysis yields similar relative effect
	5%	43% (15%‐100%)	7.94 (2.80‐22.53)	99 (2)
	14 days
	59%	81% (61%‐100%)	1.38 (1.05‐1.81)	99 (2)
Trifluridine (B) vs. vidarabine (A)	7 days				Moderate^1,2	Results partly influenced by one study restricted to geographic epithelial keratitis
	55%	58% (50%‐67%)	1.05 (0.91‐1.22)	288 (4)
	14 days
	71%	77% (70%‐87%)	1.09 (0.98‐1.22)	188 (3)
Acyclovir (B) vs. vidarabine (A)	7 days				Moderate²	Indirect analysis also favours acyclovir but one study restricted to geographic epithelial keratitis does not
	68%	84% (71%‐98%)	1.23 (1.05‐1.44)	314 (6)
	14 days
	84%	92% (84%‐99%)	1.09 (1.00‐1.18)	342 (7)
Acyclovir (B) vs. trifluridine (A)	7 days				High	Studies differ in trifluridine formulation, in solution and as ointment
	73%	73% (60%‐88%)	0.99 (0.82‐1.20)	178 (4)
	14 days
	91%	90% (82%‐99%)	0.99 (0.90‐1.09)	178 (4)
Brivudine (B) vs. trifluridine (A)	7 days				Moderate^1,2
	59%	55% (42%‐71%)	0.93 (0.71‐1.21)	147 (3)
	14 days
	85%	85% (75%‐97%)	1.00 (0.88‐1.14)	147 (3)
Brivudine (B) vs. acyclovir (A)	7 days				Moderate⁴	Direct analysis limited to one study, but indirect analysis yields similar relative effect
	80%	95% (74%‐100%)	1.19 (0.93‐1.51)	40 (1)
	14 days
	95%	100% (87%‐100%)	1.05 (0.92‐1.20)	40 (1)
Ganciclovir (B) vs. acyclovir (A)	7 days				Moderate^1,2,5	Slow healing in some studies; no significant difference found in random‐effects model
	33%	35% (28%‐43%)	1.05 (0.84‐1.31)	378 (5)
	14 days
	57%	64% (59%‐70%)	1.13 (1.04‐1.23)	672 (10)
The basis for each assumed risk* is the mean 7‐day and 14‐day healing percentages among included studies for patients who received treatment A. Each corresponding risk (and its 95% confidence interval) is based on the assumed risk and the risk ratio comparing treatment B to treatment A (and its 95% CI), with upper limits bounded at 100%. The relative risk** is the pooled risk ratio. CI: Confidence interval.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
¹ Some studies had a potential risk of bias ² Pooling was limited by inconsistent results at either 7‐day or 14‐day outcome ³ Analysis based only on adjusted indirect comparison ⁴ Few studies ⁵ Possible publication bias (Figure 1, Figure 2)

Summary of findings 2. Summary of findings: relative healing outcome with topical antiviral therapy

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Summary of findings 3. Summary of findings: relative healing outcome with oral antiviral therapy

Oral antiviral therapy of herpes simplex virus epithelial keratitis
Patient population: trial participants with dendritic or geographic epithelial keratitis Outcomes: corneal epithelial healing after 7 days and after 14 days
Treatment comparisons	*Illustrative comparative healing percentages (95% CI)**		Relative risk (95% CI)**	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed healing	Corresponding healing
	Treatment A	Treatment B
Oral antiviral (B) vs. topical antiviral (A)	7 days				Low¹	Only oral and topical acyclovir studied in comparative treatment trials
	53%	80% (60%‐100%)	1.51 (1.13‐2.02)	116 (2)
	14 days
	97%	89% (77%‐100%)	0.92 (0.79‐1.07)	56 (1)
Oral antiviral + topical antiviral (B) vs. topical antiviral (A)	7 days				Low¹	Oral acyclovir was studied with topical trifluridine and with topical idoxuridine
	63%	71% (60%‐83%)	1.13 (0.95‐1.33)	287 (1)
	14 days
	70%	75% (69%‐82%)	1.08 (0.99‐1.17)	327 (2)
The basis for the assumed risk* is the mean 7‐day and 14‐day healing percentages among included studies for patients who received treatment A. The corresponding risk (and its 95% confidence interval) is based on the assumed risk and the risk ratio comparing treatment B to treatment A (and its 95% CI), with upper limits bounded at 100%. The relative risk** is the pooled risk ratio. CI: Confidence interval.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
¹ Inconsistent and insufficient studies

Summary of findings 3. Summary of findings: relative healing outcome with oral antiviral therapy

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Summary of findings 4. Summary of findings: relative healing outcome with topical interferon

