Oral antivirals for preventing recurrence of herpes simplex virus keratitis

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the effects of oral antivirals in reducing the frequency of recurrence of HSV keratitis. Our main objective is to evaluate the prophylactic effect of oral antivirals on HSV deeper corneal involvement (i.e., necrotizing and non-necrotizing stromal keratitis, endotheliitis, and iritis) because of its implications for visual impairment.

Background

Description of the condition

Herpes simplex viruses (HSVs) are ever-present human pathogens with the capability to cause asymptomatic infection or active disease at different end-organs. Two types are known: type 1 (HSV-1), which primarily affects the oropharynx, and type 2 (HSV-2), which primarily affects the genital area. Although HSV-1 typically causes ocular disease, both types can affect the eye (Neumman-Haefelin 1978). HSV has a broad spectrum of ocular manifestations. All structures of the ocular surface including lid margins, conjunctiva and cornea can be affected; but it is herpetic stromal keratitis (HSK) that is of utmost importance because of its deleterious effects on vision.

Primary infection manifests clinically in only 1% to 6% of occasions. It is recurrence of the disease from primary infection, either symptomatic or asymptomatic, that causes significant visual morbidity. Therefore, recurrence physiopathology has drawn the attention of virologists and scientists for a long time. It is well known that recrudescent disease results from HSV reactivation from latency in trigeminal ganglion neurons (Baringer 1973, Margolis 1992, Margolis 2007). However, it has been shown that the cornea can be a reservoir for HSV viral deoxyribonucleic acid (DNA) (Kaye 1991), that the virus can become latent or can persist in an infectious state within the cornea, and that anterograde spread from the trigeminal ganglion is not necessary for recurrent HSK (Polcicova 2005). Furthermore, superinfection with a different strain of HSV may occur (Remeijer 2002).

Latency allows for spontaneous and recurrent reactivation of disease, with clinical sequelae caused by the immunologic response associated with each episode. Stromal keratitis (inflammation of the stromal layer of the cornea), a common ocular manifestation of HSV infection, usually occurs at the ocular site with the highest recurrence risk and is strongly associated with previous HSV infectious episodes (HEDS 2001).

Epidemiology

The epidemiology of HSV ocular involvement has been studied extensively (Liesegang 2001). The incidence of ocular HSV per 100,000 people per year has been estimated at 5.9 to 12 in Denmark (Mortensen 1979), compared with 20.7 in Rochester, Minnesota (Liesegang 1989), and 31.5 in France (Labetoulle 2005). The incidence of HSV epithelial keratitis is six times (120 per 100,000 people per year) higher in patients who have undergone corneal transplantation (for non-herpetic corneal disease) (Remeijer 1997). It is estimated that 10% to 12% of people with ocular HSV have bilateral disease (Liesegang 2001).

The main focus of this review will be herpetic stromal keratitis, which is the most important clinical manifestation in recurrent disease. An estimate of the recurrence rate of HSV keratitis is approximately 10% per year (Kaye 2006). Herpetic stromal disease accounts for 2% of initial presentations and 20% to 48% of cases of recurrent herpetic disease. Corneal scarring is seen in 18% to 28%, with a corresponding reduction in visual acuity to less than 20/100 in 3% to 12% of cases and to less than 20/40 in 10% to 25% (Liesegang 1989). Different stimuli have been associated with recurrent disease, such as fever, psychological stress, hormonal changes, and minor ocular trauma, among others (Binder 1977; Dawson 1977; HEDS 2001). Study results on the association between participant age, gender or race, and risk of recurrence have been conflicting; some investigators have reported no association, and others have described increased risk among male participants (Wilhelmus 1981) and members of the younger population (Wishart 1987).

Description of the intervention

Herpes simplex viruses (HSV-1 and HSV-2) belong to the α-herpesvirus family subgroup. Adequate oral treatments available for this viral family include acyclovir and its oral prodrug valacyclovir, penciclovir and its oral prodrug famciclovir, ganciclovir and its oral prodrug valganciclovir, and brivudine. As acyclic nucleoside analogues, these drugs require phosphorylation by the virus-encoded thymidine kinase to exert their antiviral activity; they do not inhibit the thymidine kinase-deficient HSV strains. When this occurs, other types of antivirals such as foscarnet can be used (De Clerq 2004). It has been shown that oral antivirals in a prophylactic schema are safe and efficient in avoiding recurrence of HSV labialis (Spruance 1993) and HSV genitalis (Gupta 2007).

Oral acyclovir has become the standard prophylactic therapy for recurrent HSV stromal keratitis. Some interventional case series (Colin 1993; Simon 1996) and randomized controlled clinical trials (RCTs) (HEDS 1998) have reported that prophylactic doses of acyclovir reduce the recurrence rate of HSV keratitis. Usually, the prophylactic dose of acyclovir is 800 mg a day in divided doses, 400 mg twice a day, or 200 mg four times daily, over varying periods of time (ranging from 1 month to 62 months). Oral valacyclovir, the acyclovir prodrug, is known to increase the bioavailability of acyclovir three to five times. The reported prophylactic dose of valacyclovir is 500 mg once a day, which provides a benefit regarding patient compliance and convenience when compared with multiple daily doses.

