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

Kirk R Wilhelmus

doi:10.1002/14651858.CD002898.pub5

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Figure 1

Funnel plot of studies comparing ganciclovir to acyclovir.

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Figure 2

Study flow diagram.

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Figure 3

Networks of clinical trials included in this systematic review. Left diagram shows a network of two‐way comparisons among topical antiviral agents. Not shown in the left diagram are trials evaluating para‐fluorophenylalanine, different trifluridine vehicles, and different ganciclovir concentrations. Right diagram illustrates a network of comparisons between topical antiviral agents and various interventions that included dual antiviral therapy, oral acyclovir, interferon without or with an antiviral, and debridement without or with an antiviral. Not shown in the right diagram are trials evaluating different interferon dosages or types, an interferon inducer, different methods of debridement, debridement with two different antivirals, and miscellaneous agents (hyaluronate, epidermal growth factor, panthenol, methyluracil, oxyphenbutazone, or inosine pranobex). Lines show direct treatment comparisons reporting outcomes at one week or two weeks. Circled numerals indicate the number of direct treatment comparisons that were included in this systematic review. The placebo groups consist of a variety of inactive controls. The number of acyclovir‐idoxuridine (IDU) comparisons includes one trial using iododeoxycytidine (IDC), even though IDC was not pooled with IDU in the meta‐analysis. The number of direct comparisons exceeds the number of studies because 21 studies compared more than two interventions.

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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

Cumulative healing data from trials evaluating idoxuridine, vidarabine, trifluridine, acyclovir, or interferon plus an antiviral agent. Antiviral healing curves were blended 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 reported healing data for idoxuridine (278 eyes), vidarabine (262 eyes), trifluridine (279 eyes), or acyclovir (480 eyes). Corneal healing with combined interferon‐antiviral was estimated from seven studies (Carmassi 1993; Colin 1983; de Koning 1982; de Koning 1983; Meurs 1985; Sundmacher 1981b; van Bijsterveld 1989) that evaluated 196 participants who received interferon with trifluridine (75), acyclovir (102), or brivudine (19). (ACV, acyclovir; ARA, vidarabine; IDU, idoxuridine; IFN+, interferon with an antiviral (trifluridine, acyclovir, or brivudine); TFT, trifluridine).

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Figure 6

Histograms of publication year for included studies and excluded studies. Most of the studies during the late 20^th century took place in Europe or North America. An upswing in studies reported since 2005 is due to trials conducted in China.

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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 Foscarnet versus acyclovir: 14‐day healing.

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Analysis 1.25

Comparison 1 Topical antiviral agents, Outcome 25 Foscarnet versus ganciclovir: 7‐day & 14‐day healing.

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Analysis 1.26

Comparison 1 Topical antiviral agents, Outcome 26 Acyclovir/vidarabine versus acyclovir: 7‐day & 14‐day healing.

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Analysis 1.27

Comparison 1 Topical antiviral agents, Outcome 27 Trifluridine (aqueous) versus trifluridine (viscous).

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Analysis 1.28

Comparison 1 Topical antiviral agents, Outcome 28 Ganciclovir 0.15% gel versus ganciclovir 0.05% gel or 0.1% solution.

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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 Interferon, Outcome 1 Interferon versus inactive control, without or with debridement.

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Analysis 3.2

Comparison 3 Interferon, Outcome 2 Interferon dosages.

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Analysis 3.3

Comparison 3 Interferon, Outcome 3 Interferon‐α with debridement versus interferon‐β with debridement.

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Analysis 3.4

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

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Analysis 3.5

Comparison 3 Interferon, Outcome 5 Interferon versus nucleoside antiviral.

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Analysis 3.6

Comparison 3 Interferon, Outcome 6 Interferon inducer versus nucleoside antiviral.

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Analysis 3.7

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

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Analysis 3.8

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

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Analysis 4.1

Comparison 4 Debridement, Outcome 1 Debridement versus control.

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Analysis 4.2

Comparison 4 Debridement, Outcome 2 Topical antiviral agent versus debridement.

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Analysis 4.3

Comparison 4 Debridement, Outcome 3 Different debridement methods.

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Analysis 4.4

Comparison 4 Debridement, Outcome 4 Debridement with antiviral or interferon versus debridement.

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Analysis 4.5

Comparison 4 Debridement, Outcome 5 Debridement with different antivirals.

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Analysis 4.6

Comparison 4 Debridement, Outcome 6 Debridement with antiviral versus antiviral: 7‐day & 14‐day healing.

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Analysis 4.7

Comparison 4 Debridement, Outcome 7 Debridement with antiviral versus antiviral: healing rate.

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Analysis 5.1

Comparison 5 Adjunctive and alternative agents: lubricant, growth factor, nonsteroidal anti‐inflammatory drug, immunomodulator, Outcome 1 Antiviral/lubricant versus antiviral.

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Analysis 5.2

Comparison 5 Adjunctive and alternative agents: lubricant, growth factor, nonsteroidal anti‐inflammatory drug, immunomodulator, Outcome 2 Antiviral/epidermal growth factor versus antiviral.

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Analysis 5.3

Comparison 5 Adjunctive and alternative agents: lubricant, growth factor, nonsteroidal anti‐inflammatory drug, immunomodulator, Outcome 3 Panthenol versus para‐fluorophenylalanine, with debridement.

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Analysis 5.4

Comparison 5 Adjunctive and alternative agents: lubricant, growth factor, nonsteroidal anti‐inflammatory drug, immunomodulator, Outcome 4 Interferon/methyl uracil versus interferon.

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Analysis 5.5

Comparison 5 Adjunctive and alternative agents: lubricant, growth factor, nonsteroidal anti‐inflammatory drug, immunomodulator, Outcome 5 Antiviral/oxyphenbutazone versus antiviral.

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Analysis 5.6

Comparison 5 Adjunctive and alternative agents: lubricant, growth factor, nonsteroidal anti‐inflammatory drug, immunomodulator, Outcome 6 Oral inosine pranobex versus inactive control, with or without antiviral.