Interferon therapy of herpes simplex virus epithelial keratitis
Patient population: trial participants with dendritic or geographic epithelial keratitis Outcomes: corneal epithelial healing after 7 days and after 14 days
Treatment comparisons	*Illustrative comparative healing percentages (95% CI)**		Relative risk (95% CI)**	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed healing	Corresponding healing
	Treatment A	Treatment B
Interferon (B) vs. inactive control (A)	7 days				Low¹	One study used débridement
	38%	56% (40%‐78%)	1.48 (1.07‐2.06)	178 (3)
	14 days
	65%	86% (69%‐100%)	1.32 (1.06‐1.64)	110 (2)
Interferon (B) vs. antiviral (A)	7 days				Low¹	Different antiviral agents used as comparative treatment; no significant difference found in random‐effects model
	55%	57% (45%‐70%)	1.03 (0.82‐1.28)	85 (3)
	14 days
	75%	92% (76%‐100%)	1.23 (1.01‐1.49)	85 (3)
Interferon + antiviral (B) vs. antiviral (A)	7 days				High	Similar result in sensitivity analysis
	43%	84% (72%‐99%)	1.96 (1.67‐2.31)	401 (8)
	14 days
	93%	95% (92%‐99%)	1.03 (0.99‐1.07)	476 (9)
The basis for the assumed risk* is the mean 7‐day and 14‐day healing percentages among included studies for patients who received treatment A. The corresponding risk (and its 95% confidence interval) is based on the assumed risk and the risk ratio comparing treatment B to treatment A (and its 95% CI), with upper limits bounded at 100%. The relative risk** is the pooled risk ratio. CI: Confidence interval.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
¹ Inconsistent results among studies using different interferon dosages

Summary of findings 4. Summary of findings: relative healing outcome with topical interferon

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Summary of findings 5. Summary of findings: relative healing outcome with débridement methods

Corneal epithelial débridement of herpes simplex virus epithelial keratitis
Patient population: trial participants with dendritic or geographic epithelial keratitis Outcomes: corneal epithelial healing after 7 days and after 14 days
Treatment comparisons	*Illustrative comparative healing percentages (95% CI)**		Relative risk (95% CI)**	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed healing	Corresponding healing
	Treatment A	Treatment B
Antiviral (B) vs. débridement (A)	7 days				Low^1,2	Débridement limited by recrudescent epithelial keratitis during healing stage
	60%	54% (45%‐64%)	0.89 (0.75‐1.06)	372 (7)
	14 days
	75%	73% (63%‐85%)	0.97 (0.84‐1.13)	317 (7)
Débridement + antiviral or interferon (B) vs. débridement (A)	7 days				Moderate¹	Débridement limited by recrudescent epithelial keratitis during healing stage; no significant difference found in random‐effects model
	66%	76% (68%‐84%)	1.15 (1.03‐1.28)	347 (8)
	14 days
	73%	89% (76%‐100%)	1.21 (1.04‐1.42)	99 (3)
Débridement + antiviral (B) vs. antiviral (A)	7 days				Moderate¹	Different antiviral agents and different interferon dosages; no significant difference found in random‐effects model
	53%	68% (56%‐81%)	1.28 (1.07‐1.53)	305 (7)
	14 days
	85%	88% (81%‐97%)	1.04 (0.95‐1.14)	248 (6)
The basis for the assumed risk* is the mean 7‐day and 14‐day healing percentages among included studies for patients who received treatment A. The corresponding risk (and its 95% confidence interval) is based on the assumed risk and the risk ratio comparing treatment B to treatment A (and its 95% CI), with upper limits bounded at 100%. The relative risk** is the pooled risk ratio. CI: Confidence interval.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
¹ Inconsistent results among studies using different physicochemical methods of corneal epithelial débridement ² Disparate relative effect found in sensitivity analysis

Summary of findings 5. Summary of findings: relative healing outcome with débridement methods

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Table 1. Overview of trial design and participant characteristics among included studies

Characteristics of trial design and conduct	Categories	No. (%) trials (n=106)
No. centres	One Two or more	90 (85%) 16 (15%)
No. study participants (sample size)	15 to 24 25 to 49 50 to 74 75 to 99 100 or more	11 (10%) 45 (43%) 29 (27%) 9 (9%) 12 (11%)
Average age of study participants	< 40 years 40 to 50 years > 50 years Not stated	9 (9%) 31 (29%) 5 (5%) 61 (57%)
Gender of study participants	Males exceed females Females exceed males Not stated	47 (44%) 3 (3%) 56 (53%)
Type of epithelial keratitis	Dendritic Dendritic or geographic Geographic Not specified	64 (60%) 37 (35%) 2 (2%) 3 (3%)
No. of intervention groups¹	Two Three Four Five	85 (80%) 16 (15%) 4 (4%) 1 (1%)
Adjunctive mydriatic or cycloplegic agent	Yes None, variable, or not stated	41 (39%) 65 (61%)
Adjunctive antibacterial agent	Yes None or not stated	10 (9%) 96 (91%)
Method of generating allocation sequence	Randomisation Ambiguous method of randomisation By alternation By contingency	70 (66%) 30 (28%) 3 (3%) 3 (3%)
Masking	Double‐masked design Single‐masked, unmasked, or unclear	58 (55%) 48 (45%)
¹ Of 97 excluded studies, 78 had two intervention groups, eight had three groups, six excluded studies had four groups, two excluded studies had five groups, two excluded studies had six groups, and one excluded study had eight groups. The proportion of studies with more than two interventions was similar in the included and excluded studies (P = 0.97, Chi² test).