How the intervention might work

Although further knowledge of the pathogenesis of HSV stromal keratitis is needed, two main factors have been implicated: host immune response and viral replication. Antiviral therapy addresses viral replication by inhibiting viral DNA synthesis in virally infected cells.

Nucleoside analogues, such as acyclovir, have in vitro and in vivo inhibitory activity against HSV-1 and HSV-2, as well as against varicella-zoster virus (VZV). Acyclovir is highly selective against herpes simplex viruses in that it binds to enzymes encoded by these viruses, specifically thymidine kinase (TK) (De Clerq 2004). This viral enzyme, TK, converts acyclovir to acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted to diphosphate by cellular guanylate kinase and to triphosphate by various cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA in three ways: (1) through competitive inhibition of viral DNA polymerase; (2) by incorporation into and termination of the growing viral DNA chain; and (3) via inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK (King 1988). In the treatment of epithelial HSV keratitis, purine nucleoside analogues have shown superiority over pyrimidine analogues, specifically, acyclovir and trifluridine were shown to be more effective in a systematic review of treatments for epithelial HSV keratitis (Wilhelmus 2010).

It has been reported that nucleoside analogues have no effect in latent HSV, but reactivation is necessary for completion of the HSV viral cycle; targeting reactivation prevents spread of the virus and disease recurrence. Studies reported that reactivation is an isolated event that is limited to a few neurons in sensory ganglia. The frequency with which an individual experiences reactivation ranges from 0 to 12 episodes per year and is positively correlated with the number of trigeminal ganglia latently infected (Sawtell 1998). Also, a high proportion of human subjects have asymptomatic shedding of HSV-1 DNA, and approximately 90% of human trigeminal ganglia contain HSV-1 DNA (Hill 2008). Suppression of asymptomatic shedding is one way that transmission of the virus might be blocked.

In vitro studies have shown that acyclovir preferentially affects cells that have been infected by HSV, and, unlike other antivirals, acyclovir has relatively little effect on normal, uninfected cells. Therefore, its toxicity is minimal. An important toxic effect of acyclovir is its potential to cause obstructive nephropathy. The drug is excreted primarily by the kidney; therefore, smaller doses may be required in patients with decreased kidney function (Lietman 1982). Valacyclovir has been reported to produce mild adverse effects. However, neurotoxicity has been reported among elderly and renally impaired patients (Asahi 2009).

It is important to note that a relatively high prevalence of acyclovir-resistant corneal HSV-1 has been reported in immunocompetent patients with HSV keratitis (Duan 2008).

Why it is important to do this review

This review is needed so the reader can better understand the potential benefits and harms of using oral antivirals for the prevention of recurrent HSV stromal keratitis.

Objectives

To evaluate the effects of oral antivirals in reducing the frequency of recurrence of HSV keratitis. Our main objective is to evaluate the prophylactic effect of oral antivirals on HSV deeper corneal involvement (i.e., necrotizing and non-necrotizing stromal keratitis, endotheliitis, and iritis) because of its implications for visual impairment.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs).

Types of participants

We will include studies in which the eligibility criteria for enrollment included participant age of at least 12 years, active HSV stromal keratitis in the previous 12 months that was inactive at the time of enrollment and untreated for at least 30 days, and immune competence. We will not include studies of people with corneal grafts as they will be included in another Cochrane review (Bhatt 2009).

Types of interventions

We will include studies in which prophylactic long-term treatment (at least 6 months) with oral antivirals was compared with placebo, different dose and/or treatment period of the same oral antiviral, treatment with other topically or orally administered antivirals, or no treatment.

Types of outcome measures

Primary outcomes

The primary outcome will be the proportion of participants experiencing at least one recurrence of active HSV keratitis, defined as epithelial keratitis, stromal keratitis, endotheliitis, and/or iritis, one year after completion of the treatment period.

Secondary outcomes

We also will consider recurrences during the prophylactic treatment period and the proportion of participants experiencing more than one recurrence of active HSV keratitis one year after completion of the treatment period. Other secondary outcomes will include the following:

  1. Best corrected visual acuity (BCVA): the mean change in BCVA (transformed to logMAR scale) from baseline to the end of the treatment period and one year after completion of the treatment period.

  2. Ocular hypertension: the proportion of participants developing ocular hypertension, defined as intraocular pressure (IOP) greater than or equal to 21 mm Hg, or as defined by the study, during the treatment period and one year after completion of the treatment period.

  3. Recurrence of nonocular HSV disease: the proportion of participants experiencing at least one episode of nonocular HSV disease (orofacial or genital) during the treatment period and one year after completion of the treatment period.

  4. Resistance to treatment: the proportion of participants developing resistance to antiviral therapy during the treatment period and one year after completion of the treatment period.

Follow-up times longer than one year after completion of the treatment period will also be considered.

Adverse events

We will document adverse events reported by included studies. Specific adverse events of interest include gastrointestinal effects, rash, renal impairment, cephalea, dizziness, hair loss, fatigue, and anxiety.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, EMBASE, Latin American and Caribbean Literature on Health Sciences (LILACS), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We will not use any date or language restrictions in the electronic search for trials.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), mRCT (Appendix 5), ClinicalTrials.gov (Appendix 6) and the ICTRP (Appendix 7).

