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Drugs 20 11. 71 <3); 331-347

001J^67/11/CXX)3-O331/S66 55/0 2011 AdK Data Intorrnatkm BV Ail rtghts lewrved.

Treatment of Viral Conjunctivitis with Antiviral Drugs

Clirysauthi L. Skevaki,^ Ioanna E. Galani,'^ Michail V. Pararas,^ Konstantina P. Giannopoulou^ and Athanassios Tsakris^
1 Department of Microbiology, School of Medicine, University of Athens, Athens, Greece 2 Center of Immunology & Transplantation, Biomdical Research Foundation of the Academy of Athens, Athens, Greece 3 First Department of Ophthalmiatrion Athinon, Athens Eye Hospital, Athens, Greece

Contents
Abstract 1. Methods of Literature Review 1.1 Literature Search 1.2 Study Selection and Eligibility Criteria 1.3 Data Evaluation 2. Results 2.1 Aciclovir 2.2 Cidofovir 2.3 Famciclovir 2.4 Idoxuridine 2.5 Interferons 2.6 RNA Interference 2.7 Trifluridine 2.8 Valaciclovir 2.9 Other Compounds Tested in Humans 2.10 Other Compounds Tested in Animal or In Vitro Studies 3. Conclusion 331 333 333 333 333 333 333 337 339 341 341 342 342 342 343 343 344

AbStrOCt

Viral conjunctivitis is one of the most common disorders observed in ophthalmic 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 treatment of viral conjunctivitis has not been previously reported. We systemically reviewed the literature to identify studies where antiviral drugs were used to treat viral conjunctivitis. Currently, aciclovir, tritluridine and valaciclovir are commonly used as antiviral agents to treat herpesvirus infections. Cidofovir has 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 their high toxicity. Interestingly, most of the antiviral drugs developed are used to treat herpesvirus infections, while less progress has been made in the field

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of adenoviral infections. For other viral causes of conjunctivitis, no effective remedy is currently available, and treatment focuses on the relief of symptoms. Caution should be exercised when coadministering other pharmacological agents, such as corticosteroids, because of emerging adverse effects.

Conjunctivitis, commonly known as 'red eye', is one of the most frequent ocular disorders observed in ophthalmic emergency departments,''-^' Possible causes include an allergic reaction or an infection of viral or bacterial origin. Acute viral conjunctivitis is commonly caused by various serotypes of adenoviruses, but herpesviruses and varicella-zoster virus, which are DNA viruses, and the RNA viruses picornaviruses, such as enterovirus serotype 70 (EV70) and coxsackievirus A24 variant (Cox A24), are also causes.'-^' Other less frequent causes of viral conjunctivitis usually occur in association with a systemic illness and include infections caused by the DNA virus Epstein-Barr virus, and the RNA viruses influenza virus, paramyxovirus (e.g. Newcastle disease virus), rubella virus and HIV. Viral conjunctivitis is usually a benign and self-limiting condition that may heal within a few weeks, and can affect all ages. Nevertheless, it can be highly infectious and has been the cause of epidemic outbreaks worldwide,'"*'"' thus constituting a major public health problem. Inflammation of the conjunctiva can also occur in combination with corneal inflammation and subepithelial infiltrates, most commonly caused by adenovirus serotypes 8, 19 and 37, causing severe adenoviral keratoconjunctivitis and epidemics.'''' Epidemic conjunctivitis due to viruses is also a common nosocomial infection.''^"'-^' Local care and interventions to minimize transmission are thus the cornerstones for management for viral conjunctivitis. Among infectious causes of conjunctivitis, viral conjunctivitis is the most common and, in some cases, coincides with a viral upper respiratory tract infection, with or without the presence of purulent discharges. Allergic conjunctivitis may be seasonal or perennial, and is mostly characterized by itching and watery discharges. The patient's history, the presence of signs, such as vesicles, ulcrations, crusting, discharge and chemosis.
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during physical examination, as well as laboratory tests, assist in the definitive diagnosis of the causative agent.''' Currently, there is no specific treatment for viral conjunctivitis. Symptomatic relief may be achieved with cool compresses and artificial tears. For severe cases of conjunctivitis and keratitis, topical corticosteroid drops are prescribed for the relief of symptoms caused by inflammation. However, prolonged use of corticosteroids increases the risk of adverse effects. Recent advances in the field of infectious conjunctivitis have introduced new diagnostic methods and novel therapeutic agents. Serological tests, ELISA, electron microscopy and polymerase chain reaction techniques have been used for the laboratory identification of specific viral strains through direct inspection or detection of their antigens and antibodies. Such methodologies, in combination with the use of antiviral medications, offer an alternative therapeutic approach that directly targets viral replication. Viral replication takes place inside the infected host cells. DNA viruses, in general, replicate inside the cell nucleus and, in many cases, depend on the host cell cycle, while RNA viruses replicate primarily in the cytoplasm, and their replication is not so strictly dependent on the host cell cycle. Viruses may rely on the host polymerases for their replication, or they can encode their own polymerases, such as adenoviruses, herpesviruses and most RNA viruses. Most antiviral drugs are nucleoside or nucleotide analogues that inhibit viral replication by acting as chain terminators during DNA or RNA synthesis. Analogues compete with the natural substrates, and when added in the newly synthesized DNA or RNA chain, they do not offer a binding position for a phosphodiester bond with the next nucleotide.''^' The rapidly increasing number of antiviral agents is quite promising; however, the efficacy of many

