out_23.pdf

Treatment of Viral Conjunctivitis withAntiviral DrugsChrysanthi L. Skevaki,1 Ioanna E. Galani,2 Michail V. Pararas,1 Konstantina P. Giannopoulou3

and Athanassios Tsakris1

1 Department of Microbiology, School of Medicine, University of Athens, Athens, Greece

2 Center of Immunology & Transplantation, Biomedical Research Foundation of the Academyof Athens, Athens, Greece

3 First Department of Ophthalmiatrion Athinon, Athens Eye Hospital, Athens, Greece

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3311. Methods of Literature Review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

1.1 Literature Search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3331.2 Study Selection and Eligibility Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3331.3 Data Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

2. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3332.1 Aciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3332.2 Cidofovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3372.3 Famciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3392.4 Idoxuridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3412.5 Interferons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3412.6 RNA Interference. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3422.7 Trifluridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3422.8 Valaciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3422.9 Other Compounds Tested in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3432.10 Other Compounds Tested in Animal or In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

Abstract Viral conjunctivitis is one of the most common disorders observed inophthalmic emergency departments, yet no established treatment exists. Lately,antiviral medications have been introduced into clinical practice; however,a systematic review focusing on their use and effectiveness in the treatmentof viral conjunctivitis has not been previously reported. We systemically re-viewed the literature to identify studies where antiviral drugs were used totreat viral conjunctivitis. Currently, aciclovir, trifluridine and valaciclovir arecommonly used as antiviral agents to treat herpesvirus infections. Cidofovirhas been used successfully to treat some cases of adenoviral conjunctivitis,although toxicity has also been reported. The use of other medications,such as idoxuridine, has been minimized in clinical practice due to theirhigh toxicity. Interestingly, most of the antiviral drugs developed are usedto treat herpesvirus infections, while less progress has been made in the field

REVIEWARTICLE Drugs 2011; 71 (3): 331-3470012-6667/11/0003-0331/$55.55/0 2011 Adis Data Information BV. All rights reserved.

of adenoviral infections. For other viral causes of conjunctivitis, no effec-tive remedy is currently available, and treatment focuses on the relief ofsymptoms. Caution should be exercised when coadministering other phar-macological agents, such as corticosteroids, because of emerging adverseeffects.

Conjunctivitis, commonly known as red eye,is one of the most frequent ocular disorders ob-served in ophthalmic emergency departments.[1,2]

Possible causes include an allergic reaction oran infection of viral or bacterial origin. Acuteviral conjunctivitis is commonly caused by var-ious serotypes of adenoviruses, but herpesvirusesand varicella-zoster virus, which are DNA viruses,and the RNA viruses picornaviruses, such asenterovirus serotype 70 (EV70) and coxsackie-virus A24 variant (Cox A24), are also causes.[3]

Other less frequent causes of viral conjunctivitisusually occur in association with a systemic ill-ness and include infections caused by the DNAvirus Epstein-Barr virus, and the RNA virusesinfluenza virus, paramyxovirus (e.g. Newcastledisease virus), rubella virus and HIV.

Viral conjunctivitis is usually a benign andself-limiting condition that may heal within a fewweeks, and can affect all ages. Nevertheless, it canbe highly infectious and has been the cause ofepidemic outbreaks worldwide,[4-8] thus constitut-ing a major public health problem. Inflammationof the conjunctiva can also occur in combinationwith corneal inflammation and subepithelial in-filtrates, most commonly caused by adenovirusserotypes 8, 19 and 37, causing severe adenoviralkeratoconjunctivitis and epidemics.[9] Epidemicconjunctivitis due to viruses is also a commonnosocomial infection.[10-12] Local care and inter-ventions to minimize transmission are thus the cor-nerstones for management for viral conjunctivitis.

Among infectious causes of conjunctivitis,viral conjunctivitis is the most common and, insome cases, coincides with a viral upper respira-tory tract infection, with or without the presenceof purulent discharges. Allergic conjunctivitis maybe seasonal or perennial, and is mostly character-ized by itching and watery discharges. The patientshistory, the presence of signs, such as vesicles,ulcerations, crusting, discharge and chemosis,

during physical examination, as well as labora-tory tests, assist in the definitive diagnosis of thecausative agent.[1]

Currently, there is no specific treatment forviral conjunctivitis. Symptomatic relief may beachieved with cool compresses and artificial tears.For severe cases of conjunctivitis and keratitis,topical corticosteroid drops are prescribed for therelief of symptoms caused by inflammation. How-ever, prolonged use of corticosteroids increasesthe risk of adverse effects.

Recent advances in the field of infectious con-junctivitis have introduced new diagnostic meth-ods and novel therapeutic agents. Serological tests,ELISA, electron microscopy and polymerasechain reaction techniques have been used for thelaboratory identification of specific viral strainsthrough direct inspection or detection of theirantigens and antibodies. Such methodologies, incombination with the use of antiviral medica-tions, offer an alternative therapeutic approachthat directly targets viral replication.

Viral replication takes place inside the infectedhost cells. DNA viruses, in general, replicate in-side the cell nucleus and, in many cases, dependon the host cell cycle, while RNA viruses replicateprimarily in the cytoplasm, and their replicationis not so strictly dependent on the host cell cycle.Viruses may rely on the host polymerases fortheir replication, or they can encode their ownpolymerases, such as adenoviruses, herpesvirusesand most RNA viruses. Most antiviral drugs arenucleoside or nucleotide analogues that inhibitviral replication by acting as chain terminatorsduring DNA or RNA synthesis. Analoguescompete with the natural substrates, and whenadded in the newly synthesized DNA or RNAchain, they do not offer a binding position for aphosphodiester bond with the next nucleotide.[13]

The rapidly increasing number of antiviral agentsis quite promising; however, the efficacy of many

332 Skevaki et al.

2011 Adis Data Information BV. All rights reserved. Drugs 2011; 71 (3)

of these drugs in treating viral conjunctivitis isstill elusive. Furthermore, some of these medica-tions have adverse effects.

The goal of this review is to evaluate ther-apeutic regimens for viral conjunctivitis that arecurrently used in clinical practice or are underdevelopment. We have thus summarized in-formation on antiviral drugs that have been usedto treat viral conjunctivitis or have been tested inexperimental systems, and which may prove use-ful for the physician.