Searching other resources

We will search the reference lists of included studies for additional, potentially relevant studies. We will search the Science Citation Index for references that have cited included studies to identify additional, potentially relevant studies. We will not handsearch conference proceedings specifically for this review as they routinely are searched by the Cochrane Eyes and Vision Group, and reports from any identified trials are included in CENTRAL.

Data collection and analysis

Selection of studies

Two review authors will assess independently titles and abstracts from the search results. Each author will classify each record as (1) relevant, (2) possibly relevant or unclear, or (3) definitely not relevant, according to the Criteria for considering studies for this review. Discrepancies will be resolved by a third review author. For all records classified as (1) or (2), we will obtain the full-text articles, and two review authors will assess each article independently for inclusion in the review. Each full-text article will be assessed as (1) include, (2) unclear, or (3) definitely exclude. We will contact primary investigators of studies classified as (2) for clarification. We will document the reasons for excluding full-text articles. Discrepancies will be resolved by a third review author.

Data extraction and management

Two review authors will extract data for each included study independently, using forms developed by the Cochrane Eyes and Vision Group. We will extract data relevant to study methods, participants, interventions, and outcomes. Discrepancies will be resolved by consensus. One review author will enter data into RevMan 5 (RevMan 2012), and a second review author will verify the data entry.

Assessment of risk of bias in included studies

Two review authors will assess independently the risk of bias for each included study according to Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Specific risk of bias parameters to be assessed will include selection bias (sequence generation and allocation concealment), performance bias (masking of participants and study personnel), detection bias (masking of outcome assessors), attrition bias (loss to follow-up and intent-to-treat analysis), and reporting bias (selective outcome reporting), as well as other sources of bias such as the funding source. We will judge each parameter to be low risk, unclear risk, or high risk. For studies in which risk of bias information is unclear or is not reported, we will contact the primary investigators for clarification, or we will make assessments on the basis of available information. Discrepancies will be resolved by consensus.

Measures of treatment effect

Dichotomous outcomes will be reported as risk ratios with 95% confidence intervals. We will consider the following as dichotomous outcomes: (1) the proportion of participants experiencing at least one recurrence of active ocular HSV; (2) the proportion of participants experiencing more than one recurrence of active ocular HSV; (3) the proportions of participants developing ocular hypertension at one and at two years; (4) the proportion of participants experiencing at least one episode of nonocular HSV disease; (5) the proportion of participants developing resistance to antiviral therapy; and (6) the proportion of participants experiencing adverse events.

Continuous outcomes will be reported as mean differences with 95% confidence intervals. We will consider the following as a continuous outcome: the mean change in BCVA from baseline.

Unit of analysis issues

The unit of analysis will be the individual when possible. We anticipate that most studies will include one study eye per participant because ocular HSV tends to present unilaterally; however, we will not exclude studies that included participants with bilateral disease. We will document studies where both eyes of participants were randomly assigned and/or were analyzed separately. We will perform subgroup analyses for participants with unilateral or bilateral disease when sufficient data are available.

Dealing with missing data

We will contact primary investigators to ask for missing data related to study characteristics, risk of bias parameters, and/or outcome data. We will allow six weeks for a response, and then we will use the information that is available.

Assessment of heterogeneity

We will assess statistical heterogeneity using the I2 statistic. An I2 value greater than 50% will indicate the presence of substantial statistical heterogeneity. We will also assess clinical and methodological heterogeneity by comparing designs, populations, interventions and comparisons, and outcome assessments among studies. We will examine forest plots to assess the direction and magnitude of effects.

Assessment of reporting biases

If 10 or more studies are included in a meta-analysis, we will assess reporting biases by examining the funnel plot.

Data synthesis

When data are sufficient and no substantial heterogeneity is detected, we will combine study results in a meta-analysis. We will use the random-effects model when three or more studies are included and the fixed-effect model when fewer than three studies are meta-analyzed. If heterogeneity is detected, we will not combine results. Instead we will present a narrative and a tabular summary of results.

Subgroup analysis and investigation of heterogeneity

When sufficient data are available, we will perform subgroup analyses that are based on use of oral antivirals for preventing recurrence in HSV bilateral disease.

Sensitivity analysis

When sufficient data are available, we will conduct sensitivity analyses to assess the impact of including unpublished studies, studies assessed as having a high risk of bias for any of the domains listed above (see section on Assessment of risk of bias in included studies), and industry-funded or affiliated studies. We will document when sensitivity analyses were performed and will report the summary effects.

Acknowledgements

We acknowledge Lori Rosman, Trial Search Co-ordinator for CEVG@US, for developing the electronic search strategies. We thank the Cochrane Eyes and Vision Group (CEVG) for assisting with preparations for this protocol and the peer reviewers for providing feedback on the manuscript.

Richard Wormald (Co-ordinating Editor for CEVG) acknowledges financial support for his CEVG research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology.