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Summary of findings for the main comparison. Network analysis of antiviral agents and combination interventions

Network analysis of antiviral agents and combination interventions
Study population: trial participants with dendritic or geographic epithelial keratitis Outcomes: relative corneal epithelial healing at two weeks following trial enrolment
Treatment	Comparison	Pooling method ¹	Risk ratio (95% CI)²	No. trials (no. participants) of direct comparisons	No. indirect network intermediates studied
Idoxuridine	Inactive control	Combined	1.74 (1.03‐2.91)⁸	2 (63)	1
Vidarabine	Inactive control	Combined	1.81 (1.09‐3.01)	1 (43)	1
Vidarabine	Idoxuridine	Combined	1.13 (1.02‐1.25)	3 (243)	3
Trifluridine	Idoxuridine	Combined	1.30 (1.18‐1.43)	5 (256)	3
Trifluridine	Vidarabine	Combined	1.17 (1.03‐1.32)⁸	3 (188)	2
Acyclovir	Idoxuridine	Combined	1.23 (1.14‐1.34)⁸	11 (606)	3
	Vidarabine	Combined	1.11 (1.03‐1.19)	7 (342)	2
	Trifluridine	Combined	0.96 (0.90‐1.04)	4 (178)	3
Brivudine	Idoxuridine	Combined	1.34 (1.18‐1.51)	2 (99)	2
	Trifluridine	Combined	1.01 (0.92‐1.12)	3 (147)	2
	Acyclovir	Combined	1.04 (0.95‐1.15)	1 (40)	2
Ganciclovir	Acyclovir	Combined	1.34 (1.20‐1.51)⁸	28 (2062)	1
Foscarnet	Trifluridine	Combined	1.09 (0.92‐1.29)	1 (20)	1
	Acyclovir	Combined	1.15 (1.01‐1.32)	1 (104)	2
	Ganciclovir	Combined	0.92 (0.75‐1.13)	1 (60)	1
Interferon	Inactive control	Direct	1.32 (1.06‐1.64)	2 (110)	0
Interferon	Antiviral³	Direct	1.22 (0.91‐1.62)	4 (222)	0
Interferon + antiviral⁴	Antiviral⁴	Direct	1.06 (0.99‐1.13)⁸	12 (718)	0
Antiviral⁵	Debridement	Direct	0.98 (0.72‐1.32)⁸	7 (317)	0
Debridement + Antiviral⁶	Debridement	Direct	1.25 (0.78‐2.00)⁸	3 (99)	0
Debridement + Antiviral⁷	Antiviral⁷	Direct	1.05 (0.94‐1.17)⁸	7 (334)	0
¹ Combined method uses direct and indirect risk ratios in a multiple treatment meta‐analysis; direct method is the risk ratio of the direct meta‐analysis. ² Adjusted RRs of antiviral comparisons are taken from Table 1 for combined direct and indirect estimates in network meta‐analysis. Corresponding direct RRs for antiviral comparisons are tabulated in summary of findings Table 2 and are supplemented with HRs in summary of findings Table 3. Direct RRs of interferon comparisons are taken from Analysis 3.1; Analysis 3.5; and Analysis 3.7. Direct RRs of debridement comparisons are taken from Analysis 4.2; Analysis 4.4; and Analysis 4.6. Direct comparisons that are restricted to studies of randomized, double‐masked trials are tabulated in Table 2. ³ Idoxuridine or acyclovir ⁴ Trifluridine, acyclovir, brivudine, or ganciclovir ⁵ Idoxuridine, trifluridine, acyclovir, or brivudine ⁶ Trifluridine or interferon ⁷ Idoxuridine, trifluridine, brivudine, or ganciclovir ⁸ I² > 50% of direct comparison suggests diversity among studies

Summary of findings for the main comparison. Network analysis of antiviral agents and combination interventions