Table 1. Overview of trial design and participant characteristics among included studies

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Table 2. Outcomes reported in trials excluded due to insufficient healing data

Study	Treatment group (no. eyes)¹	Mean healing time±SD, days²
Antiviral agents and/or débridement
Assetto 1981	Débridement (8) Idoxuridine (16) Cytarabine (16) Trifluridine (8)	3‐19 10‐18 13‐21 6‐13
Babushkin 1993	Idoxuridine (60) Acyclovir (24)	NS 5.9±1.2
Fellinger 1980	Idoxuridine (13) Trifluridine (16) Débridement/idoxuridine (13) Débridement/trifluridine (18)	8.1±2.5 5.5±2.5 13.4±9 6.8±4.2
Guo 2003	Antiviral (34) Cryotherapy/antiviral (35)	NS NS
Hilsdorf 1969	Iodinisation/idoxuridine (20) Cryotherapy/idoxuridine (20)	4.3 14.0
Inocencio 1982	Idoxuridine (9) Acyclovir (14)	10.4 7.0
Koev 2007	Acyclovir (25) Acyclovir/pandavir (24) Débridement/acyclovir/pandavir (26)	9.3±1.2 8.2±1.1 6.2±1.3
Leopold 1965	Idoxuridine (5) Cytarabine (5)	NS NS
Mathur 1984	Iodinisation (50) Cryotherapy (20) Cryotherapy/autologous serum (24) Débridement (30) Débridement/idoxuridine (30)	11 9 7 9 6
McGill 1981	Vidarabine (29) Acyclovir (28)	6.2±1.8 4.5±2.7
Mohan 1987	Vidarabine (19) Acyclovir (21)	8.3±0.9 6.5±0.6
Patterson 1967c	Débridement (9) Idoxuridine (15)	P<0.01
Pavan‐Langston 1972	Idoxuridine (14) Vidarabine (15)	3.0‐4.5 3.5‐4.5
Pavan‐Langston 1977	Idoxuridine (17) Trifluridine (23)	5.3 5.5
Pietruschka 1968	Fluorophenylalanine (30) Idoxuridine (28) Fluorophenylalanine/idoxuridine (40)	15 18 22
Shimomura 1987	Débridement/idoxuridine (16) Idoxuridine (15)	P>0.05
Tarakji 1978	Cryotherapy (21) Idoxuridine (14)	2.4 6.2
Wang 2009	Acyclovir (39) Ganciclovir (39)	P<0.05
Whitcher 1976	Débridement (20) Idoxuridine (31)	5 13
Interferon and interferon/antiviral combinations
Chen 2007	Acyclovir (43) Acyclovir/interferon (69)	P<0.01
Gu 2005	Acyclovir (20) Acyclovir/interferon (19)	P<0.05
Huang 2009	Acyclovir (36) Acyclovir/interferon (29)	39.6 30.4
Jin 1992	Acyclovir (41) Interferon (59)	8.2‐9.6 9.9‐12.4
Kuyama 1979	Interferon‐α (NS) Interferon‐β (NS)	NS NS
Liu 2003	Antiviral (21) Antiviral/interferon (21)	NS NS
Scialdone 1986	Idoxuridine (8) Interferon (12)	10‐14 7‐10
Shiota 1988	Interferon 100,000 IU/ml (14) Interferon 1 million IU/ml (46)	4.4±3.8 4.2±4.1
Tamburi 1990	Acyclovir (8) Interferon (8) Acyclovir/interferon (8)	5.2 9.0 5.0
Zhang 2003	Interferon‐α‐1b (29) Interferon‐α‐2b (17)	12.9±2.1 9.4±3.0
Zhao 2001	Acyclovir (89) Acyclovir/interferon (97)	P<0.01
Zhou 2008	Acyclovir (35) Acyclovir/interferon (66)	P<0.05
Interferon inducers
Galin 1976	Idoxuridine (20) Poly I:C (19)	NS NS
Kasparov 1972	Idoxuridine (16) Poly A:U (43) Immunomodulators (167) Débridement/immunomodulators (33)	P<0.01
Kasparov 1974	Control (30) Idoxuridine (28) Poly A:U (27) Idoxuridine/poly A:U (15)	14.1±2.0 14.5±2.0 10.2±1.3 13.8±3.2
Kasparov 1991	Acyclovir (45) Poly A:U (65) Acyclovir/poly A:U (40)	13.8±0.8 14.6±1.2 9.5±1.1
Lin 2009	Acyclovir (27) Acyclovir/poly I:C (22)	P<0.05
Cytokines, growth factors, and immunomodulators
Kolomiets 1986	Control (10) HSV‐immunoglobulin (14)	28.6 16.8
Liu 2007	Acyclovir (50) Acyclovir/fibroblast growth factor (46)	P<0.05
Pivetti‐Pezzi 1985	Placebo (13) Thymic extract (11)	23±13 23±9
Prost 1986	Cryotherapy (20) Cryotherapy/oral isoprinosine (19)	6.8±3.9 6.5±3.8
Salcedo Hernandez 2007	Autologous serum (9) Acyclovir (8)	10 7
Sellitti 1982	Topical/oral isoprinosine (20) Oral isoprinosine (20)	13.3 25
Topciu 1992	Idoxuridine/foscarnet (120) Idoxuridine/foscarnet/immunostimulant (113)	30 3‐4
Xu 2009b	Acyclovir (30) Acyclovir/interleukin‐2 (32)	11±2.7‐41±6.7 9±2.5‐28±4.5
Zhang 1992	Acyclovir/interferon (20) Acyclovir/interferon/transfer factor (21)	P<0.05
Zhi 2001	Acyclovir (30) Acyclovir/interleukin‐2 (38)	9±2.5‐30±4.5 13±2.7‐25±3.1
¹ Similar treatment groups were combined when possible; further details on interventions are tabulated in Characteristics of excluded studies ² A range of values indicates that mean estimates were provided for subcategories (e.g., dendritic vs. geographic epithelial keratitis) without summary estimation; P values comparing proportions healed in study groups at a time other than 14 days are provided for studies not reporting mean healing times NS, not stated; SD, standard deviation (when reported)