The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS or the Department of Health.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Keratitis, Herpetic] explode all trees
#2 MeSH descriptor: [Keratitis, Dendritic] explode all trees
#3 (herpe* or simplex) near (cornea* or kerati* or dendr* or epithel* or endothel* or stroma* or uveiti* or ocular)
#4 #1 or #2 or #3
#5 (oral* near/3 (antiviral* or antivirus*))
#6 MeSH descriptor: [Antiviral Agents] explode all trees
#7 MeSH descriptor: [Antimetabolites] explode all trees
#8 MeSH descriptor: [Acyclovir] explode all trees
#9 MeSH descriptor: [Guanine] explode all trees
#10 #9 from 1966 to 1982
#11 (Acerpes or acevir or acg or acic or acicloftal or aciclor or aciclosina or aciclostad or acyclovir* or acihexal or "acilax cream" or acitop or acivir or "acivir eye" or aclova or aclovir or aclovirax or activir or acv or "acyclo v" or acycloguanosine or acyclovidar or acylene or acyron or acyrova or acyvir or apicol or avirax or avorax or azovir or bearax or "bw 248u" or bw248u or cicloferon or cicloviral or cicloviran or clovicin or clover or cloviran or colsor or cusiviral or cyclivex or cyclomed or cyclorax or cyclostad or cyclovir or cycloviran or cyllanvir or danovir or deherp or dravyr or dumophar or duvimex or eduvir or entir or erlvirax or eurovir or exavir or expit or genvir or herpefug or herpetad or herpex or herpofug or herpoviric or inmerax or innovirax or isavir or juviral or laciken or leramex or lermex or lesaclor or libravir or lisovyr or lover or lovire or maclov or marvir or matrovir or maynor or medovir or norum or olvit or oppvir or opthavir or poviral or proviral or qualiclovir or quavir or ranvir or raxclo or supra-vir or supraviran or syntovir or vacrax or vacrovir or vicorax or viraban or viralex or viralex-ds or virax or vircella or virest or virex or virless or viroclear or virogon or virolan or virolex or viromed or vironida or viropump or virules or virupos or viruseen or vivir or warviron or "wellcome 248 u" or zaclovir or zetavir or "zeven cream" or zevin or zoral or zorax or zorel or zoter or zovir or zovirax or zoylex or zumasid or zyclir or zyvir or Aciclovir or "Wellcome 248U" or Wellcome248U or "Aci Sanorania" or Aciclobeta or Acifur or "Acipen Solutab" or "Antiherpes Crème" or Clonorax or Herpotern or Herpoviric or Mapox or Maynar or Milavir or Viclovir or Vipral or ViraxPuren or Virherpes or Virmen or Virzin or Zoliparin or acivirax)
#12 (Ganciclovir or Gancyclovir or "b 759 u" or "b 759u" or b759u or "biolf 62" or biolf62 or "bw 759" or "bw 759 u" or "bw 759u" or "bw 759u77" or "bw b759u" or bw759 or bw759u or bw759u77 or "bwb 759 u" or "bwb 759u" or bwb759u or cameven or cymevan or cymeven or cymevene or cytovene or denocin or denosine or dihydroxypropoxymethylguanine or "rs 21592" or rs21592 or virgan or vitrasert or zirgan)
#13 (Valacyclovir or valaciclovir or 256U or L-valylacyclovir or 256u87 or "bw 256u87" or bw256u87 or rapivir or vacv or valciclovir or valcyclor or valcyclovir or valtrex or zelitrex)
#14 (penciclovir or denavir or vectavir or "brl 39123" or "brl 39123a" or brl39123 or brl39123a)
#15 (famciclovir or famvir or "brl 42810" or brl42810 or famtrex or oravir or pentavir)
#16 (brivudine or "5-BVDU" or brivudin or bromovinyldeoxyuridine or brvudr or BVDU or helpin or "sc 38394" or sc38394 or zostex)
#17 MeSH descriptor: [Foscarnet] explode all trees
#18 (foscarnet or "phosphonoformic acid" or foscavir or phosphonoformate)
#19 MeSH descriptor: [Deoxyuridine] explode all trees
#20 (deoxyuridine or desoxyuridine or "uracil deoxyriboside")
#21 MeSH descriptor: [Idoxuridine] explode all trees
#22 (idoxuridine or "5 iodo 2 deoxy uridine" or "5 iodo 2 deoxyuridine" or "5 iodo 2 desoxy uridine" or "5 iodo 2 omega deoxyuridine" or "5 iododeoxyuridine" or "5 iododesoxyuridine" or "5 iodoxyuridine" or "8 iododeoxyuridine" or "allergan 211" or "apridin gel" or "citol idoxuridina" or dendrid or "desoxy 5 iodouridin" or "gel v pos" or herpid or herpidu or herplex or idina or idoxene or idu or iducutit or idulea or idur or iduridin or iduridine or idurivan or idustatin or iduviran or "iodo deoxyuridine" or iododeoxyuridine or iododesoxyuridine or iodoxuridine or iodoxyuridine or "isotic ixodine" or iudr or kerecid or kerecide or "nsc 39661" or nsc39661 or "oftan idu" or oftanIDU or ridinox or spectanefran or stoxil or synmiol or virexen or virpex or virunguent or virusan or zostrum)
#23 MeSH descriptor: [Trifluridine] explode all trees
#24 (trifluridine or trifluoridine or "5 trifluoromethyl 2 deoxyuridine" or "5 trifluoromethyl 2 desoxy uridine" or "5 trifluoromethyl deoxyuridine" or "5 trifluoromethyldeoxyuridine" or aflomin or bephen or ocufridine or tft or thriherpine or triflumann or "trifluor thymidine" or "trifluoro thymidine" or trifluorodeoxythymidine or trifluorothymidine or triherpin or triherpine or viromidin or virophta or viroptic)
#25 #5 or #6 or #7 or #8 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24
#26 #4 and #25