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Table 1. 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)	Combined risk ratio (95% CI)²
Idoxuridine versus placebo	Direct	2	1.31 (0.45‐3.84)*	1.74 (1.03‐2.91)
Idoxuridine versus placebo	Indirect (vidarabine)	3, 1	1.89 (1.04‐3.40)	1.74 (1.03‐2.91)
Vidarabine versus placebo	Direct	1	1.96 (1.10‐3.49)	1.81 (1.09‐3.01)
Vidarabine versus placebo	Indirect (idoxuridine)	3, 2	1.36 (0.46‐4.01)*	1.81 (1.09‐3.01)
Vidarabine versus idoxuridine	Direct	3	1.04 (0.92‐1.18)	1.13 (1.02‐1.25)
	Indirect (inactive control)	1, 2	1.67 (0.55‐5.12)
	Indirect (trifluridine)	3, 5	1.23 (0.89‐1.70)*
	Indirect (acyclovir)	7, 11	1.12 (0.96‐1.30)
Trifluridine versus idoxuridine	Direct	5	1.38 (1.19‐1.60)	1.30 (1.18‐1.43)
	Indirect (vidarabine)	3, 3	1.17 (0.85‐1.59)*
	Indirect (acyclovir)	4, 11	1.23 (1.06‐1.44)*
	Indirect (brivudine)	3, 2	1.38 (1.02‐1.87)
Acyclovir versus idoxuridine	Direct	11	1.22 (1.08‐1.38)*	1.23 (1.14‐1.34)
	Indirect (vidarabine)	7, 3	1.13 (0.98‐1.32)
	Indirect (trifluridine)	4, 5	1.37 (1.15‐1.63)
	Indirect (brivudine)	1, 2	1.31 (0.97‐1.78)
Brivudine versus idoxuridine	Direct	2	1.38 (1.05‐1.81)	1.34 (1.18‐1.51)
	Indirect (trifluridine)	3, 5	1.38 (1.13‐1.68)
	Indirect (acyclovir)	1, 11	1.28 (1.07‐1.54)*
Trifluridine versus vidarabine	Direct	3	1.12 (0.84‐1.49)*	1.17 (1.03‐1.32)
	Indirect (idoxuridine)	5, 3	1.33 (1.09‐1.61)
	Indirect (acyclovir)	4, 7	1.10 (0.97‐1.25)
Acyclovir versus vidarabine	Direct	7	1.09 (1.00‐1.18)	1.11 (1.03‐1.19)
	Indirect (idoxuridine)	11, 3	1.17 (0.99‐1.40)*
	Indirect (trifluridine)	4, 3	1.11 (0.82‐1.50)*
Acyclovir versus trifluridine	Direct	4	0.99 (0.90‐1.09)	0.96 (0.90‐1.04)
	Indirect (idoxuridine)	11, 5	0.90 (0.76‐1.06)*
	Indirect (vidarabine)	7, 3	0.97 (0.72‐1.31)*
	Indirect (brivudine)	1, 3	0.95 (0.79‐1.15)
Brivudine versus trifluridine	Direct	3	1.00 (0.88‐1.14)	1.01 (0.92‐1.12)
	Indirect (idoxuridine)	2, 5	1.00 (0.73‐1.36)
	Indirect (acyclovir)	1, 4	1.04 (0.88‐1.22)
Brivudine versus acyclovir	Direct	1	1.05 (0.92‐1.20)	1.04 (0.95‐1.15)
	Indirect (idoxuridine)	2, 11	1.13 (0.84‐1.53)
	Indirect (trifluridine)	4, 3	1.01 (0.86‐1.19)
Ganciclovir versus acyclovir	Direct	28	1.38 (1.22‐1.57)*	1.34 (1.20‐1.51)
Ganciclovir versus acyclovir	Indirect (foscarnet)	1, 1	1.20 (0.92‐1.57)	1.34 (1.20‐1.51)
Foscarnet versus trifluridine	Direct	1	1.00 (0.75‐1.34)	1.09 (0.92‐1.29)
Foscarnet versus trifluridine	Indirect (acyclovir)	1, 4	1.14 (0.92‐1.41)	1.09 (0.92‐1.29)
Foscarnet versus acyclovir	Direct	1	1.15 (0.95‐1.40)	1.15 (1.01‐1.32)
	Indirect (trifluridine)	1, 4	1.01 (0.74‐1.37)
	Indirect (ganciclovir)	1, 17	1.27 (0.99‐1.63)*
Foscarnet versus ganciclovir	Direct	1	0.96 (0.80‐1.16)	0.92 (0.75‐1.13)
Foscarnet versus ganciclovir	Indirect (acyclovir)	1, 12	0.86 (0.62‐1.20)*	0.92 (0.75‐1.13)
¹ Data derive from a network of antiviral treatment trials (Figure 3). Comparisons are based on reported outcomes at 14 days in which two antivirals were directly compared in at least one clinical trial. Indirect comparisons are limited to a linked network of trials having a single shared intermediate intervention since multiple intermediates were not considered for indirect adjustment. The number of trials indicate the number of direct comparisons made in either head‐to‐head trials or the number of trials between the first antiviral and the intermediate antiviral followed by the number of trials between the intermediate antiviral and the second antiviral. ² While I² < 25% for all combined direct and indirect comparisons estimated by the DerSimonian‐Laird random‐effects model method, networks that had at least one heterogeneous head‐to‐head comparison are identified (*). CI: confidence interval; NA: not applicable (only direct or indirect comparison available)

Table 1. Combined direct and indirect comparisons: relative healing of HSV epithelial keratitis at 14 days between topical antiviral agents

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Table 2. Sensitivity analysis including only higher‐quality studies: relative healing at 14 days using only randomised, double‐masked trials

Treatment comparisons	Randomised, double‐masked studies¹	Risk ratio (95% CI) all studies	I² (with all studies)	Risk ratio (95% CI) ‐ only randomised, double‐masked studies	I² (with only randomised, double‐masked studies)
Idoxuridine versus inactive control	Markham 1977	1.31 (0.45‐3.84)	92%	1.79 (0.98‐3.26)	NA
Vidarabine versus idoxuridine	Markham 1977; Pavan‐Langston 1976	1.04 (0.92‐1.18)	0%	1.03 (0.90‐1.17)	0%
Trifluridine versus idoxuridine	Panda 1995; Sugar 1980; Wellings 1972	1.38 (1.19‐1.60)	0%	1.47 (1.23‐1.75)	0%
Acyclovir versus idoxuridine	Colin 1981; Collum 1980; Coster 1980; Kitano 1985; Kumar 1987; McCulley 1982; Panda 1995	1.22 (1.08‐1.38)	63%	1.17 (1.02‐1.34)	69%
Brivudine versus idoxuridine	Panda 1995	1.38 (1.05‐1.81)	30%	1.64 (1.15‐2.35)	NA
Trifluridine versus vidarabine	Coster 1976	1.12 (0.84‐1.49)	74%	1.07 (0.98‐1.17)	NA
Acyclovir versus vidarabine	Collum 1985; Denis 1983; Genée 1987; Pavan‐Langston 1981; Yeakley 1981; Young 1982	1.09 (1.00‐1.18)	0%	1.07 (0.98‐1.18)	0%
Acyclovir versus trifluridine	Høvding 1989; La Lau 1982; Panda 1995	0.99 (0.90‐1.09)	0%	1.01 (0.91‐1.12)	0%
Brivudine versus trifluridine	Panda 1995; Power 1991	1.00 (0.88‐1.14)	0%	0.98 (0.89‐1.08)	0%
Brivudine versus acyclovir	Panda 1995	1.05 (0.92‐1.20)	NA	NA	NA
Ganciclovir versus acyclovir	Colin 2007a	1.38 (1.22‐1.57)	79%	1.21 (0.95‐1.54)	NA
Foscarnet versus trifluridine	Behrens‐Baumann 1992	1.00 (0.75‐1.34)	NA	NA	NA
Acyclovir, vidarabine versus acyclovir	Colin 1987	1.00 (0.89‐1.12)	NA	NA	NA
Oral versus topical antiviral	Collum 1986	0.92 (0.79‐1.07)	NA	NA	NA
Oral + topical antivirals versus topical antiviral	HEDS Group 1997	1.36 (0.68‐2.74)	90%	1.01 (0.93‐1.09)	NA
Interferon + antiviral versus antiviral	Colin 1983; de Koning 1982; de Koning 1983; Meurs 1985; Sundmacher 1987; van Bijsterveld 1989	1.06 (0.99‐1.13)	67%	1.02 (0.98‐1.06)	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 2. Sensitivity analysis including only higher‐quality studies: relative healing at 14 days using only randomised, double‐masked trials