Table 2. Outcomes reported in trials excluded due to insufficient healing data

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Table 3. Heterogeneity evaluation: analyses with inconsistency (I2 > 50%) at 14‐day outcome

Treatment comparisons	I²
Idoxuridine versus inactive control	66%¹
Acyclovir versus idoxuridine	63%^1,2
Trifluridine versus vidarabine	74%¹
Ganciclovir versus acyclovir	71%³
Oral/topical antivirals versus topical antiviral	90%
Interferon versus nucleoside antiviral	81%
Topical antiviral agent versus débridement	79%²
Débridement with antiviral or interferon versus débridement	89%²
¹ In addition, I² > 50% for pooled hazard ratio ² In addition, I² > 50% for pooled risk ratio at seven days 3 Possible publication bias

Table 3. Heterogeneity evaluation: analyses with inconsistency (I2 > 50%) at 14‐day outcome

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Table 4. Sensitivity analysis of studies that were potentially prone to bias: relative healing at 14 days after excluding trials with incomplete randomisation, concealment, or masking

Treatment comparisons¹	Studies under investigation²	Risk ratio (95% confidence interval) ‐ with studies included	I² (with studies included)	Risk ratio (95% confidence interval) ‐ with studies excluded	I² (with studies excluded)
Idoxuridine vs. inactive control	Luntz 1963	1.31 (0.80‐2.15)	0%	1.79 (0.98‐3.26)	NA
Trifluridine vs. idoxuridine	Struck 1989	1.38 (1.19‐1.60)	32%	1.43 (1.23‐1.67)	0%
Acyclovir vs. idoxuridine	Abe 1987, Altinisik 1987, Maychuk 1988	1.23 (1.14‐1.32)	63%	1.19 (1.10‐1.29)	66%
Brivudine vs. idoxuridine	Struck 1989	1.38 (1.05‐1.81)	30%	1.64 (1.15‐2.35)	NA
Trifluridine vs. vidarabine	Coster 1979	1.09 (0.98‐1.22)	74%	1.09 (0.98‐1.21)	0%
Brivudine vs. trifluridine	Struck 1989	1.00 (0.88‐1.14)	0%	0.98 (0.89‐1.08)	36%
Ganciclovir vs. acyclovir	Colin 1997a, Colin 1997b, Yang 2000, Colin 2007b, Chen 2008, Huang 2008a, Li 2008, Liu 2009a, Xu 2009a	1.13 (1.04‐1.23)	71%	1.21 (0.95‐1.54)	NA
Oral/topical antivirals vs. topical antiviral	Srinivas 1993	1.08 (0.99‐1.17)	90%	1.01 (0.93‐1.09)	NA
Interferon vs. nucleoside antiviral	Kitano 1983, Vannini 1986	0.33 (0.11‐1.02)	43%	0.20 (0.01‐3.35)	NA
Interferon/nucleoside antiviral vs. nucleoside antiviral	Maychuk 1988	1.03 (0.99‐1.07)	0%	1.03 (0.99‐1.07)	0%
Topical antiviral agent vs. débridement	Bartholomew 1977, Kato 1979, MacKenzie 1964, O'Day 1975, Patterson 1967a, Struck 1989	0.97 (0.84‐1.13)	79%	1.23 (0.91‐1.67)	87%
Débridement with antiviral or interferon vs. débridement	Sundmacher 1976a	1.04 (0.95‐1.14)	89%	1.25 (1.01‐1.54)	96%
Débridement with antiviral vs. antiviral	Daniel 1972, Richter 1986,Wilhelmus 1981a	1.04 (0.95‐1.14)	0%	0.98 (0.79‐1.21)	0%
¹ Three comparisons that included a study judged to have a potentially high risk of bias were limited to a single study (Matthäus 1970, Serifoglu 1987, Sundmacher 1976a) ² Two studies judged to have a potentially high risk of bias did not provide data for the 14‐day outcome (Patterson 1967a, Travers 1978) NA: not applicable (single study available for evaluation)

Table 4. Sensitivity analysis of studies that were potentially prone to bias: relative healing at 14 days after excluding trials with incomplete randomisation, concealment, or masking

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Table 5. Sensitivity analysis of higher quality studies: effect on relative healing at 14 days using only randomised, double‐masked trials