Appendix 2. MEDLINE (OvidSP) search strategy

1. Randomized Controlled Trial.pt.
2. Controlled Clinical Trial.pt.
3. (randomized or randomised).ab,ti.
4. placebo.ab,ti.
5. drug therapy.fs.
6. randomly.ab,ti.
7. trial.ab,ti.
8. groups.ab,ti.
9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10. exp animals/ not humans.sh.
11. 9 not 10
12. exp Keratitis, Herpetic/
13. exp Keratitis, Dendritic/
14. ((herpe* or simplex) adj4 (cornea* or kerati* or dendr* or ocular)).tw.
15. or/12-14
16. (oral* adj3 (antiviral* or antivirus*)).tw.
17. exp Antiviral Agents/
18. exp Antimetabolites/
19. exp Acyclovir/
20. exp Guanine/
21. limit 20 to yr="1966 - 1982"
22. (Acerpes or acevir or acg or acic or acicloftal or aciclor or aciclosina or aciclostad or acyclovir* or acihexal or "acilax cream" or acitop or acivir or "acivir eye" or aclova or aclovir or aclovirax or activir or acv or "acyclo v" or acycloguanosine or acyclovidar or acylene or acyron or acyrova or acyvir or apicol or avirax or avorax or azovir or bearax or "bw 248u" or bw248u or cicloferon or cicloviral or cicloviran or clovicin or clover or cloviran or colsor or cusiviral or cyclivex or cyclomed or cyclorax or cyclostad or cyclovir or cycloviran or cyllanvir or danovir or deherp or dravyr or dumophar or duvimex or eduvir or entir or erlvirax or eurovir or exavir or expit or genvir or herpefug or herpetad or herpex or herpofug or herpoviric or inmerax or innovirax or isavir or juviral or laciken or leramex or lermex or lesaclor or libravir or lisovyr or lover or lovire or maclov or marvir or matrovir or maynor or medovir or norum or olvit or oppvir or opthavir or poviral or proviral or qualiclovir or quavir or ranvir or raxclo or supra-vir or supraviran or syntovir or vacrax or vacrovir or vicorax or viraban or viralex or viralex-ds or virax or vircella or virest or virex or virless or viroclear or virogon or virolan or virolex or viromed or vironida or viropump or virules or virupos or viruseen or vivir or warviron or "wellcome 248 u" or zaclovir or zetavir or "zeven cream" or zevin or zoral or zorax or zorel or zoter or zovir or zovirax or zoylex or zumasid or zyclir or zyvir or Aciclovir or "Wellcome 248U" or Wellcome248U or "Aci Sanorania" or Aciclobeta or Acifur or "Acipen Solutab" or "Antiherpes Crème" or Clonorax or Herpotern or Herpoviric or Mapox or Maynar or Milavir or Viclovir or Vipral or ViraxPuren or Virherpes or Virmen or Virzin or Zoliparin or acivirax).tw.
23. (Ganciclovir or Gancyclovir or "b 759 u" or "b 759u" or b759u or "biolf 62" or biolf62 or "bw 759" or "bw 759 u" or "bw 759u" or "bw 759u77" or "bw b759u" or bw759 or bw759u or bw759u77 or "bwb 759 u" or "bwb 759u" or bwb759u or cameven or cymevan or cymeven or cymevene or cytovene or denocin or denosine or dihydroxypropoxymethylguanine or "rs 21592" or rs21592 or virgan or vitrasert or zirgan).tw.
24. (Valacyclovir or valaciclovir or 256U or L-valylacyclovir or 256u87 or "bw 256u87" or bw256u87 or rapivir or vacv or valciclovir or valcyclor or valcyclovir or valtrex or zelitrex).tw.
25. (penciclovir or denavir or vectavir or "brl 39123" or "brl 39123a" or brl39123 or brl39123a).tw.
26. (famciclovir or famvir or "brl 42810" or brl42810 or famtrex or oravir or pentavir).tw.
27. (brivudine or "5-BVDU" or brivudin or bromovinyldeoxyuridine or brvudr or BVDU or helpin or "sc 38394" or sc38394 or zostex).tw.
28. exp Foscarnet/
29. (foscarnet or "phosphonoformic acid" or foscavir or phosphonoformate).tw.
30. exp Deoxyuridine/
31. (deoxyuridine or desoxyuridine or "uracil deoxyriboside").tw.
32. exp Idoxuridine/
33. (idoxuridine or "5 iodo 2 deoxy uridine" or "5 iodo 2 deoxyuridine" or "5 iodo 2 desoxy uridine" or "5 iodo 2 omega deoxyuridine" or "5 iododeoxyuridine" or "5 iododesoxyuridine" or "5 iodoxyuridine" or "8 iododeoxyuridine" or "allergan 211" or "apridin gel" or "citol idoxuridina" or dendrid or "desoxy 5 iodouridin" or "gel v pos" or herpid or herpidu or herplex or idina or idoxene or idu or iducutit or idulea or idur or iduridin or iduridine or idurivan or idustatin or iduviran or "iodo deoxyuridine" or iododeoxyuridine or iododesoxyuridine or iodoxuridine or iodoxyuridine or "isotic ixodine" or iudr or kerecid or kerecide or "nsc 39661" or nsc39661 or "oftan idu" or oftanIDU or ridinox or spectanefran or stoxil or synmiol or virexen or virpex or virunguent or virusan or zostrum).tw.
34. exp Trifluridine/
35. (trifluridine or trifluoridine or "5 trifluoromethyl 2 deoxyuridine" or "5 trifluoromethyl 2 desoxy uridine" or "5 trifluoromethyl deoxyuridine" or "5 trifluoromethyldeoxyuridine" or aflomin or bephen or ocufridine or tft or thriherpine or triflumann or "trifluor thymidine" or "trifluoro thymidine" or trifluorodeoxythymidine or trifluorothymidine or triherpin or triherpine or viromidin or virophta or viroptic).tw.
36. 16 or 17 or 18 or 19 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35
37. 11 and 15 and 36