1. Methods of Literature Review

1.1 Literature Search

We systematically searched the MEDLINEdatabase using PubMed up to December 2010.The keywords used were MESH terms: viralconjunctivitis and antiviral drugs. Referencesof relevant articles were also hand-searched.

1.2 Study Selection and Eligibility Criteria

Studies were selected if they included clinicaldata or experimental animal data on the effect ofantiviral drugs for the treatment of viral con-junctivitis. In addition, in vitro experimental dataon the effect of antiviral drugs on the replicationof clinically relevant viruses were included. Reviewarticles were excluded, but were manually screenedfor additional references. Finally, studies wereonly included if written in English, German,French or Italian.

1.3 Data Evaluation

Studies including clinical or animal experi-mental data were evaluated according to thestudy population, the type of infection, the anti-viral agent used, the dosage regimen administeredand the outcome of the disease. The in vitroexperimental data were analysed based on theantiviral agent in use, the method by which theeffectiveness of the antiviral agent was determined,and the outcome of the experiment. The datawere evaluated and are presented herewith basedon the PRISMA statement for reporting system-atic reviews and meta-analyses.[14]

2. Results

The process of study selection is depicted as aflow diagram, according to PRISMA, in figure 1.Initially, 110 articles were identified. In addition,17 articles were also included via a hand-search ofreferences. A total of 56 studies, published be-tween August 1969 and August 2010, were finallyincluded in this review. Among the studies fur-ther analysed in the present review, 27 were clin-ical studies, 17 were animal studies and 12 werein vitro studies. We present the results of our re-view based on the antiviral agent used in alpha-betical order. In addition, tables I, II and IIIsummarize the clinical data, the animal and thein vitro experimental studies, respectively.

2.1 Aciclovir

Aciclovir is a guanosine analogue with anti-viral properties. It is inactive until it becomesphosphorylated by viral thymidine kinase, thus itdoes not affect uninfected cells. After phosphor-ylation, aciclovir is incorporated into viral DNAand blocks its replication. It is an establishedtreatment for herpes simplex virus (HSV) infec-tions, which is administered topically, orally orintravenously. Six studies were identified in theliterature as using aciclovir in the treatment ofconjunctivitis.[15-20] Three were clinical trials[15-17]

and three were case reports.[18-20]

In one clinical trial, 71 non-immunocompro-mised patients with herpes zoster ophthalmicuswere treated with a 10-day course of oral aciclovir(600mg five times daily). Aciclovir was well tol-erated and significantly reduced the incidenceand severity of complications of the infection.[15]

In addition, the long-term oral aciclovir admin-istration (12 months) for the treatment of ocularHSV infection was effective in decreasing virusrecurrence.[16] Another clinical trial comparedtopical versus oral aciclovir treatment for earlyherpes zoster ophthalmicus. Fifty-seven patientsreceived either topical aciclovir ointment or oralaciclovir 800mg, both five times daily for 7 days,and were followed up for 12 months. The studyconcluded that patients receiving topical aciclovirexhibited more ocular complications than the

Antiviral Treatment for Viral Conjunctivitis 333


orally treated group.[17] In a case report study, a95-year-old woman diagnosed with ophthalmiczoster sine herpete was effectively treated withintravenous aciclovir given at 10mg/kg threetimes daily for 3 days, followed by oral aciclovirat 800mg five times daily for 14 days.[18] A14-year-old girl who presented with Parinaudsoculoglandular syndrome, an uncommon mani-festation of primary HSV type 1 (HSV-1) infec-tion, was treated with oral and local aciclovir thatallowed improvement of her symptoms.[19] Fi-nally, a 17-year-old man was treated with acic-lovir ointment 3% w/w four times daily, togetherwith antibacterials and corticosteroids, in orderto treat a suspected herpesvirus infection; treat-ment with aciclovir was interrupted after 2 days,when it was determined that keratoconjunctivitis

was due to the coexistence of adenoviral andAcanthamoeba infection.[20]

A study involving rabbits showed that a 3%aciclovir ointment applied topically one to fivetimes daily during an acute ocular HSV infectionwas beneficial in reducing conjunctivitis occur-rence among other ophthalmic complications,but was not effective in preventing conjunctivitiswhen applied 24 hours after viral inoculation. Inaddition, aciclovir was not effective in eradicatingestablished latent HSV infection.[42]

Despite its inability to eradicate latent infec-tion,[71] therapeutic and/or prophylactic admin-istration of aciclovir is considered a standardantiviral therapy for several manifestations ofHSV infection. In addition to aciclovir, twosecond-generation antiviral agents, famciclovir

Iden

tifica

tion

Scre

enin

gEl

igib

ility

Incl

uded

110 articles identified throughPubMed search

17 additional articles identifiedthrough hand-search

100 articles screened

56 full-text articlesassessed for eligibility

56 articles included inqualitative synthesis

44 full-text articles excludedbecause of no relevancy toantiviral treatment or viral conjunctivitis Focus on other disease (n = 19) No treatment mentioned (n = 19) Non-antiviral therapy used (n = 3) Reviews (n = 3)

27 articles excluded No abstract available (n = 12) Articles written in non-eligible

languages (n = 15)

127 total articles

Fig. 1. Flow diagram of the selection process of articles eligible for inclusion in this review.

334 Skevaki et al.


Table I. Summary of clinical data on therapeutic regimens used to treat viral conjunctivitis

Study (year) Infectious agent Drug Treatment Study groups Efficacya

Cobo et al.[15]

(1986)

HZO Aciclovir Oral 600mg, five times daily

for 10 d

Aciclovir vs placebo (n =71) Well tolerated, reduced incidenceand severity

Uchoa et al.[16]

(2003)

HSV Aciclovir Oral 400mg, twice daily for

12 or 18mo

Aciclovir 12mo (n= 18) vs 18mo(n =22)

Decrease in virus recurrence after

long-term treatment

Neoh et al.[17]

(1994)

HZO Aciclovir Topical ointment or oral

800mg, both five times

daily for 7 d

Topical vs oral (n =57) More ocular complications inthe topically treated group

Goon et al.[18]

(2000)