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Summary of findings 2. Relative healing outcomes with topical antiviral therapy

Relative healing outcomes with topical antiviral therapy
Study population: trial participants with dendritic or geographic epithelial keratitis Outcomes: corneal epithelial healing at 7 and 14 days
Treatment comparisons	*Illustrative comparative healing percentages (95% CI)**		Relative risk (95% Cl)**	No. of participants (no. studies)	Quality of the evidence (GRADE)	Comments
	Assumed healing	Corresponding healing
	Treatment A	Treatment B
Idoxuridine (B) versus inactive control (A)	7 days				⊕⊕⊝⊝ low^1,2	Different substances used as inactive control; random‐effects model used
	25%	52% (31%‐88%)	2.09 (1.24‐3.51)	392 (10)
	14 days
	50%	65% (22%‐100%)	1.31 (0.45‐3.84)	63 (2)
Vidarabine (B) versus inactive control (A)	7 days				⊕⊕⊝⊝ low⁴	Direct analysis limited to one study
	25%	54% (20%‐100%)	2.17 (0.81‐5.87)	23 (1)
	14 days
	50%	98% (55%‐100%)	1.96 (1.10‐3.49)	23 (1)
Vidarabine (B) versus idoxuridine (A)	7 days				⊕⊕⊕⊝ moderate⁴	Combined direct and indirect comparisons indicate vidarabine more effective than idoxuridine; neither antiviral commercially marketed
	50%	55% (43%‐71%)	1.10 (0.85‐1.42)	243 (3)
	14 days
	75%	78% (69%‐89%)	1.04 (0.92‐1.18)	243 (3)
Trifluridine (B) versus idoxuridine (A)	7 days				⊕⊕⊕⊝ moderate^1,2	Indirect comparison shows similar results
	50%	100% (87%‐100%)	2.52 (1.74‐3.63)	223 (4)
	14 days
	75%	100% (89%‐100%)	1.38 (1.19‐1.60)	256 (5)
Acyclovir (B) versus idoxuridine (A)	7 days				⊕⊕⊕⊝ moderate^1,2	Indirect comparison shows similar results; random‐effects model used
	50%	99% (68%‐100%)	1.98 (1.35‐2.90)	468 (9)
	14 days
	75%	92% (81%‐100%)	1.22 (1.08‐1.38)	606 (11)
Brivudine (B) versus idoxuridine (A)	7 days				⊕⊕⊕⊝ moderate⁴	Few studies, with slow healing of idoxuridine‐treated eyes, but indirect analysis yields similar relative effect at 14 days
	50%	100% (100%‐100%)	7.94 (2.80‐22.53)	99 (2)
	14 days
	75%	100% (79%‐100%)	1.38 (1.05‐1.81)	99 (2)
Trifluridine (B) versus vidarabine (A)	7 days				⊕⊕⊕⊝ moderate^1,2	Results partly influenced by one study restricted to geographic epithelial keratitis; random‐effects model used
	65%	70% (61%‐80%)	1.08 (0.94‐1.23)	288 (4)
	14 days
	82%	92% (69%‐100%)	1.12 (0.84‐1.49)	188 (3)
Acyclovir (B) versus vidarabine (A)	7 days				⊕⊕⊕⊝ moderate²	Indirect analysis also favours acyclovir but one study restricted to geographic epithelial keratitis does not
	58%	71% (61%‐84%)	1.23 (1.05‐1.44)	314 (6)
	14 days
	84%	92% (84%‐99%)	1.09 (1.00‐1.18)	342 (7)
Acyclovir (B) versus trifluridine (A)	7 days				⊕⊕⊕⊝ moderate	Studies differ in trifluridine formulation, in solution and as ointment
	71%	70% (58%‐85%)	0.99 (0.82‐1.20)	178 (4)
	14 days
	90%	89% (81%‐98%)	0.99 (0.90‐1.09)	178 (4)
Brivudine (B) versus trifluridine (A)	7 days				⊕⊕⊕⊝ moderate^1,2	Heterogeneity among studies at 7‐day outcome
	61%	57% (43%‐74%)	0.93 (0.71‐1.21)	147 (3)
	14 days
	88%	88% (77%‐100%)	1.00 (0.88‐1.14)	147 (3)
Brivudine (B) versus 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) versus acyclovir (A)	7 days				⊕⊕⊝⊝ low^1,2,5	Slow healing in some studies results in unusually low assumed healing rate with acyclovir; substantial heterogeneity among studies; random‐effects model used to estimate relative risk
	43%	49% (41%‐58%)	1.14 (0.96‐1.35)	551 (7)
	14 days
	55%	76% (67%‐86%)	1.38 (1.22‐1.57)	2062 (28)
Foscarnet (B) versus trifluridine (A)	7 days				⊕⊕⊕⊝ moderate⁴	Direct analysis limited to one study
	‐	‐	‐	‐
	14 days
	90%	90% (68%‐100%)	1.00 (0.75‐1.34)	20 (1)
Foscarnet (B) versus acyclovir (A)	7 days				⊕⊕⊕⊝ moderate⁴	Direct analysis limited to one study
	‐	‐	‐	‐
	14 days
	75%	86% (71%‐100%)	1.15 (0.95‐1.40)	104 (1)
Foscarnet (B) versus ganciclovir (A)	7 days				⊕⊕⊕⊝ moderate⁴	Direct analysis limited to one study
	83%	80% (63%‐100%)	0.96 (0.76‐1.22)	60 (1)
	14 days
	90%	86% (72%‐100%)	0.96 (0.80‐1.16)	60 (1)
The assumed risk* for inactive control is chosen to be 25% at 7 days and 50% at 14 days. The assumed risk for idoxuridine, based on observational studies and trials using idoxuridine as a control, is chosen to be 50% at 7 days and 75% at 14 days. For other comparisons, the basis for each assumed risk is the mean baseline risk estimated as the overall healing percentage, at 7 and 14 days respectively, among all included studies for participants who received treatment A. Each corresponding risk (and its 95% confidence interval, with an upper bound of 100%) is based on the assumed risk and the risk ratio directly comparing treatment B to treatment A. The relative risk** is the pooled risk ratio. Pooling was based on fixed‐effects models except for heterogenous comparisons in which a random‐effects model was used. 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 for either the 7‐day or 14‐day outcome ³ Analysis based only on indirect comparison ⁴ Few studies ⁵ Possible publication bias (Figure 1)