Treatment comparisons	Randomised, double‐masked studies¹	Risk ratio (95% confidence interval) ‐ all studies	I² (with all studies)	Risk ratio (95% confidence interval) ‐ only randomised, double‐masked studies	I² (with only randomised, double‐masked studies)
Idoxuridine vs. inactive control	Markham 1977	1.31 (0.80‐2.15)	47%	1.79 (0.98‐3.26)	NA
Vidarabine vs. idoxuridine	Markham 1977, Pavan‐Langston 1976	1.04 (0.92‐1.18)	0%	1.03 (0.90‐1.17)	0%
Trifluridine vs. idoxuridine	Panda 1995, Sugar 1980, Wellings 1972	1.38 (1.19‐1.60)	0%	1.47 (1.23‐1.75)	0%
Acyclovir vs. idoxuridine	Colin 1981, Collum 1980, Coster 1980, Kitano 1985, Kumar 1987, McCulley 1982, Panda 1995	1.23 (1.14‐1.32)	63%	1.17 (1.08‐1.27)	69%
Brivudine vs. idoxuridine	Panda 1995	1.38 (1.05‐1.81)	30%	1.64 (1.15‐2.35)	NA
Trifluridine vs. vidarabine	Coster 1976	1.09 (0.98‐1.22)	74%	1.07 (0.98‐1.17)	NA
Acyclovir vs. vidarabine	Collum 1985, Denis 1983, Genée 1987, Pavan‐Langston 1981, Yeakley 1981, Young 1982	1.08 (1.00‐1.17)	0%	1.07 (0.98‐1.18)	0%
Acyclovir vs. trifluridine	Høvding 1989, La Lau 1982, Panda 1995	0.99 (0.90‐1.09)	0%	1.01 (0.91‐1.12)	0%
Brivudine vs. trifluridine	Panda 1995, Power 1991	1.00 (0.88‐1.14)	0%	0.98 (0.89‐1.08)	0%
Brivudine vs. acyclovir	Panda 1995	1.05 (0.92‐1.20)	NA	NA	NA
Ganciclovir vs. acyclovir	Colin 2007a	1.13 (1.04‐1.23)	71%	1.21 (0.95‐1.54)	NA
Foscarnet vs. trifluridine	Behrens‐Baumann 1992	1.00 (0.89‐1.12)	NA	NA	NA
Acyclovir/vidarabine vs. acyclovir	Colin 1987	1.00 (0.89‐1.12)	NA	NA	NA
Oral vs. topical antiviral	Collum 1986	0.92 (0.79‐1.07)	NA	NA	NA
Oral/topical antivirals vs. topical antiviral	HEDS Group 1997	1.08 (0.99‐1.17)	90%	1.01 (0.93‐1.09)	NA
Interferon/antiviral vs. antiviral	Colin 1983, de Koning 1982, de Koning 1983, Meurs 1985, Sundmacher 1987, Van Bijsterveld 1989	1.03 (0.99‐1.07)	0%	1.03 (0.99‐1.08)	0%
¹ Thirteen of 46 randomised, double‐masked trials are not tabulated because two‐week outcome data were not provided (Burns 1963; Wang 2004) or because comparative interventions not listed in this table were studied (Cellini 1994; Colin 1984; Coster 1977a; Guerra 1979; Parlato 1985; Sundmacher 1976b; Sundmacher 1978a; Sundmacher 1984a; Sundmacher 1985; Uchida 1981; Uchida 1982) NA: not applicable (single study available for evaluation)

Table 5. Sensitivity analysis of higher quality studies: effect on relative healing at 14 days using only randomised, double‐masked trials

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Table 6. Combined direct and indirect comparisons: relative healing of HSV epithelial keratitis at 14 days between topical antiviral agents

Treatment comparisons	Type of comparison (intermediate comparator)	No. trials¹	Risk ratio (95% CI)	I² among direct and indirect comparisons	Combined risk ratio (95% CI)²
Vidarabine vs. idoxuridine	Direct	3	1.04 (0.92‐1.18)	0%	1.11 (1.03‐1.19)
	Indirect (inactive control)	1, 2	1.21 (0.60‐2.44)
	Indirect (trifluridine)	3, 5	1.12 (0.98‐1.42)
	Indirect (acyclovir)	7, 11	1.15 (1.03‐1.28)
Trifluridine vs. idoxuridine	Direct	5	1.38 (1.19‐1.60)	0%	1.31 (1.20‐1.42)
	Indirect (vidarabine)	3, 3	1.29 (0.97‐1.70)
	Indirect (acyclovir)	4, 11	1.25 (1.11‐1.42)
	Indirect (brivudine)	3, 2	1.38 (1.02‐1.87)
Acyclovir vs. idoxuridine	Direct	11	1.23 (1.14‐1.32)	4%	1.23 (1.16‐1.31)
	Indirect (vidarabine)	7, 3	1.12 (0.97‐1.30)
	Indirect (trifluridine)	4, 5	1.37 (1.14‐1.63)
	Indirect (brivudine)	1, 2	1.31 (0.97‐1.78)
Brivudine vs. idoxuridine	Direct	2	1.38 (1.05‐1.81)	0%	1.38 (1.18‐1.61)
	Indirect (trifluridine)	3, 5	1.38 (1.13‐1.68)
	Indirect (acyclovir)	1, 11	1.30 (0.69‐2.46)
Ganciclovir vs. idoxuridine	Direct	0	NA	NA	1.40 (1.25‐1.57)
Ganciclovir vs. idoxuridine	Indirect (acyclovir)	10, 11	1.40 (1.25‐1.57)	NA	1.40 (1.25‐1.57)
Trifluridine vs. vidarabine	Direct³	3	1.09 (0.98‐1.22)	12%	1.12 (1.04‐1.21)
	Indirect (idoxuridine)	5, 3	1.33 (1.09‐1.61)
	Indirect (acyclovir)	4, 7	1.09 (0.96‐1.23)
Acyclovir vs. vidarabine	Direct	7	1.08 (1.00‐1.17)	0%	1.11 (1.05‐1.19)
	Indirect (idoxuridine)	11, 3	1.19 (1.03‐1.38)
	Indirect (trifluridine)	4, 3	1.16 (1.00‐1.34)
Acyclovir vs. trifluridine	Direct	4	0.99 (0.90‐1.09)	0%	0.95 (0.89‐1.02)
	Indirect (idoxuridine)	11, 5	0.90 (0.76‐1.06)
	Indirect (vidarabine)	7, 3	0.92 (0.81‐1.06)
	Indirect (brivudine)	1, 3	0.95 (0.79‐1.15)
Brivudine vs. trifluridine	Direct	3	1.00 (0.88‐1.14)	0%	1.02 (0.92‐1.12)
Brivudine vs. trifluridine	Indirect (acyclovir)	1, 4	1.04 (0.88‐1.22)	0%	1.02 (0.92‐1.12)
Brivudine vs. acyclovir	Direct	1	1.05 (0.92‐1.20)	0%	1.04 (0.95‐1.15)
	Indirect (idoxuridine)	2, 11	1.11 (0.84‐1.48)
	Indirect (trifluridine)	4, 3	1.01 (0.86‐1.19)
Ganciclovir vs. trifluridine	Direct	0	NA	NA	1.12 (0.98‐1.27)
Ganciclovir vs. trifluridine	Indirect (acyclovir)	10, 4	1.12 (0.98‐1.27)	NA	1.12 (0.98‐1.27)
Ganciclovir vs. acyclovir	Direct³	10	1.13 (1.04‐1.23)	NA	1.13 (1.04‐1.23)
¹ Data derive from a network of 12 different interconnections among 46 trials that enrolled 1238 study participants (Figure 6). Comparisons are based on reported two‐week outcomes among various combinations of seven topical interventions: inactive control, idoxuridine, vidarabine, trifluridine, acyclovir, brivudine, and ganciclovir. Indirect comparisons are limited to a linked network of trials having a single shared intermediate intervention; multiple intermediates were not considered for indirect adjustment ² Combination of direct and indirect comparisons estimated by the fixed‐effect Mantel‐Haenszel method ³ Heterogeneity of studies in direct comparison, with lack of significant difference using random‐effects Mantel‐Haenszel method (Table 3) CI: confidence interval; NA: not applicable (only direct or indirect comparison available)