HZO Aciclovir IV 10mg/kg, three times dailyfor 3 d, then oral 800mg,

five times daily for 14 d

n =1 Efficient treatment

Parentin

et al.[19] (2007)

HSV-1 Aciclovir Oral and local n =1 Improvement of symptoms

Gajdatsy

et al.[20] (2000)

Adenovirus and

Acanthamoeba

Aciclovir, antibacterials

and corticosteroids

Topical ointment 3% w/w,four times daily for 2 d

n =1 Aciclovir treatment wasinterrupted when infectious

agent was determined

Gordon et al.[21]

(1996)

Adenovirus Cidofovir Topical eye drops 0.2%,four times daily for 8 d

n =1 Resolution of clinical sings in theinfected eye, prophylaxis from

infection in the noninfected eye

Castleton and

Kottaridis[22]

(2007)

Adenovirus

subgroup D

Cidofovir IV 1mg/kg, three times weeklyfor 4wk

n =1 Successful treatment

Hillenkamp

et al.[23] (2001)

Adenovirus Cidofovir, ciclosporin or

cidofovir + ciclosporinTopical eyedrops 0.2% (1%ciclosporin eye drops), four

times daily for 21 d

Cidofovir vs ciclosporin vs

cidofovir + ciclosporin vs sodiumchloride (control) [n =39]

No acceleration of resolution vs

natural course in any of the

therapeutic regimens

Hillenkamp

et al.[24] (2002)

Adenovirus Cidofovir, ciclosporin or

cidofovir + ciclosporinTopical eyedrops 1%, fouror ten times daily (1%ciclosporin 1% eyedropsfour times daily) for 21 d

Cidofovir four times daily (n= 9) vs cidofovirten times daily (n= 5) vs cidofovir andciclosporin four times daily (n= 10) vssodium chloride four times daily (control)

[n = 10]

Cidofocir treatment led to

reduction in the frequency of

corneal opacities, but was

accompanied by adverse effects

Tyring et al.[25]

(2001)

HZO Famciclovir or aciclovir Oral 500mg, three times daily

for 7 d (famciclovir); oral

800mg, five times daily for 7 d

(aciclovir)

Famciclovir (n = 251) vs aciclovir(n =203)

The two drugs had equal

efficiency, but famciclovir provided

a better dosing regimen

Dudgeon

et al.[26] (1969)

Adenovirus Idoxuridine Topical ointment 0.5%, every3 h during the day and every

6 h during the night for 7 d

Idoxuridine (n= 35) vs placebo (n =35) No beneficial effect of idoxuridineover placebo

Continued next page

Antiv

iralTreatm

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Table I. Contd

Study (year) Infectious agent Drug Treatment Study groups Efficacya

Adams et al.[27]

(1984)

Adenovirus Plasmid-derived

IFNa-2ND IFNa-2 vs placebo (n = 14) No effect on disease duration

or virus shedding

Romano

et al.[28] (1980)

Adenovirus HuIFNb orcorticosteroids

Topical 12 105 referenceunits daily divided into 810

drops

HuIFNb vs corticosteroids vs placebo Reduction in length of disease inHuIFNb-treated groups

Wilhelmus

et al.[29] (1987)

Adenovirus HuIFNb Topical 7.5 105 IU/mL,five times daily for 1wk

HuIFNb vs placebo (n =37) Improvement only when left eyeswere infected

Hutter[30] (1990) Ad8 IFNa or trifluridine orpovidine-iodine or

combinations

ND n =150 Best results observed withpovidone-iodine

Rossa and

Sundmacher[31]

(1991)

ND IFN Topical eye drops, once daily

for 12 d

n =130 Prevention of highly contagiousviral keratoconjunctivitis

Romano and

Sadan[32]

(1988)

Adenovirus, HZO or

HSV-1

HuIFNb Topical cream 20000 IU/g(for HSV-1 and HZO);

topical eye drops

500 0001000 000U

(for Ad and HSV-1)

ND Efficient in prophylaxis and

duration of disease when applied

early during infection

Ward et al.[33]

(1993)

ND Trifluridine or

dexamethasone or

artificial tears

Topical eye drops n =74 No beneficial effect of trifluridineover other regimens

Colin and

Chastel[34]

(1985)

HSV-1 Trifluridine Topical eye drops 1% n =6 Successful treatment

Hu et al.[35]

(2004)

Vaccinia virus Trifluridine and

vaccinia immune

globulin

Topical eye drops 1% for 14 d(trifluridine); IV single-dose

vaccinia immune globulin

n =1 Successful treatment

Fillmore et al.[36]

(2004)

Vaccinia virus Trifluridine or

trifluridine + vacciniaimmune globulin

Topical eye drops 1%(trifluridine); IV single-dose

vaccinia immune globulin

Trifluridine (n= 10) vs trifluridine +vaccinia immune globulin (n= 1)

Successful treatment

Wander[37]

(1984)

HSV Trifluridine Topical eye drops, several

times daily

NA Prophylactic treatment in immune

suppressed patients

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(see section 2.3) and valaciclovir (see section 2.8),have recently been introduced in clinical practicefor the treatment of viral conjunctivitis caused byherpesviruses.

2.2 Cidofovir

Cidofovir, also known as HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine],is an acyclic nucleoside phosphonate, which hasbeen used for the treatment of cytomegalovirusretinitis in patients with AIDS. Maintenancetherapy with cidofovir involves an infusion onlyonce every 2 weeks, making it a convenient treat-ment option. Two case reports[21,22] and two clinicaltrials[23,24] assessing the effect of cidofovir in viralconjunctivitis were identified.