Summary of findings 2. Relative healing outcomes with topical antiviral therapy

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Summary of findings 3. Relative healing rates with antiviral agents and combination interventions

Relative healing rates with antiviral agents and combination interventions
Study population: trial participants with dendritic or geographic epithelial keratitis Outcomes: rate of corneal epithelial healing following trial enrolment
Treatment	Comparison	Hazard ratio (95% CI)	No. of participants (no. studies)
Idoxuridine	Inactive control	1.62 (1.00‐2.65)¹	95 (3)
Vidarabine	Inactive control	2.47 (1.14‐5.33)	43 (1)
Vidarabine	Idoxuridine	1.36 (0.81‐2.28)	74 (2)
Trifluridine	Idoxuridine	2.29 (1.37‐3.83)	78 (1)
Trifluridine	Vidarabine	1.31 (0.96‐1.79)¹	188 (3)
Acyclovir	Idoxuridine	2.15 (1.70‐2.72)¹	355 (8)
	Vidarabine	1.13 (0.86‐1.47)	259 (5)
	Trifluridine	0.92 (0.65‐1.32)	140 (3)
Brivudine	Trifluridine	0.60 (0.35‐1.02)	60 (1)
Interferon + antiviral²	Antiviral²	2.84 (2.13‐3.79)¹	229 (5)
Debridement + antiviral³	Antiviral³	1.76 (1.32‐2.35)¹	248 (6)
¹ I² > 50% ² Trifluridine or acyclovir ³ Idoxuridine, trifluridine, or acyclovir

Summary of findings 3. Relative healing rates with antiviral agents and combination interventions

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Summary of findings 4. Relative healing outcomes with combined topical or topical and oral antiviral therapy

Relative healing outcomes with combined topical and/or oral antiviral therapy
Study population: trial participants with dendritic or geographic epithelial keratitis Outcomes: corneal epithelial healing at 7 and 14 days
Treatment comparisons	*Illustrative comparative healing percentages (95% CI)**		Relative risk (95% CI)**	No. of participants (no. studies)	Quality of the evidence (GRADE)	Comments
	Assumed healing	Corresponding healing
	Treatment A	Treatment B
Topical acyclovir/vidarabine (B) versus topical acyclovir (A)	7 days				⊕⊕⊕⊝ moderate	Analysis limited to one study
	62%	93% (63%‐100%	1.50 (1.01‐2.24)	32 (1)
	14 days
	100%	100% (89%‐100%)	1.00 (0.89‐1.12)	32 (1)
Oral antiviral (B) versus topical antiviral (A)	7 days				⊕⊕⊝⊝ low¹	Only oral and topical acyclovir studied in comparative treatment trials; substantial heterogeneity between 2 trials at 7‐day outcome
	52%	79% (59%‐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) versus topical antiviral (A)	7 days				⊕⊕⊝⊝ low¹	Oral acyclovir was studied with topical trifluridine and with topical idoxuridine; random‐effects model used
	63%	71% (60%‐84%)	1.13 (0.95‐1.33)	287 (1)
	14 days
	84%	100% (57%‐100%)	1.36 (0.68‐2.74)	327 (2)
The basis for the assumed risk* is the overall 7‐day or 14‐day healing percentage among included studies for participants who received treatment A of both treatment comparisons (oral versus topical and oral/topical versus topical). 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 4. Relative healing outcomes with combined topical or topical and oral antiviral therapy

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Summary of findings 5. Relative healing outcomes with topical interferon

Relative healing outcomes with topical interferon
Study population: trial participants with dendritic or geographic epithelial keratitis Outcomes: corneal epithelial healing at 7 and 14 days
Treatment comparisons	*Illustrative comparative healing percentages (95% CI)**		Relative risk (95% CI)**	No. of participants (no. studies)	Quality of the evidence (GRADE)	Comments
	Assumed healing	Corresponding healing
	Treatment A	Treatment B
Interferon (B) versus inactive control (A)	7 days				⊕⊝⊝⊝ very low¹	One study used debridement
	25%	37% (27%‐52%)	1.48 (1.07‐2.06)	178 (3)
	14 days
	50%	66% (53%‐82%)	1.32 (1.06‐1.64)	110 (2)
Interferon (B) versus antiviral (A)	7 days				⊕⊕⊝⊝ low^1,2	Different antiviral agents used as comparative treatment; random‐effects model used
	55%	57% (45%‐70%)	0.99 (0.81‐1.21)	85 (3)
	14 days
	69%	84% (63%‐100%)	1.22 (0.91‐1.62)	222 (4)
Interferon + antiviral (B) versus antiviral (A)	7 days				⊕⊕⊕⊝ moderate²	Heterogeneity among trials at 7 and 14 days; slow healing with antiviral monotherapy in some trials; smaller relative effect size in sensitivity analyses
	44%	83% (72%‐96%)	1.64 (1.35‐2.55)	475 (9)
	14 days
	86%	95% (90%‐100%)	1.06 (0.99‐1.13)	718 (12)
The assumed risk* for inactive control is chosen to be 25% at 7 days and 50% at 14 days. The basis for the assumed risk of antiviral therapy is the overall 7‐day or 14‐day healing percentage among included studies for participants 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 ² Different antiviral agents and different types and routes of interferon administration among studies