Table 6. Combined direct and indirect comparisons: relative healing of HSV epithelial keratitis at 14 days between topical antiviral agents

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Table 7. Safety assessment among antiviral treatment studies

Topical antiviral agent	No. studies with at least one topical antiviral treatment arm	No. studies reporting corneal toxicity assessment	No. antiviral‐treated participants assessed for corneal toxicity	Median prevalence of punctate epithelial erosions during antiviral use (interquartile range)
Idoxuridine	43	14¹	430	10% (5%‐20%)
Vidarabine	14	12²	395	11% (4%‐17%)
Trifluridine	20	9³	220	4% (2%‐7%)
Acyclovir	42	25⁴	667	10% (0%‐17%)
Brivudine	5	3⁵	72	0%
Ganciclovir	10	4⁶	156	4% (0%‐11%)
All of above	88	40	1940	8% (0%‐17%)
¹ Included idoxuridine studies: Altinisik 1987; Blake 1977; Colin 1981; Collum 1980; Kitano 1985; Klauber 1982; Laibson 1977; MacKenzie 1964; Markham 1977; McCulley 1982; Panda 1995; Pavan‐Langston 1976; Vannini 1986; Wellings 1972 ² Included vidarabine studies: Blake 1977; Collum 1985; Coster 1976; Coster 1979; Denis 1983; Jackson 1984; Markham 1977; Pavan‐Langston 1976; Pavan‐Langston 1981; Van Bijsterveld 1980; Yeakley 1981; Young 1982 ³ Included trifluridine studies: Behrens‐Baumann 1992; Coster 1976; Coster 1979; Hoang‐Xuan 1984; Panda 1995; Parlato 1985; Power 1991; Van Bijsterveld 1980; Wellings 1972 (excluding La Lau 1982 because of imprecise assessment) ⁴ Included acyclovir studies: Altinisik 1987; Carmassi 1993; Colin 1981; Colin 1983; Colin 1984; Colin 1987; Colin 1997a; Colin 1997b; Colin 2007b; Collum 1980; Collum 1985; Collum 1986; Denis 1983; Hoang‐Xuan 1984; Huang 2008a; Jackson 1984; Jensen 1982; Kitano 1985; Klauber 1982; McCulley 1982; Panda 1995; Pavan‐Langston 1981; Wilhelmus 1981a; Yeakley 1981; Young 1982 (excluding La Lau 1982 because of imprecise assessment) ⁵ Included brivudine studies: Panda 1995; Power 1991; Van Bijsterveld 1989 ⁶ Included ganciclovir studies: Colin 1997a; Colin 1997b; Colin 2007b; Huang 2008a

Table 7. Safety assessment among antiviral treatment studies

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Comparison 1. Topical antiviral agents

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Idoxuridine versus inactive control: 7‐day & 14‐day healing Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Healing at 7 days	10	392	Risk Ratio (M‐H, Fixed, 95% CI)	2.26 [1.71, 3.00]
1.2 Healing at 14 days	2	63	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.80, 2.15]
2 Idoxuridine versus inactive control: healing rate Show forest plot	3	95	Hazard Ratio (95% CI)	2.02 [1.16, 3.49]