The first case report involved a 31-year-oldwoman who was treated with cidofovir for ade-noviral conjunctivitis. Cidofovir was used as a0.2% solution four times daily for 8 days, result-ing in resolution of clinical signs and symptoms inthe infected eye, and preventing spread of infec-tion in the uninfected eye.[21] In the second casereport, a 44-year-old man with haemorrhagicadenoviral keratoconjunctivitis was successfullytreated with intravenous cidofovir 1mg/kg threetimes weekly for 4 weeks.[22] In a clinical trial,cidofovir was used as 0.2% eye drops alone, or incombination with 1% ciclosporin eye drops fourtimes daily for a period of 21 days, to treat 39 pa-tients with acute adenoviral keratoconjunctivitis.The use of cidofovir and ciclosporin alone or co-administered did not accelerate the improvementof clinical symptoms of acute adenoviral kerato-conjunctivitis compared with the natural courseof the infection.[23] In a second clinical study con-ducted by the same research team, 34 patients withrecent onset of acute adenoviral keratoconjunctivi-tis were treated using a higher dose of topical cido-fovir (1%) with or without 1% ciclosporin for21 days. The higher dose of cidofovir lowered thefrequency of severe corneal opacities, but was ac-companied by local adverse effects, such as erythemaof the lids and injection of the conjunctiva.[24]

In vitro, cidofovir and other nucleoside mono-phosphate analogues, such as HPMPA [(S)-9-(3-hydroxy-2-phosphonomethoxypropyl)adenine]Ta

bleI.Contd

Study(year)

Infectiousagent

Drug

Treatm

ent

Studygroups

Efficacya

Zaaletal.[38]

(2001)

VZV

Valaciclovir

Oral1000mg,threetimesdaily

for10d

n=21

Resolutionofvirusinfection,not

complete

resolutionof

inflammation

Colin

etal.[39]

(2000)

HZO

Valacicloviroraciclovir

Oral1000mg,threetimesdaily

for7d(valaciclovir);oral

800mg,fivetimesdaily

for7d

(aciclovir)

Valaciclovir(n=56)vsaciclovir(n=54)

Both

drugsequally

welltolerated

andeffectiveinpreventingocular

complications;valaciclovir

providedabetterdosingscheme

Teuchner

etal.[40](2005)

Ad3,Ad4,Ad8,

Ad19andAd37,

enterovirusesor

staphylococci

N-chlorotaurineor

gentamicin

Topicaleyedrops1%

for7d

N-chlorotaurine(n=33)vs

gentamicin(n=27)

N-chlorotaurinewaswelltolerated

andshortenedthedurationof

illness

Pelletieretal.[41]

(2009)

Adenovirus

Povidone-iodineand

dexamethasone

Topicaleyedrops0.4%

povidone-iodine/0.1%

dexamethasone,fourtimes

daily

for5d

n=6

Clinicalresolutionanddecrease

inviraltitre

aBasedonthestatementsoftheauthors.

Ad=adenovirusserotype;HSV=herpessimplexvirus;HuIFN=humaninterferon;HZO=herpeszosterophthalmicus;IFN=interferon;IV=intravenous;NA=notapplicable;

ND=notdeterm

ined;VZV=varicella

zostervirus.



Table II. Summary of antiviral regimens for viral conjunctivitis tested in experimental animal models

Study (year) Experimental

animal model

Infection agent Drug Treatment Efficacya

Trousdale and

Nesburn[42]

(1982)

New Zealand

white rabbit

HSV-1 parent McKrae

strain and idoxuridine- or

vidarabine-resistant

variants

Aciclovir, idoxuridine or

vidarabine

Topical, eye drops 3%, 15 timesdaily; IV 50mg/kg, twice daily(aciclovir)

Aciclovir reduced conjunctivitis occurrence

only when applied prophylactically; IV

aciclovir suppressed infection in the nervous

system

Romanowski

et al.[43] (2001)

New Zealand

white rabbit

Ad5 clinical isolate Cidofovir or placebo Topical, eye drops 0.5% or 1%,twice daily for 7 d

Reduction in viral titres only when applied

prophylactically; no ocular toxicity was

observed

Gordon

et al.[44] (1994)

New Zealand

white rabbit

Ad5 clinical isolates Cidofovir or placebo Topical, eye drops 0.1% or 0.2%,29 times daily for up to 10 d

Reduction in viral titres and duration of

shedding when applied therapeutically;

ocular toxicity was observed in high doses

Romanowski

et al.[45] (1997)

New Zealand

white rabbit

Ad5 clinical isolate Cidofovir, cidofovir +corticosteroids or placebo

Topical, eye drops 1%, twice daily for3 d (cidofovir); topical, eye drops 1%,four times daily for 14 d

(corticosteroids)

Cidofovir reduced viral titres and duration of

shedding when applied therapeutically.

Corticosteroids reversed the antiviral activity

of cidofovir

Romanowski

et al.[46] (2001)

New Zealand

white rabbit

Ad5 prototype VR-5 strain

and three in vitro isolated

cidofovir-resistant

variants

Cidofovir or placebo Topical, eye drops 0.5%, twice dailyfor 7 d

Significant antiviral activity against parental

but not resistant isolates

Kaneko

et al.[47] (2004)

Cotton rat Ad5 prototype Cidofovir or placebo Topical, eye drops 1%, twice dailyfor up to 14 d

Reduction in viral titres when applied

therapeutically

Fontenelle

et al.[48] (2008)

Cat FHV-1 Cidofovir or placebo Topical, eye drops 0.5%, twice dailyfor 10 d

Decrease in viral shedding and severity

of disease

Inoue et al.[49]

(2009)

Japanese

white rabbit

Absence of infection Cidofovir, zalcitabine,

stavudine or placebo

Topical, eye drops 1%, four timesdaily for 14 d

Adverse effects observed: redness

of eyelids and conjunctival injection by all

drugs; narrowing of lacrimal canaliculus by

cidofovir

Malik et al.[50]

(2009)

Cat FHV-1 Famciclovir Oral 62.5mg (~15mg/kg), once dailyfor 7 d, then twice daily for 736d

Well tolerated, positive impact on the

condition

Tokumaru[51]

(1975)

Hamster and

rabbit

HSV and vesicular

stomatitis virus

Tilorone dihydrochloride

as IFN inducer

Topical solution Improvement in conjunctivitis occurrence

Bitko et al.[52]

(2007)

BALB/cmouse

RSV siRNA against RSV Topical solution 1 nmol dose given

once

Prevented infection when applied

prophylactically but not therapeutically

Stiles[53]

(1995)

Cat FHV-1 Idoxuridine, vidarabine,

trifluridine, antibacterials,

atropine, corticosteroids or

human IFNa

Topical (for all antiviral agents);

oral (human IFNa)Difficult to determine superiority of the

various antiviral treatments

Mohanty

et al.[54] (1980)

Calf Bovine rhinotracheitis

virus

2-deoxy-D-glucose Topical solution Reduced severity of disease when applied

prophylactically and therapeutically

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htsreserved.