Summary of findings 5. Relative healing outcomes with topical interferon

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Summary of findings 6. Relative healing outcomes with corneal debridement

Relative healing outcomes with corneal debridement
Study population: trial participants with dendritic or geographic epithelial keratitis Outcomes: corneal epithelial healing at 7 and 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) versus debridement (A)	7 days				⊕⊕⊝⊝ low^1,2	Debridement limited by recrudescent epithelial keratitis during healing stage; random‐effects model used
	61%	57% (45%‐73%)	0.94 (0.74‐1.20)	372 (7)
	14 days
	72%	71% (52%‐95%)	0.98 (0.72‐1.32)	317 (7)
Debridement + antiviral or interferon (B) versus debridement (A)	7 days				⊕⊕⊕⊝ moderate¹	Debridement limited by recrudescent epithelial keratitis during healing stage; random‐effects model used
	71%	80% (67%‐97%)	1.13 (0.94‐1.36)	347 (8)
	14 days
	81%	100% (63%‐100%)	1.25 (0.78‐2.00)	99 (3)
Debridement + antiviral (B) versus antiviral (A)	7 days				⊕⊕⊕⊝ moderate¹	Different antiviral agents and different interferon dosages; random‐effects model used
	53%	68% (57%‐81%)	1.28 (1.07‐1.53)	305 (7)
	14 days
	75%	79% (70%‐88%)	1.05 (0.94‐1.17)	334 (7)
The basis for the assumed risk* is the overall 7‐day or 14‐day healing percentage among included studies for participants 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 debridement ² Disparate relative effect found in sensitivity analysis

Summary of findings 6. Relative healing outcomes with corneal debridement

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Table 3. Overview of trial and participant characteristics among included studies

Study characteristics	Categories	No. (%) trials (n=137)
No. centres	One Two or more	118 (86%) 19 (14%)
No. eyes per study	< 50 50 to 100 > 100	62 (45%) 58 (42%) 17 (12%)
Average age of participants	< 40 years 40 to 50 years > 50 years Not stated	24 (18%) 36 (26%) 6 (4%) 71 (52%)
Gender of participants	Males exceed females Females exceed males Not stated	71 (52%) 7 (5%) 59 (43%)
Type of epithelial keratitis	Dendritic Dendritic or geographic Geographic Not specified	74 (54%) 59 (43%) 2 (1%) 2 (1%)
No. of intervention groups¹	Two Three Four Five	116 (85%) 16 (12%) 4 (3%) 1 (1%)
Cycloplegic or mydriatic eye drops	Yes None, variable, or not stated	51 (37%) 86 (63%)
Antibacterial eye drops	Yes None or not stated	19 (14%) 118 (86%)
¹ Of 142 excluded studies, 121 had two intervention groups, ten had three groups, six had four groups, two had five groups, two had six groups, and one had eight groups.

Table 3. Overview of trial and participant characteristics among included studies

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Table 4. Outcomes reported in studies excluded due to insufficient healing data

Study (n=57)	Treatment group (no. eyes)¹	Mean healing time ± SD, days; or P value²
Antiviral agents
Babushkin 1993	Idoxuridine (60) Acyclovir (24)	NS 5.9 ± 1.2
Huang 2007	Acyclovir (62) Ganciclovir (62)	12 9.6
Inocencio 1982	Idoxuridine (9) Acyclovir (14)	10.4 7.0
Jing 2010	Acyclovir (22) Ganciclovir (24)	P = 0.005
Leopold 1965	Idoxuridine (5) Cytarabine (5)	NS NS
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
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
Wang 2009	Acyclovir (39) Ganciclovir (39)	P < 0.05
Debridement
Assetto 1981	Debridement (8) Idoxuridine (16) Cytarabine (16) Trifluridine (8)	3 ‐ 19 10 ‐ 18 13 ‐ 21 6 ‐ 13
Fellinger 1980	Idoxuridine (13) Trifluridine (16) Debridement, idoxuridine (13) Debridement, 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
Koev 2007	Acyclovir (25) Acyclovir, pandavir (24) Debridement, acyclovir, pandavir (26)	9.3 ± 1.2 8.2 ± 1.1 6.2 ± 1.3
Mathur 1984	Iodinisation (50) Cryotherapy (20) Cryotherapy, autologous serum (24) Debridement (30) Debridement, idoxuridine (30)	11 9 7 9 6
Patterson 1967c	Debridement (9) Idoxuridine (15)	P < 0.01
Shimomura 1987	Debridement, idoxuridine (16) Idoxuridine (15)	P > 0.05
Tarakji 1978	Cryotherapy (21) Idoxuridine (14)	2.4 6.2
Whitcher 1976	Debridement (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
Lin 2013b	Ganciclovir (33) Ganciclovir, interferon (33)	P < 0.05
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
Su 2010	Ganciclovir (40) Ganciclovir, interferon (38)	P < 0.05
Tamburi 1990	Acyclovir (8) Interferon (8) Acyclovir, interferon (8)	5.2 9.0 5.0
Wan 2014	Ganciclovir (24) Ganciclovir, interferon (26)	6.5 ± 2.1 4.2 ± 1.1
Weng 2014	Acyclovir (35) Acyclovir, interferon (35)	P < 0.05
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) Debridement, 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
Liu 2014b	Acyclovir (NS) Poly I:C (NS) Acyclovir, poly I:C (NS)	NS
Wei 2012	Ganciclovir (24) Poly I:C (24)	22.75 ± 5.09 13.54 ± 4.06
Cytokines, growth factors, and immunomodulators
He 2014	Antiviral (34) Autologous serum (34)	P = 0.015
Kolomiets 1986	Control (10) HSV‐immunoglobulin (14)	28.6 16.8
Liu 2007	Acyclovir (50) Acyclovir, fibroblast growth factor (46)	P < 0.05
Li 2014c	Ganciclovir, acyclovir (21) Ganciclovir, fibroblast growth factor (21)	P < 0.05
Pivetti‐Pezzi 1985	Placebo (13) Thymic extract (11)	23 ± 13 23 ± 9
Prost 1986	Cryotherapy (20) Cryotherapy, oral inosine pranobex (19)	6.8 ± 3.9 6.5 ± 3.8
Salcedo Hernandez 2007	Autologous serum (9) Acyclovir (8)	10 7
Sellitti 1982	Topical/oral inosine pranobex (20) Oral inosine pranobex (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
Yu 2012b	Ganciclovir (30) Ganciclovir, measles vaccine (30)	P < 0.05
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; interventions are tabulated in Characteristics of excluded studies. ² A range of average healing times indicates that mean estimates were provided for subcategories (e.g., dendritic vs. geographic epithelial keratitis) without summary estimation. For studies not reporting mean healing times, P values are given that either compare the proportion healed in study groups at a time other than 14 days or compare clinical scores of symptoms and signs between study groups. NS, not stated; SD, standard deviation (when reported)