3 Vidarabine versus inactive control: 7‐day & 14‐day healing Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Healing at 7 days	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	2.17 [0.81, 5.87]
3.2 Healing at 14 days	1	43	Risk Ratio (M‐H, Fixed, 95% CI)	1.96 [1.10, 3.49]
4 Vidarabine versus inactive control: healing rate Show forest plot	1	43	Hazard Ratio (95% CI)	2.47 [1.14, 5.33]

5 Vidarabine versus idoxuridine: 7‐day & 14‐day healing Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Healing at 7 days	3	243	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.85, 1.42]
5.2 Healing at 14 days	3	243	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.92, 1.18]
6 Vidarabine versus idoxuridine: healing rate Show forest plot	2	74	Hazard Ratio (95% CI)	1.36 [0.81, 2.28]

7 para‐Fluorophenylalanine versus idoxuridine: 7‐day & 14‐day healing Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 Healing at 7 days: without débridement	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.59, 1.54]
7.2 Healing at 14 days: without débridement	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.75, 1.14]
7.3 Healing at 7 days: with débridement	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.87, 1.43]
7.4 Healing at 14 days: with débridement	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.83, 1.18]
8 Trifluridine versus idoxuridine: 7‐day & 14‐day healing Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.1 Healing at 7 days	4	223	Risk Ratio (M‐H, Fixed, 95% CI)	2.52 [1.74, 3.63]
8.2 Healing at 14 days	5	256	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [1.19, 1.60]
9 Trifluridine versus idoxuridine: healing rate Show forest plot	1	78	Hazard Ratio (95% CI)	2.29 [1.37, 3.83]

10 Acyclovir versus idoxuridine: 7‐day & 14‐day healing Show forest plot	12		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 Healing at 7 days: acyclovir vs. idoxuridine	9	468	Risk Ratio (M‐H, Fixed, 95% CI)	1.96 [1.64, 2.34]
10.2 Healing at 14 days: acyclovir vs. idoxuridine	11	606	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [1.14, 1.32]
10.3 Healing at 7 days: acyclovir vs. iododeoxycytidine	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.76, 2.63]
10.4 Healing at 14 days: acyclovir vs. iododeoxycytidine	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.89, 1.12]
11 Acyclovir versus idoxuridine: healing rate Show forest plot	8	355	Hazard Ratio (95% CI)	2.15 [1.70, 2.72]

12 Brivudine versus idoxuridine: 7‐day & 14‐day healing Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

12.1 Healing at 7 days	2	99	Risk Ratio (M‐H, Fixed, 95% CI)	7.94 [2.80, 22.53]
12.2 Healing at 14 days	2	99	Risk Ratio (M‐H, Fixed, 95% CI)	1.38 [1.05, 1.81]
13 Trifluridine versus vidarabine: 7‐day & 14‐day healing Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

13.1 Healing at 7 days: all groups	4	288	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.91, 1.22]
13.2 Healing at 14 days: all groups	3	188	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.98, 1.22]
13.3 Healing at 7 days: geographic epithelial keratitis	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.55, 3.13]
13.4 Healing at 14 days: geographic epithelial keratitis	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.96 [1.16, 3.33]
14 Trifluridine versus vidarabine: healing rate Show forest plot	3	188	Hazard Ratio (95% CI)	1.31 [0.96, 1.79]

15 Acyclovir versus vidarabine: 7‐day & 14‐day healing Show forest plot	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

15.1 Healing at 7 days: all groups	6	314	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [1.05, 1.44]
15.2 Healing at 14 days: all groups	7	342	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [1.00, 1.18]
15.3 Healing at 7 days: geographic epithelial keratitis	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.94, 2.94]
15.4 Healing at 14 days: geographic epithelial keratitis	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.63, 1.14]
16 Acyclovir versus vidarabine: healing rate Show forest plot	5	259	Hazard Ratio (95% CI)	1.13 [0.86, 1.47]

17 Acyclovir versus trifluridine: 7‐day & 14‐day healing Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

17.1 Healing at 7 days	4	178	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.82, 1.20]
17.2 Healing at 14 days	4	178	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.90, 1.09]
18 Acyclovir versus trifluridine: healing rate Show forest plot	3	140	Hazard Ratio (95% CI)	0.92 [0.65, 1.32]

19 Brivudine versus trifluridine: 7‐day & 14‐day healing Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

19.1 Healing at 7 days	3	147	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.71, 1.21]
19.2 Healing at 14 days	3	147	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.88, 1.14]
20 Brivudine versus trifluridine: healing rate Show forest plot	1	60	Hazard Ratio (95% CI)	0.60 [0.35, 1.02]

21 Brivudine versus acyclovir: 7‐day & 14‐day healing Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

21.1 Healing at 7 days	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.93, 1.51]
21.2 Healing at 14 days	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.92, 1.20]
22 Ganciclovir versus acyclovir: 7‐day & 14‐day healing Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

22.1 Healing at 7 days	5	378	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.84, 1.31]
22.2 Healing at 14 days	10	672	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [1.04, 1.23]
23 Foscarnet versus trifluridine: 7‐day & 14‐day healing Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

23.1 Healing at 14 days	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.75, 1.34]
24 Acyclovir/vidarabine versus acyclovir: 7‐day & 14‐day healing Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