Drugs2011;71(3)

and 20-nor-cyclic guanosine monophosphate, havedemonstrated significant inhibitory activity againstcommon clinical ocular isolates and standardadenoviral serotypes (1, 5, 8 and 19) related toviral conjunctivitis.[59] In addition, in a series ofexperiments in the New Zealand rabbit ocularmodel, topical administration of cidofovir sig-nificantly reduced adenovirus serotype 5 (Ad5)ocular titres and shortened the duration of shed-ding in comparison with control eyes when admin-istered prophylactically[43] or after an establishedAd5 infection.[44,45] In one of these studies, com-bined treatment with corticosteroids significantlyreversed the antiviral activity of cidofovir;[45]

therefore, caution should be taken when treatingsymptomatic adenoviral ocular infection. In an-other study performed with the New Zealandrabbit ocular model, although topical cidofovirtreatment demonstrated significant antiviral activityagainst the parental Ad5 strain, three cidofovir-resistant variants of this virus were identified.[46]

The antiviral effect of cidofovir was also testedusing the cotton rat model for adenovirus sero-types 4, 8 and 37,[47] and with primary ocular felineherpesvirus-1 infection in cats,[48] where the in-hibitory effect of cidofovir on viral replicationwas confirmed. Finally, another study examinedthe possible adverse effects from the use of cido-fovir, as well as of zalcitabine and stavudine, whichhave been used for the treatment of HIV, in ade-novirus infections; a solution containing 1% ofeach aforementioned agent was administered aseye drops to healthy female Japanese albino rabbitsfour times daily for 14 days. Redness of eyelidsand conjunctival injection were observed in allstudy groups, while narrowing of the lacrimalcanaliculus was observed in the cidofovir group.[49]

2.3 Famciclovir

Famciclovir is a guanine analogue used for thetreatment of various herpesvirus infections, mostcommonly for herpes zoster. It is a prodrug formof penciclovir with improved oral bioavailability.Famciclovir displays the same antiviral spectrumas aciclovir in regards to herpesviruses. Only oneclinical study so far has reported famciclovir forthe treatment of viral conjunctivitis.[25]Ta

bleII.Contd

Study(year)

Experimental

animalmodel

Infectionagent

Drug

Treatm

ent

Efficacya

Brandt

etal.[55](1996)

BALB/c

mouse

HSV-1

KOSstrain

Peptidomimeticribonucleotide

reductaseinhibitororplacebo

Topicalcream

0.1%,1%

or5%,six

timesdaily

for3d,thenfourtimes

daily

for4d

Reducedseverityofinfectionandviral

sheddingatthehigherdoseused

Epstein

etal.[56](2006)

NewZealand

whiterabbit

Ad5prototypeVR-5

strain

Cobaltchelate

orplacebo

Topicalsolution25or50mg/m

L,

69timesdaily

for21d

Reduceddiseaseseverityandviraltitresby

allconcentrationsandfrequenciesusedvs

placebo

Trousdale

etal.[57](1994)

Cottonrat

Ad5wild-type300

Ganciclovirorplacebo

Topicaleyedrops0.3%,

1%

or3%

for21d

Decreaseinincidence,durationandvirus

titrewith3%

ganciclovir,althoughnot

statistically

significant

Romanowski

etal.[58](2009)

NewZealand

whiterabbit

Ad5clinicalisolate

ddC,cidofovirorplacebo

Topicaleyedrops2%

or3%,four

timesdaily

for7d(ddC);topical,eye

drops0.5%,twicedaily

for7d

(cidofovir)

ddCwasmore

efficientthancidofovirin

reducingviraltitresintheearlyphaseof

infection

aBasedonthestatementsoftheauthors.

Ad5=adenovirusserotype5;ddC=2

0 ,30 -dideoxycytidine;FHV=felineherpesvirus;HSV=herpessimplexvirus;IFN=interferon;IV=intravenous;RSV=respiratory

syncytialvirus;

siRNA=small-interferingRNA.



A large clinical study comprising of 454 pa-tients with ophthalmic herpes zoster of the tri-geminal nerve V1 branch took place in 87 centresworldwide and compared the efficacy and safetyof famciclovir with aciclovir. Famciclovir 500mgwas administered three times daily and aciclovir800mg five times daily, both orally for 7 days.The percentage of patients who experienced an

ocular manifestation, such as conjunctivitis, ker-atitis and glaucoma, during the study was similarfor the famciclovir and aciclovir groups, demon-strating that there was no difference between thetwo therapeutic agents. Nevertheless, as is the casewith valaciclovir, famciclovir provides patientswith a more convenient dosing regimen thanaciclovir.[25]

Table III. Summary of antiviral regimens for viral conjunctivitis tested in in vitro experimental systems

Study (year) Experimental system Infectious agent Drug Efficacya

Gordon et al.[59]

(1991)

A549 human alveolar epithelial

cells

Ad1, Ad5, Ad8

or Ad19

Cidofovir (HPMPC) or

HPMPA or 20-nor-cyclicGMP

Inhibition of viral replication;

cidofovir was the least toxic

Langford

et al.[60] (1988)

Changs human conjunctival

cells

Cox A24 Human IFNa or IFNb Both equally reduced virus infectionand production

Langford

et al.[61] (2003)

Human conjunctival and lens

cells

EV70 Rabbit or human serum

IFNaIFNa enhanced the protective effect ofserum, observed only in conjunctival cells

Langford

et al.[62] (1983)

WISH human amniotic

epithelial cells, Changs human

conjunctival cells and RK-13

rabbit kidney cells

Ad3, Cox

A24, EV70

or HSV-1(F)

Human IFNa, IFNb orIFNg antiviralantibodies

Synergistic effect of treatments in

reducing viral production, which was

dependent on the type of IFN

Jun et al.[63]

(2008)

Primary human conjunctival

cells

Cox A24 siRNA against the cis-

acting replication

element of Cox A24

Decrease of viral replication

Jun et al.[64]

(2011)

MRC5 human lung fibroblasts

and primary human

conjunctival cells

Cox A24 or

EV70

siRNA against the viral

polymerase 3D gene of

both viruses

Cytoprotective effect; decrease in viral

replication protein synthesis

Tan et al.[65]