Table 4. Outcomes reported in studies excluded due to insufficient healing data

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Table 5. Sensitivity analysis omitting potentially biased studies: relative healing at 14 days after omitting trials with incomplete randomisation, concealment, or masking

Treatment comparisons¹	Studies under investigation²	Risk ratio (95% CI) with studies included	I² (with studies included)	Risk ratio (95% CI) with studies omitted	I² (with studies omitted)
Idoxuridine versus inactive control	Luntz 1963	1.31 (0.45‐3.84)	92%	1.79 (0.98‐3.26)	NA
Trifluridine versus idoxuridine	Struck 1989	1.38 (1.19‐1.60)	32%	1.43 (1.23‐1.67)	0%
Acyclovir versus idoxuridine	Abe 1987; Altinisik 1987; Maichuk 1988	1.22 (1.08‐1.38)	63%	1.18 (1.03‐1.35)	66%
Brivudine versus idoxuridine	Struck 1989	1.38 (1.05‐1.81)	30%	1.64 (1.15‐2.35)	NA
Trifluridine versus vidarabine	Coster 1979	1.12 (0.84‐1.49)	74%	0.99 (0.79‐1.25)	65%
Brivudine versus trifluridine	Struck 1989	1.00 (0.88‐1.14)	0%	0.98 (0.89‐1.08)	36%
Ganciclovir versus acyclovir	Colin 1997a; Colin 1997b; Colin 2007b; Chen 2008; Dai 2009a; Dai 2009b; Han 2010; Han 2014; Huang 2008a; Li 2008; Li 2013a; Lin 2011; Lin 2014; Liu 2009a; Liu 2010; Liu 2012a; Liu 2012b; Liu 2014a; Ramirez 2002; Sun 2013a; Wang 2014a; Xu 2009a; Yang 2000; Yang 2008; Zhang 2014; Zhao 2006; Zhen 2012	1.38 (1.22‐1.57)	79%	1.21 (0.95‐1.54)	NA
Oral + topical antivirals versus topical antiviral	Srinivas 1993	1.36 (0.68‐2.74)	90%	1.01 (0.93‐1.09)	NA
Interferon versus nucleoside antiviral	Kitano 1983; Tanaka 1988b; Vannini 1986	1.22 (0.91‐1.62)	67%	1.57 (0.77‐3.22)	NA
Interferon + antiviral versus antiviral	Fu 2012; Li 2009; Li 2013b; Maichuk 1988	1.06 (0.99‐1.13)	67%	1.02 (0.98‐1.05)	0%
Topical antiviral versus debridement	Bartholomew 1977; Kato 1979; MacKenzie 1964; O'Day 1975; Patterson 1967a; Struck 1989	0.98 (0.72‐1.32)	79%	1.43 (0.44‐4.67)	87%
Debridement + antiviral or interferon versus debridement	Sundmacher 1976a	1.25 (0.78‐2.00)	89%	1.54 (0.21‐11.5)	96%
Debridement + antiviral versus antiviral	Daniel 1972; Richter 1986; Shen 2014; Wilhelmus 1981a	1.05 (0.99‐1.17)	66%	1.01 (0.89‐1.15)	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 5. Sensitivity analysis omitting potentially biased studies: relative healing at 14 days after omitting trials with incomplete randomisation, concealment, or masking

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Table 6. Safety assessment among antiviral treatment studies

Topical antiviral agent	No. studies reporting corneal toxicity prevalence	No. antiviral‐treated participants assessed for corneal toxicity	Median prevalence of punctate epithelial erosions during antiviral use (interquartile range)
Idoxuridine	14¹	430	10% (5%‐20%)
Vidarabine	12²	395	11% (4%‐17%)
Trifluridine	9³	220	4% (2%‐7%)
Acyclovir	25⁴	667	10% (0%‐17%)
Brivudine	3⁵	72	0%
Ganciclovir	4⁶	156	4% (0%‐11%)
All of above	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 (omitting 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 (omitting 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 6. 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, Random, 95% CI)	Subtotals only

1.1 Healing at 7 days	10	392	Risk Ratio (M‐H, Random, 95% CI)	2.09 [1.24, 3.51]
1.2 Healing at 14 days	2	63	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.45, 3.84]
2 Idoxuridine versus inactive control: healing rate Show forest plot	3	95	Hazard Ratio (95% CI)	1.62 [1.00, 2.65]

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 debridement	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.59, 1.54]
7.2 Healing at 14 days: without debridement	2	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.75, 1.14]
7.3 Healing at 7 days: with debridement	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.87, 1.43]
7.4 Healing at 14 days: with debridement	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, Random, 95% CI)	Subtotals only