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville et al (Glanville 2006).

Appendix 3. EMBASE.com search strategy

#1 'randomized controlled trial'/exp
#2 'randomization'/exp
#3 'double blind procedure'/exp
#4 'single blind procedure'/exp
#5 random*:ab,ti
#6 #1 OR #2 OR #3 OR #4 OR #5
#7 'animal'/exp OR 'animal experiment'/exp
#8 'human'/exp
#9 #7 AND #8
#10 #7 NOT #9
#11 #6 NOT #10
#12 'clinical trial'/exp
#13 (clin* NEAR/3 trial*):ab,ti
#14 ((singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*)):ab,ti
#15 'placebo'/exp
#16 placebo*:ab,ti
#17 random*:ab,ti
#18 'experimental design'/exp
#19 'crossover procedure'/exp
#20 'control group'/exp
#21 'latin square design'/exp
#22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21
#23 #22 NOT #10
#24 #23 NOT #11
#25 'comparative study'/exp
#26 'evaluation'/exp
#27 'prospective study'/exp
#28 control*:ab,ti OR prospectiv*:ab,ti OR volunteer*:ab,ti
#29 #25 OR #26 OR #27 OR #28
#30 #29 NOT #10
#31 #30 NOT (#11 OR #23)
#32 #11 OR #24 OR #31
#33 'herpes simplex keratitis'/exp
#34 ((herpe* OR simplex) NEAR/4 (cornea* OR kerati* OR dendr* OR ocular)):ab,ti
#35 #33 OR #34
#36 (oral NEAR/3 antiviral*):ab,ti
#37 'antivirus agent'/exp
#38 'antimetabolite'/exp
#37 'aciclovir'/exp
#39 acerpes:ab,ti OR acevir:ab,ti OR acg:ab,ti OR acic:ab,ti OR acicloftal:ab,ti OR aciclor:ab,ti OR aciclosina:ab,ti OR aciclostad:ab,ti OR acyclovir*:ab,ti OR acihexal:ab,ti OR 'acilax cream':ab,ti OR acitop:ab,ti OR acivir:ab,ti OR 'acivir eye':ab,ti OR aclova:ab,ti OR aclovir:ab,ti OR aclovirax:ab,ti OR activir:ab,ti OR acv:ab,ti OR 'acyclo v':ab,ti OR acycloguanosine:ab,ti OR acyclovidar:ab,ti OR acylene:ab,ti OR acyron:ab,ti OR acyrova:ab,ti OR acyvir:ab,ti OR apicol:ab,ti OR avirax:ab,ti OR avorax:ab,ti OR azovir:ab,ti OR bearax:ab,ti OR 'bw 248u':ab,ti OR bw248u:ab,ti OR cicloferon:ab,ti OR cicloviral:ab,ti OR cicloviran:ab,ti OR clovicin:ab,ti OR clover:ab,ti OR cloviran:ab,ti OR colsor:ab,ti OR cusiviral:ab,ti OR cyclivex:ab,ti OR cyclomed:ab,ti OR cyclorax:ab,ti OR cyclostad:ab,ti OR cyclovir:ab,ti OR cycloviran:ab,ti OR cyllanvir:ab,ti OR danovir:ab,ti OR deherp:ab,ti OR dravyr:ab,ti OR dumophar:ab,ti OR duvimex:ab,ti OR eduvir:ab,ti OR entir:ab,ti OR erlvirax:ab,ti OR eurovir:ab,ti OR exavir:ab,ti OR expit:ab,ti OR genvir:ab,ti OR herpefug:ab,ti OR herpetad:ab,ti OR herpex:ab,ti OR herpofug:ab,ti OR inmerax:ab,ti OR innovirax:ab,ti OR isavir:ab,ti OR juviral:ab,ti OR laciken:ab,ti OR leramex:ab,ti OR lermex:ab,ti OR lesaclor:ab,ti OR libravir:ab,ti OR lisovyr:ab,ti OR lover:ab,ti OR lovire:ab,ti OR maclov:ab,ti OR marvir:ab,ti OR matrovir:ab,ti OR maynor:ab,ti OR medovir:ab,ti OR norum:ab,ti OR olvit:ab,ti OR oppvir:ab,ti OR opthavir:ab,ti OR poviral:ab,ti OR proviral:ab,ti OR qualiclovir:ab,ti OR quavir:ab,ti OR ranvir:ab,ti OR raxclo:ab,ti OR 'supra vir':ab,ti OR supraviran:ab,ti OR syntovir:ab,ti OR vacrax:ab,ti OR vacrovir:ab,ti OR vicorax:ab,ti OR viraban:ab,ti OR viralex:ab,ti OR 'viralex ds':ab,ti OR virax:ab,ti OR vircella:ab,ti OR virest:ab,ti OR virex:ab,ti OR virless:ab,ti OR viroclear:ab,ti OR virogon:ab,ti OR virolan:ab,ti OR virolex:ab,ti OR viromed:ab,ti OR vironida:ab,ti OR viropump:ab,ti OR virules:ab,ti OR virupos:ab,ti OR viruseen:ab,ti OR vivir:ab,ti OR warviron:ab,ti OR 'wellcome 248 u':ab,ti OR zaclovir:ab,ti OR zetavir:ab,ti OR 'zeven cream':ab,ti OR zevin:ab,ti OR zoral:ab,ti OR zorax:ab,ti OR zorel:ab,ti OR zoter:ab,ti OR zovir:ab,ti OR zovirax:ab,ti OR zoylex:ab,ti OR zumasid:ab,ti OR zyclir:ab,ti OR zyvir:ab,ti OR aciclovir:ab,ti OR 'wellcome 248u':ab,ti OR wellcome248u:ab,ti OR 'aci sanorania':ab,ti OR aciclobeta:ab,ti OR acifur:ab,ti OR 'acipen solutab':ab,ti OR 'antiherpes crème':ab,ti OR clonorax:ab,ti OR herpotern:ab,ti OR herpoviric:ab,ti OR mapox:ab,ti OR maynar:ab,ti OR milavir:ab,ti OR viclovir:ab,ti OR vipral:ab,ti OR viraxpuren:ab,ti OR virherpes:ab,ti OR virmen:ab,ti OR virzin:ab,ti OR zoliparin:ab,ti OR acivirax:ab,ti