(2008)

Human rhabdomyosarcoma

cells

EV70 siRNA against the viral

polymerase 3D gene of

EV70

Prevention of viral replication when the

siRNA was added prophylactically;

reduction of viral production when added

after infection

Monnerat

et al.[66] (2006)


cells

Ad8 Povidone-iodine Effective against free adenovirus but not

against intracellular adenoviral particles in

already infected cell; low cytotoxicity for

healthy cells

Uchio et al.[67]

(2007)


cells

Ad3, Ad4,

Ad8, Ad19

or Ad37

Zalcitabine, stavudine,

nevirapine, indinavir or

amprenavir

Zalcitabine and stavudine reduced

adenoviral replication

Langford

et al.[68] (1985)

WISH human amniotic

epithelial cells

Cox A24 or

EV70

Arildone, IFNb orArildone + IFNb

Arildone reduced viral replication and did

not affect IFN production; additive effect of

arildone and IFNb in reducing viral titres

Langford

et al.[69] (1995)

Changs human conjunctival,

Hep-2 laryngeal and glioma

cells

Cox A24 or

EV70

Benzimidazoles Inhibition of virus production and of the

viral cytopathogenic effect

Johansson

et al.[70] (2007)

Human corneal epithelial cells Ad37 Multivalent sialic acid

conjugated to HAS

or monosaccharidic

sialic acid

Multivalent sialic acid conjugated to HAS

was more efficient in preventing infection

of cells

a Based on the statements of the authors.

Ad =adenovirus serotype; Cox A24 = coxsackie virus A24 variant; EV70= enterovirus 70; GMP =guanosine monophosphate; HAS =humanserum albumin; HPMPC= (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; HPMPA= (S)-9-(3-hydroxy-2-phosphonomethoxypropyl)a-denine; HSV=herpes simplex virus; IFN= interferon; siRNA= small-interfering RNA.

340 Skevaki et al.


In addition, in a small-scale study (n = 10) onfeline herpesvirus-1-associated disease in cats,famciclovir was well tolerated and, in all cases,had a positive impact on the animals condition;however, no untreated controls or animals thatreceived another therapeutic regimen were in-cluded in the study.[50]

2.4 Idoxuridine

Idoxuridine, a modified form of deoxyuridine,is a nucleoside analogue, which is incorporatedinto viral DNA during replication and blocks basepairing. It is used as an anti-herpesvirus drug.Effective treatment of herpetic keratitis withidoxuridine was first reported in 1962,[72] and formany years idoxuridine was the only antiviral agentavailable for its treatment. We identified a clinicaltrial involving 70 patients with conjunctivitis whowere treated with 0.5% idoxuridine ointment orplacebo, applied several times daily for 7 days.Idoxuridine treatment did not have any influencein the typical course of the disease.[26] Idoxuridinetreatment has been reported to be associated withhigh toxicity. The adverse effects arising fromtopical application of idoxuridine have been re-viewed elsewhere.[73]

2.5 Interferons

Interferons (IFNs) are natural proteins pro-duced by cells in response to viral infection andaim to control viral spread. Our search identifiedsix clinical evaluations of the effect of IFNs inviral conjunctivitis.[27-32] Five of these were clinicaltrials[27-31] and one summarized clinical data.[32]

Plasmid-derived IFNa-2 or placebo was usedto treat a total of 14 patients with adenoviralconjunctivitis. The authors found no statisticallysignificant effect of the IFN used on diseaseduration or virus shedding, although they ob-served a tendency towards asymptomatic infec-tion in the second eye in the IFN-treated groupversus the control group.[27] Topical applicationof human fibroblast-derived IFNb (HuIFNb)was used in the treatment of epidemic kerato-conjunctivitis caused by an adenovirus. A total of12 105 reference units daily, divided into eightto ten drops, reduced the length of the disease

compared with corticosteroid- and placebo-trea-ted groups.[28] In another clinical trial involving37 participants, HuIFNb was again topicallyadministered (7.5 105 IU/mL, one drop fivetimes daily for 1 week) to patients with adeno-viral keratoconjunctivitis. Improvement with top-ical HuIFNb compared with placebo was foundto be statistically significant when left eyes wereaffected, but not when right eyes were involved,an observation that could not be explained by theauthors.[29] In a larger-scale clinical trial, a totalof 150 patients with keratoconjunctivitis, due toadenovirus serotype 8 (Ad8), were randomly treatedwith exogenous IFNa combined with other med-ications; however, this regimen proved less effi-cient than polyvinylpyrrolidone-iodine treatment.In the same study, no prophylactic effect of IFNaon uninflamed fellow eyes was observed.[30] Ofnote, another large-scale clinical trial reportedthe prevention of highly contagious viral kerato-conjunctivitis by an unidentified virus in 123 of130 patients in total after topical IFN applica-tion. The treatment comprised of one drop pereye daily for a period of 12 days.[31] Finally,clinical data collected from the use of HuIFNb,either in the form of cream (20 000 IU/g) to treatHSV-1 and herpes zoster ophthalmicus, or in theform of eye drops (500 0001 000 000U) for thetreatment of adenovirus infections, proved to beefficient in shortening the course of the diseasewhen applied in the eyes of patients who were inthe early stages of the viral infection.[32]

In animal models of hamster and rabbit cornea,IFN production was induced by treatment withthe chemical compound tilorone dihydrochloride,used to treat HSV and vesicular stomatitis virus.This compound was reported to have promisingresults in improving conjunctivitis.[51]

In a study comprised of in vitro data, naturaland recombinant human IFNs (rIFNa and rIFNb)added to Changs human conjunctival cell cul-tures, which were infected with epidemic isolatesof Cox A24, were shown to inhibit Cox A24 in-fection with varying effectiveness depending onthe Cox A24 isolate and the type of IFN used.[60]

In another study, IFNa enhanced the protectiveeffect of rabbit and human sera with regards toEV70 infection of conjunctival epithelial cells.[61]



The possibility of a synergistic antiviral effect ofIFNa, IFNb or IFNg plus specific antibodyagainst EV70, Cox A24, adenovirus serotype 3(Ad3) and HSV was investigated in Changsconjunctival cells. Combinations of 10 units ofanti-EV70 and anti-Cox A24 with 50 units ofIFNa, IFNb or IFNg resulted in an enhancedinhibition of virus yields, which was greater thanthe sum of the individual effects; the results weresimilar for Ad3.[62]

In summary, the data existing from the use ofIFNs in the treatment of viral conjunctivitis areencouraging. Nevertheless, there are reports thatfailed to observe a beneficial effect of IFNs. Thesite of infection, time of IFN application, doseand type of IFN, as well as viral sensitivity to IFNare critical to the efficacy of this type of treatment.