24.1 Healing at 7 days	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	1.5 [1.01, 2.24]
24.2 Healing at 14 days	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.89, 1.12]
25 Trifluridine (aqueous) versus trifluridine (viscous) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

25.1 Healing at 7 days	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.58, 4.05]
25.2 Healing at 14 days	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [0.96, 2.41]
26 Ganciclovir 0.15% versus ganciclovir 0.05% Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

26.1 Healing at 7 days	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.53, 1.74]
26.2 Healing at 14 days	2	116	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.90, 1.28]

Comparison 1. Topical antiviral agents

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Comparison 2. Oral antiviral agents

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Oral antiviral versus topical antiviral Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Healing at 7 days	2	116	Risk Ratio (M‐H, Fixed, 95% CI)	1.51 [1.13, 2.02]
1.2 Healing at 14 days	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.79, 1.07]
2 Oral/topical antivirals versus topical antiviral Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Healing at 7 days	1	287	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.95, 1.33]
2.2 Healing at 14 days	2	327	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.99, 1.17]

Comparison 2. Oral antiviral agents

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Comparison 3. Topical interferon formulations

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Interferon versus inactive control, without or with débridement Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Healing at 7 days	3	178	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [1.07, 2.06]
1.2 Healing at 14 days	2	110	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [1.06, 1.64]
2 Interferon dosages Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Healing at 7 days: interferon 1000 IU/ml vs. interferon 1 million IU/ml	1	68	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.81, 2.60]
2.2 Healing at 7 days: trifluridine + interferon 10 million IU/ml vs. trifluridine + interferon 30 million IU/ml	1	51	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.94, 1.17]
2.3 Healing at 7 days: trifluridine + interferon 0.3 or 1.5 million IU/ml vs. trifluridine + interferon 30 million IU/ml	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.90, 1.38]
2.4 Healing at 7 days: trifluridine + interferon 30 million IU/ml vs. trifluridine + interferon 100 million IU/ml	1	36	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.86, 1.18]
3 Interferon‐α with débridement versus interferon‐β with débridement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Healing at 7 days	1	38	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.81, 1.09]
4 Natural interferon‐α with trifluridine versus recombinant interferon‐α with trifluridine Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Healing at 7 days	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.89, 1.12]
5 Interferon versus nucleoside antiviral Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Healing at 7 days	3	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.82, 1.28]
5.2 Healing at 14 days	3	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [1.01, 1.49]
6 Interferon inducer versus nucleoside antiviral Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Healing at 7 days	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.14, 3.17]
6.2 Healing at 14 days	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.08, 1.05]
7 Interferon/nucleoside antiviral versus nucleoside antiviral: 7‐day & 14‐day healing Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 Healing at 7 days	8	401	Risk Ratio (M‐H, Fixed, 95% CI)	1.96 [1.67, 2.31]
7.2 Healing at 14 days	9	476	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.99, 1.07]
8 Interferon/nucleoside antiviral versus nucleoside antiviral: healing rate Show forest plot	5	229	Hazard Ratio (95% CI)	2.84 [2.13, 3.79]

Comparison 3. Topical interferon formulations

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Comparison 4. Methods of physicochemical débridement

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Débridement versus control Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Healing at 7 days	2	105	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.82, 2.11]
1.2 Healing at 14 days	1	55	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.85, 1.43]
2 Topical antiviral agent versus débridement Show forest plot	11		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Healing at 7 days	7	372	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.75, 1.06]
2.2 Healing at 14 days	7	317	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.84, 1.13]
3 Different débridement methods, with interferon Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Healing at 7 days	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.86, 1.13]
3.2 Healing at 14 days	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.91, 1.10]
4 Débridement with antiviral or interferon versus débridement Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Healing at 7 days	8	347	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [1.03, 1.28]
4.2 Healing at 14 days	3	99	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [1.04, 1.42]
5 Débridement with different antivirals Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Healing at 7 days	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.80, 2.02]
5.2 Healing at 14 days	1	25	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.86, 1.16]
6 Débridement with antiviral versus antiviral: 7‐day & 14‐day healing Show forest plot	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Healing at 7 days	7	305	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [1.07, 1.53]
6.2 Healing at 14 days	6	248	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.95, 1.14]
7 Débridement with antiviral versus antiviral: healing rate Show forest plot	6	248	Hazard Ratio (95% CI)	1.76 [1.32, 2.35]

Comparison 4. Methods of physicochemical débridement

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Comparison 5. Adjunctive agents: growth factors, non‐steroidal anti‐inflammatory drugs, immunomodulators

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Acyclovir/epidermal growth factor versus acyclovir Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Healing at 7 days	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.54, 1.86]
1.2 Healing at 14 days	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.91, 1.10]
2 Panthenol versus para‐fluorophenylalanine, with débridement Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Healing at 7 days	1	120	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.79, 1.14]
2.2 Healing at 14 days	1	120	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.08]
3 Idoxuridine/oxyphenbutazone versus idoxuridine/placebo Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Healing at 7 days	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.56, 1.11]
4 Oral isoprinosine versus inactive control Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Healing at 7 days	1	26	Risk Ratio (M‐H, Fixed, 95% CI)	5.14 [0.72, 36.94]
4.2 Healing at 14 days	1	26	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.74, 2.75]

Comparison 5. Adjunctive agents: growth factors, non‐steroidal anti‐inflammatory drugs, immunomodulators

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