#40 'ganciclovir'/exp
#41 ganciclovir:ab,ti OR gancyclovir:ab,ti OR 'b 759 u':ab,ti OR 'b 759u':ab,ti OR b759u:ab,ti OR 'biolf 62':ab,ti OR biolf62:ab,ti OR 'bw 759':ab,ti OR 'bw 759 u':ab,ti OR 'bw 759u':ab,ti OR 'bw 759u77':ab,ti OR 'bw b759u':ab,ti OR bw759:ab,ti OR bw759u:ab,ti OR bw759u77:ab,ti OR 'bwb 759 u':ab,ti OR 'bwb 759u':ab,ti OR bwb759u:ab,ti OR cameven:ab,ti OR cymevan:ab,ti OR cymeven:ab,ti OR cymevene:ab,ti OR cytovene:ab,ti OR denocin:ab,ti OR denosine:ab,ti OR dihydroxypropoxymethylguanine:ab,ti OR 'rs 21592':ab,ti OR rs21592:ab,ti OR virgan:ab,ti OR vitrasert:ab,ti OR zirgan:ab,ti
#42 'valaciclovir'/exp
#43 valacyclovir:ab,ti OR valaciclovir:ab,ti OR 256u:ab,ti OR 'l valylacyclovir':ab,ti OR 256u87:ab,ti OR 'bw 256u87':ab,ti OR bw256u87:ab,ti OR rapivir:ab,ti OR vacv:ab,ti OR valciclovir:ab,ti OR valcyclor:ab,ti OR valcyclovir:ab,ti OR valtrex:ab,ti OR zelitrex:ab,ti
#44 'penciclovir'/exp
#45 penciclovir:ab,ti OR denavir:ab,ti OR vectavir:ab,ti OR 'brl 39123':ab,ti OR 'brl 39123a':ab,ti OR brl39123:ab,ti OR brl39123a:ab,ti
#46 'famciclovir'/exp
#47 famciclovir:ab,ti OR famvir:ab,ti OR 'brl 42810':ab,ti OR brl42810:ab,ti OR famtrex:ab,ti OR oravir:ab,ti OR pentavir:ab,ti
#48 '5 (2 bromovinyl) 2` deoxyuridine'/exp
#49 brivudine:ab,ti OR '5-bvdu':ab,ti OR brivudin:ab,ti OR bromovinyldeoxyuridine:ab,ti OR brvudr:ab,ti OR bvdu:ab,ti OR helpin:ab,ti OR 'sc 38394':ab,ti OR sc38394:ab,ti OR zostex:ab,ti
#50 'foscarnet'/exp
#51 foscarnet:ab,ti OR 'phosphonoformic acid':ab,ti OR foscavir:ab,ti OR phosphonoformate:ab,ti
#52 'deoxyuridine'/exp
#53 deoxyuridine:ab,ti OR desoxyuridine:ab,ti OR 'uracil deoxyriboside':ab,ti
#54 'idoxuridine'/exp
#55 idoxuridine:ab,ti OR '5 iodo 2 deoxy uridine':ab,ti OR '5 iodo 2 deoxyuridine':ab,ti OR '5 iodo 2 desoxy uridine':ab,ti OR '5 iodo 2 omega deoxyuridine':ab,ti OR '5 iododeoxyuridine':ab,ti OR '5 iododesoxyuridine':ab,ti OR '5 iodoxyuridine':ab,ti OR '8 iododeoxyuridine':ab,ti OR 'allergan 211':ab,ti OR 'apridin gel':ab,ti OR 'citol idoxuridina':ab,ti OR dendrid:ab,ti OR 'desoxy 5 iodouridin':ab,ti OR 'gel v pos':ab,ti OR herpid:ab,ti OR herpidu:ab,ti OR herplex:ab,ti OR idina:ab,ti OR idoxene:ab,ti OR idu:ab,ti OR iducutit:ab,ti OR idulea:ab,ti OR idur:ab,ti OR iduridin:ab,ti OR iduridine:ab,ti OR idurivan:ab,ti OR idustatin:ab,ti OR iduviran:ab,ti OR 'iodo deoxyuridine':ab,ti OR iododeoxyuridine:ab,ti OR iododesoxyuridine:ab,ti OR iodoxuridine:ab,ti OR iodoxyuridine:ab,ti OR 'isotic ixodine':ab,ti OR iudr:ab,ti OR kerecid:ab,ti OR kerecide:ab,ti OR 'nsc 39661':ab,ti OR nsc39661:ab,ti OR 'oftan idu':ab,ti OR oftanidu:ab,ti OR ridinox:ab,ti OR spectanefran:ab,ti OR stoxil:ab,ti OR synmiol:ab,ti OR virexen:ab,ti OR virpex:ab,ti OR virunguent:ab,ti OR virusan:ab,ti OR zostrum:ab,ti
#56 'trifluridine'/exp
#57 trifluridine:ab,ti OR trifluoridine:ab,ti OR '5 trifluoromethyl 2 deoxyuridine':ab,ti OR '5 trifluoromethyl 2 desoxy uridine':ab,ti OR '5 trifluoromethyl deoxyuridine':ab,ti OR '5 trifluoromethyldeoxyuridine':ab,ti OR aflomin:ab,ti OR bephen:ab,ti OR ocufridine:ab,ti OR tft:ab,ti OR thriherpine:ab,ti OR triflumann:ab,ti OR 'trifluor thymidine':ab,ti OR 'trifluoro thymidine':ab,ti OR trifluorodeoxythymidine:ab,ti OR trifluorothymidine:ab,ti OR triherpin:ab,ti OR triherpine:ab,ti OR viromidin:ab,ti OR virophta:ab,ti OR viroptic:ab,ti
#58 #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57
#59 #32 AND #35 AND #58