2.6 RNA Interference

RNA interference is an emerging technologythat aims to block gene expression. Three in vitrostudies and one animal study evaluated the use ofsmall-interfering RNA (siRNA) molecules forreplication inhibition of viruses responsible forthe development of viral conjunctivitis.[52,63-65]

An siRNA targeting a conserved region ofCox A24 was assessed for its antiviral potential inan in vitro system of HeLa or primary humanconjunctival cells infected with several variantsand clinical isolates of Cox A24. Viral replicationin these cells was decreased when the specificsiRNA was administered.[63] The same researchteam, 2 years later, developed a novel siRNA thattargeted a conserved region of both EV70 andCox A24, which was able to decrease replicationand protein synthesis of both viruses in MRC5and primary human conjunctival cells.[64] In ad-dition, an siRNA against EV70 reduced viralRNA in a rhabdomyosarcoma cell line when ad-ministered prior to or shortly after infection.[65]

In a mouse model of respiratory syncytial virus(RSV) infection of the eye, synthetic anti-RSVsiRNA, applied topically shortly before viral in-oculation, prevented spread of infection in theeye and lung; in contrast, when siRNAwas addedat different timepoints after RSV infection, it of-fered little or no protection.[52]

2.7 Trifluridine

Trifluridine (trifluorothymidine) is also a pyr-imidine nucleoside; however, it appears to be moreeffective and less toxic than idoxuridine. Our searchfound six evaluations on the treatment of viralconjunctivitis with trifluridine, two of which areclinical trials[30,33] and four are case reports.[34-37]

In a clinical study that included 150 patientswith Ad8 infection who were treated at random,trifluorothymidine drops in combination withexogenous IFNawas less successful than povidone-iodine administration.[30] In addition, randomtreatment of 74 patients with epidemic kerato-conjunctivitis did not show any beneficial effectof trifluridine over treatment with dexametha-sone or artificial tears.[33] In a case series, six pa-tients with a previous medical history of herpetickeratitis were treated with trifluridine early onthe course of the HSV-1 conjunctivitis, showinga fast recovery.[34] Another case report involveda 26-year-old woman who was treated success-fully with a 14-day course of topical trifluridine incombination with a single dose of intravenousvaccinia immune globulin for conjunctival infec-tion.[35] Sixteen confirmed or probable cases ofocular vaccinia infection occurred in the US De-partment of Defenses Smallpox Vaccination Pro-gramout of a total of 450293 smallpox vaccinationsand some of them were successfully treated withtopical trifluridine 1%.[36] Finally, Wander[37]proposed prophylactic trifluridine treatment for pa-tients with a history of ocular HSV who were toundergo immune suppression, although, accordingto the author, no therapy to date has significantlydecreased the recurrence rate for HSV infections.

In a study involving 17 cats with ocular herpes-virus disease, topical trifluridine treatment did notprove to be superior to idoxuridine or vidarabine.[53]

In summary, trifluridine treatment has been usedto treat cases of conjunctivitis caused by adeno-viruses, herpesviruses or smallpox. Nevertheless,current data in regards to its efficacy are ambiguous.

2.8 Valaciclovir

Valaciclovir is the esterified prodrug of acic-lovir, to which it is converted in vivo. As such, it

342 Skevaki et al.


has greater bioavailability than acyclovir and isused to treat HSV infections and herpes zoster.

We found two studies in the literature in whichvalaciclovir was used for the treatment of viralconjunctivitis.[38,39] In one of these articles, oralvalaciclovir was administered at 1000mg threetimes daily for 10 days. No placebo or other treat-ment group was included in this study and, there-fore, conclusions regarding the efficacy of this drugcannot be drawn.[38] In contrast, a study includ-ing 110 immunocompetent patients with herpeszoster ophthalmicus compared the efficacy andsafety of valaciclovir with aciclovir. Valaciclovirwas administered as two 500mg tablets threetimes daily and aciclovir as one 800mg tablet fivetimes daily, both for 7 days. The two drugs wereshown to be equally tolerable and effective inpreventing ocular complications of herpes zosterophthalmicus, including conjunctivitis, superficialand stromal keratitis, and pain. However, theauthors considered valaciclovir to be advantageousversus aciclovir because it provides a better dos-ing regimen. This study was mainly descriptiveand no statistical evaluation was performed.[39]

2.9 Other Compounds Tested in Humans

Additional agents that do not directly blockviral replication have also been used for thetreatment of viral conjunctivitis. An endogenousagent that has been mainly characterized for itsantimicrobial activity, N-chlorotaurine, has beentested for tolerability and efficacy in patients withepidemic keratoconjunctivitis. Treatment for 7 dayswith eye drops containing a 1% aqueous solutionof N-chlorotaurine (n = 33) or the antibacterialgentamicin (n = 27) as a control was well toleratedand shortened the duration of illness in patientswith infections caused by a variety of microbes,such as adenovirus types 3, 4, 8, 19 and 37, en-teroviruses or staphylococci.[40]

The broad-spectrum bactericide povidone-iodine, which is a stable chemical complex ofpolyvinylpyrrolidone and elemental iodine, hasbeen used as a 0.4% ophthalmic suspension incombination with 0.1% dexamethasone to treatadenoviral conjunctivitis. The suspension wasgiven four times daily for 5 days. The results of

the study were regarded as promising by the au-thors; however, no placebo control patients wereincluded, thus precluding any definitive conclu-sions.[41] In vitro, povidone-iodine was highly ef-fective against free adenovirus but less effectiveagainst intracellular adenoviral particles in al-ready infected cells.[66]