10.1 Healing at 7 days: acyclovir versus idoxuridine	9	468	Risk Ratio (M‐H, Random, 95% CI)	1.98 [1.35, 2.90]
10.2 Healing at 14 days: acyclovir versus idoxuridine	11	606	Risk Ratio (M‐H, Random, 95% CI)	1.22 [1.08, 1.38]
10.3 Healing at 7 days: acyclovir versus iododeoxycytidine	1	32	Risk Ratio (M‐H, Random, 95% CI)	1.42 [0.76, 2.63]
10.4 Healing at 14 days: acyclovir versus iododeoxycytidine	1	32	Risk Ratio (M‐H, Random, 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, Random, 95% CI)	Subtotals only

13.1 Healing at 7 days: all groups	4	288	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.94, 1.23]
13.2 Healing at 14 days: all groups	3	188	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.84, 1.49]
13.3 Healing at 7 days: geographic epithelial keratitis	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.55, 3.13]
13.4 Healing at 14 days: geographic epithelial keratitis	1	30	Risk Ratio (M‐H, Random, 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	28		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

22.1 Healing at 7 days	7	551	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.96, 1.35]
22.2 Healing at 14 days	28	2062	Risk Ratio (M‐H, Random, 95% CI)	1.38 [1.22, 1.57]
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 Foscarnet versus acyclovir: 14‐day healing Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

24.1 Healing at 14 days	1	104	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.95, 1.40]
25 Foscarnet versus ganciclovir: 7‐day & 14‐day healing Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

25.1 Healing at 7 days	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.76, 1.22]
25.2 Healing at 14 days	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.80, 1.16]
26 Acyclovir/vidarabine versus acyclovir: 7‐day & 14‐day healing Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

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

27.1 Healing at 7 days	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.58, 4.05]
27.2 Healing at 14 days	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [0.96, 2.41]
28 Ganciclovir 0.15% gel versus ganciclovir 0.05% gel or 0.1% solution Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

28.1 Healing at 7 days	1	45	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.53, 1.74]
28.2 Healing at 14 days	4	355	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.98, 1.14]

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, Random, 95% CI)	Subtotals only

2.1 Healing at 7 days	1	287	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.95, 1.33]
2.2 Healing at 14 days	2	327	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.68, 2.74]

Comparison 2. Oral antiviral agents

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Comparison 3. Interferon

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Interferon versus inactive control, without or with debridement 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	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Healing at 7 days: interferon 1000 IU/ml versus interferon 1‐10 million IU/ml	2	104	Risk Ratio (M‐H, Fixed, 95% CI)	1.81 [1.15, 2.86]
2.2 Healing at 7 days: trifluridine + interferon 10 million IU/ml versus 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 versus 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 versus 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 debridement versus interferon‐β with debridement 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	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Healing at 7 days	3	85	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.81, 1.21]
5.2 Healing at 14 days	4	222	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.91, 1.62]
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	13		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 Healing at 7 days	9	475	Risk Ratio (M‐H, Random, 95% CI)	1.85 [1.35, 2.55]
7.2 Healing at 14 days	12	718	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.99, 1.13]
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. Interferon

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Comparison 4. Debridement

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Debridement 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 debridement Show forest plot	11		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Healing at 7 days	7	372	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.74, 1.20]
2.2 Healing at 14 days	7	317	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.72, 1.32]
3 Different debridement methods Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Healing at 7 days: cryotherapy versus carbolisation	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	1.48 [0.95, 2.31]
3.2 Healing at 7 days: cryotherapy/idoxuridine versus carbolisation/idoxuridine	1	31	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.99, 2.07]
3.3 Healing at 7 days: thermocautery/interferon versus wiping/interferon	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.86, 1.13]
3.4 Healing at 7 days: iodinisation/panthenol versus cryotherapy/panthenol	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.66, 1.12]
3.5 Healing at 7 days: iodinisation/fluorophenylalanine versus cryotherapy/fluorophenylalanine	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.92, 1.46]
3.6 Healing at 14 days: thermocautery/interferon versus wiping/interferon	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.91, 1.10]
3.7 Healing at 14 days: iodinisation/panthenol versus cryotherapy/panthenol	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.73, 1.00]
3.8 Healing at 14 days: iodinisation/fluorophenylalanine versus cryotherapy/fluorophenylalanine	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.91, 1.14]
3.9 Healing at 14 days: photoinactivation versus carbolisation	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.41, 1.48]
4 Debridement with antiviral or interferon versus debridement Show forest plot	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Healing at 7 days	8	347	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.94, 1.36]
4.2 Healing at 14 days	3	99	Risk Ratio (M‐H, Random, 95% CI)	1.25 [0.78, 2.00]
5 Debridement 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 Debridement with antiviral versus antiviral: 7‐day & 14‐day healing Show forest plot	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Healing at 7 days	7	305	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.84, 1.79]
6.2 Healing at 14 days	7	334	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.94, 1.17]
7 Debridement with antiviral versus antiviral: healing rate Show forest plot	6	248	Hazard Ratio (95% CI)	1.76 [1.32, 2.35]

Comparison 4. Debridement

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Comparison 5. Adjunctive and alternative agents: lubricant, growth factor, nonsteroidal anti‐inflammatory drug, immunomodulator

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

1.1 Healing at 7 days	1	26	Risk Ratio (M‐H, Fixed, 95% CI)	3.86 [1.03, 14.50]
1.2 Healing at 14 days	1	26	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.73, 1.91]
2 Antiviral/epidermal growth factor versus antiviral Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

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

3.1 Healing at 7 days	1	120	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.79, 1.14]
3.2 Healing at 14 days	1	120	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.08]
4 Interferon/methyl uracil versus interferon Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Healing at 7 days	1	39	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.27, 2.67]
4.2 Healing at 14 days	1	39	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.79, 1.41]
5 Antiviral/oxyphenbutazone versus antiviral Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Healing at 7 days	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.56, 1.11]
6 Oral inosine pranobex versus inactive control, with or without antiviral Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Healing at 7 days	2	50	Risk Ratio (M‐H, Fixed, 95% CI)	1.92 [1.07, 3.47]
6.2 Healing at 14 days	2	50	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.91, 1.62]

Comparison 5. Adjunctive and alternative agents: lubricant, growth factor, nonsteroidal anti‐inflammatory drug, immunomodulator

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