Appendix 4. LILACS search strategy

((Herpe$ or MH:C02.256.466.382.465$ or MH:C02.325.465$ or MH:C11.204.564.425$ or MH:C11.294.800.475$ or simplex) and (cornea$ or kerati$ or querati$ or ceratit$ or dendr$ or MH:C02.256.466.382.465.450$ or MH:C02.325.465.450$ or MH:C11.204.564.425.450$ or MH:C11.294.800.475.450$ or ocular)) and (Acyclovir or Aciclovir or Acycloguanosine or MH:D03.438.759.758.399.454.250$ or Ganciclovir or Valacyclovir or penciclovir or famciclovir or brivudine or Foscarnet  or Phosphonoformate or "phosphonoformic acid" or MH:D02.241.081.018.677.250$ or MH:D02.705.429.875.500$ or Deoxyuridine or "Deoxyuracil Nucleotides" or "Nucleótidos de Desoxiuracil" or "Nucleotídeos de Desoxiuracil" or MH:D03.383.742.686.850.210$ or MH:D13.695.201.200$ or MH:D13.695.740.850.210$ or Idoxuridine or Idoxuridina or Iododeoxyuridine or IUdR or MH:D03.383.742.680.852.300.400$ or MH:D13.570.230.430.609$ or MH:D13.570.685.852.300.400$ or Antimetabolites or Antimetabolitos or MH:D27.505.519.186$ or MH:D27.888.569.042$ or Antiviral Agents or Antiviral$ or Antivirais  or Antivirus or MH:D27.505.954.122.388$ or Trifluridine or Trifluridina or Trifluorothymidine or MH:D03.383.742.680.705.900$ or MH:D13.570.230.855.900$ or MH:D13.570.685.705.900$)

Appendix 5. metaRegister of Controlled Trials search strategy

herpe* simplex AND keratitis

Appendix 6. ClinicalTrials.gov search strategy

(herpes OR simplex) AND (corneal OR keratitis OR dendritic OR ocular)

Appendix 7. ICTRP search strategy

herpes OR simplex = Condition AND keratitis = Intervention

Contributions of authors

Conceiving the protocol: Paola de la Parra-Colin.
Designing the protocol: all authors.
Writing the protocol draft: Paola de la Parra-Colin.
Providing general advice and substantive feedback on the protocol: all authors.
Final approval of the protocol: all authors.

Declarations of interest

None known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Grant 1 U01 EY020522-01, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.

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