2.10 Other Compounds Tested in Animalor In Vitro Studies

Many compounds that have not been used yetin clinics have been reported to have an antiviraleffect against conjunctivitis-relevant viral strains.In one study, ocular instillation of 2-deoxy-D-glucose markedly reduced the severity of viral-induced conjunctivitis and keratoconjunctivitis incalves. Of note, the drug was effective both whengiven at the onset of the infection and after clin-ical conjunctivitis had already developed.[54]

A peptidomimetic compound, named BILD 1263,which blocks the ribonucleotide reductase ofHSV-1, was used to treat HSV-1 KOS-infectedmice; the treatment was shown to prevent signs ofconjunctivitis.[55] The antiviral potency of topicalcobalt chelate CTC-96 was tested in New Zealandwhite rabbits infected with Ad5, an in vivo modelof adenoviral keratoconjunctivitis most similar tohuman disease; CTC-96 treatment resulted inmilder inflammation of the conjunctiva com-pared with the placebo-treated group.[56] Treat-ment with 3% ganciclovir reduced adenovirustitres in cotton rat eyes.[57] Finally, 3% and 2%20,30-dideoxycytidine treatments were significantlymore efficacious than 0.5% cidofovir treatmentagainst ocular Ad5 infection in the New Zealandwhite rabbit replication model.[58]

In an in vitro study with A549 cells, whichevaluated the efficiency of various anti-HIV agentsagainst adenoviruses, zalcitabine and stavudine,two nucleoside reverse transcriptase inhibitors,showed significant activity for adenovirus sero-types 3, 4, 8, 19 and 37; in contrast, nevirapine,a non-nucleoside reverse transcriptase inhibitor,and indinavir and amprenavir, which are bothprotease inhibitors, were ineffective against adeno-viruses.[67] In addition, arildone inhibited theinfectivity of acute haemorrhagic conjunctivitis



viruses EV70 and Cox A24 in human amnionicWISH cells in vitro.[68] The benzimidazoles en-viroxime (LY 122772) and enviradene (LY 127123)inhibited EV70 and Cox A24 infection of con-junctival and laryngeal cells in vitro.[69] Finally,multivalent sialic acid conjugated to human serumalbumin prevented adenovirus serotype 37 frombinding to and infecting human corneal epithelialcells 1000-fold more efficiently than mono-saccharidic sialic acid.[70]

3. Conclusion

We have systematically reviewed the availableliterature and summarized our findings concern-ing the use of antiviral medications for the treat-ment of viral conjunctivitis. Most of the antiviralmedications currently in clinical use target DNAviruses: mainly herpesviruses, but also adeno-viruses. Data on antiviral agents targeting RNAviruses as causes of conjunctivitis are mostlylimited to animal and in vitro studies. Identifica-tion of the causative viral agent in clinical prac-tice is thus of crucial importance. Subsequently,the type of treatment should be selected depen-ding on the severity of symptoms and the mag-nitude of possible consequences, since severeconjunctivitis, as in the case of epidemic kerato-conjunctivitis, requires aggressive management.

Of note, reported cases of chronic con-junctivitis have been related to corticosteroidtreatment that prolongs viral infection. Indeed,two studies of the Ad5/New Zealand white rabbitocular model showed that corticosteroid treat-ment significantly enhanced viral replication andincreased the duration of viral shedding.[74,75] Inaddition, topical application ofNSAIDswas shownto be ineffective in controlling replication of ade-novirus serotypes 1, 5, 8 or 19 in the New Zealandwhite rabbit ocular model.[76] Corticosteroids arealso contraindicated for the treatment of HSV-1ocular infections. Treatment of conjunctivitiscaused by HSV-1 with corticosteroids could leadto increased viral replication and, possibly, her-petic epithelial keratitis.[77] Thus, caution is rec-ommended in the use of this type of treatment inviral conjunctivitis, since it may lead to enhancedrisk of viral transmission and epidemics.

Additional approaches have been used overthe years for the management of conjunctivitis.Vaccination against viral strains causing con-junctivitis has been unsuccessfully used in thepast. Military recruits were vaccinated for ade-novirus serotypes 4 and 7 between 1971 and 1996,but the vaccine is currently unavailable after twofatal cases were reported.[78] In recent years, anumber of viruses have been shown to directlyinterfere with programmed cell death or apopto-sis, an active process of cellular self-destructionthat plays an important role during development,but also acts as a defence mechanism against viralinfections.[79] Viral products can either blockapoptosis to prevent premature cell death andmaximize viral progeny, or they can promoteapoptosis to enhance their spread. Recently, itwas shown that glycyrrhizic acid disrupts latentinfection of HSV in Kaposi sarcoma by selec-tively inducing cell death of the HSV-infectedcells.[80] Study of the viral processes that block orinduce apoptosis may provide opportunities forfuture drug interventions.

Finally, significant advances in the treatmentof viral conjunctivitis have been achieved overrecent years with specialized medications thatblock viral proliferation, which are reported on inthis review. Many of these are used in clinicalpractice, while others have proved their useful-ness only in animal or in vitromodels. Issues suchas efficacy and toxicity still raise questions.Nevertheless, drugs such as aciclovir, trifluridineand valaciclovir are the main agents used for themanagement of conjunctivitis of herpetic origin.In a recent retrospective review on the effect ofprophylactic oral antiviral treatment on HSV re-currences in a community-based cohort, oral an-tiviral prophylaxis was associated with a de-creased risk of recurrence of several eye disorderscaused by HSV.[81] Further research is required inorder to find efficacious yet tolerable dosage re-gimens of antiviral drugs.

Acknowledgements

No sources of funding were used to assist in the prepara-tion of this review. The authors have no conflicts of interestthat are directly relevant to the content of this review.

344 Skevaki et al.


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Correspondence: Dr Chrysanthi L. Skevaki, 41 Fidipidou str,11527 Athens, Greece.E-mail: [email protected]



Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

Treatment of Viral Conjunctivitis with Antiviral DrugsAbstract1. Methods of Literature Review1.1 Literature Search1.2 Study Selection and Eligibility Criteria1.3 Data Evaluation

2. Results2.1 Aciclovir2.2 Cidofovir2.3 Famciclovir2.4 Idoxuridine2.5 Interferons2.6 RNA Interference2.7 Trifluridine2.8 Valaciclovir2.9 Other Compounds Tested in Humans2.10 Other Compounds Tested in Animal orInVitro Studies

3. ConclusionAcknowledgementsReferences

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