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of these drugs in treating viral conjunctivitis is still elusive. Furthermore, some of these medications have adverse effects. The goal of this review is to evaluate therapeutic regimens for viral conjunctivitis that are currently used in clinical practice or are under development. We have thus summarized information on antiviral drugs that have been used to treat viral conjunctivitis or have been tested in experimental systems, and which may prove useful for the physician. 1. Methods of Literature Review .,1 Literature Search We systematically searched the MEDLINE database using PubMed up to December 2010. The keywords used were MESH terms: 'viral conjunctivitis' and 'antiviral drugs". References of relevant articles were also hand-searched. 1.2 Study Selection and Eligibility Criteria Studies were selected if they included clinical data or experimental animal data on the effect of antiviral drugs for the treatment of viral conjunctivitis. In addition, in vitro experimental data on the effect of antiviral drugs on the replication of clinically relevant viruses were included. Review articles were excluded, but were manually screened for additional references. Finally, studies were only included if written in English, German, French or Italian. 1.3 Data Evaiuation Studies including clinical or animal experimental data were evaluated according to the study population, the type of infection, the antiviral agent used, the dosage regimen administered and the outcome of the disease. The in vitro experimental data were analysed based on the antiviral agent in use, the method by which the effectiveness of the antiviral agent was determined, and the outcome of the experiment. The data were evaluated and are presented herewith based on the PRISMA statement for reporting systematic reviews and meta-analyses.''"*'
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2. Resuits The process of study selection is depicted as a flow diagram, according to PRISMA, in figure 1. Initially, 110 articles were identified. In addition, 17 articles were also included via a hand-search of references. A total of 56 studies, published between August 1969 and August 2010, were fmally included in this review. Among the studies further analysed in the present review, 27 were clinical studies, 17 were animal studies and 12 were in vitro studies. We present the results of our review based on the antiviral agent used in alphabetical order. In addition, tables I, II and III summarize the clinical data, the animal and the in vitro experimental studies, respectively. 2.1 Aciclovir Aciclovir is a guanosine analogue with antiviral properties. It is inactive until it becomes phosphorylated by viral thymidine kinase, thus it does not affect uninfected cells. After phosphorylation, aciclovir is incorporated into viral DNA and blocks its replication. It is an established treatment for herpes simplex virus (HSV) infections, which is administered topically, orally or intravenously. Six studies were identified in the literature as using aciclovir in the treatment of conjunctivitis.''-^"^"1 Three were clinical trials''-^"'^1 and three were case reports.'"*"'^"1 In one clinical trial, 71 non-immunocompromised patients with herpes zoster ophthalmicus were treated with a 10-day course of oral aciclovir (600 mg five times daily). Aciclovir was well tolerated and significantly reduced the incidence and severity of complications of the infection.''^' In addition, the long-term oral aciclovir administration (12 months) for the treatment of ocular HSV infection was effective in decreasing virus recurrence.'""' Another clinical trial compared topical versus oral aciclovir treatment for early herpes zoster ophthalmicus. Fifty-seven patients received either topical aciclovir ointment or oral aciclovir 800 mg, both five times daily for 7 days, and were followed up for 12 months. The study concluded that patients receiving topical aciclovir exhibited more ocular complications than the
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110 articles identified through PubMed search

17 additional articles identitied through hand-search

127 total articles 27 articles excluded No abstract available (n = 12) Articles written in non-eligible languages (n = 15) 100 articles screened 44 full-text articles excluded because of no relevancy to antiviral treatment or viral conjunctivitis Focus on other disease (n = 19) No treatment mentioned (n = 19) Non-antiviral therapy used (n = 3) Reviews (n = 3) 56 tull-text articles assessed tor eligibility

56 articles included in qualitative synthesis

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

orally treated group.''''1 In a case report study, a 95-year-old woman diagnosed with ophthalmic zoster sine herpete was effectively treated with intravenous aciclovir given at lOmg/kg three times daily for 3 days, followed by oral aciclovir at 800mg five times daily for 14 days,''**' A 14-year-old girl who presented with Parinaud's oculoglandular syndrome, an uncommon manifestation of primary HSV type 1 (HSV-1) infection, was treated with oral and local aciclovir that allowed improvement of her symptoms,''"^l Finally, a 17-year-old man was treated with aciclovir ointment 3% w/w four times daily, together with antibacterial and corticosteroids, in order to treat a suspected herpesvirus infection; treatment with aciclovir was interrupted after 2 days, when it was determined that keratoconjunctivitis
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was due to the coexistence of adenoviral and Acanthamoeha infection,'^1 A study involving rabbits showed that a 3% aciclovir ointment applied topically one to five times daily during an acute ocular HSV infection was beneficial in reducing conjunctivitis occurrence among other ophthalmic complications, but was not effective in preventing conjunctivitis when applied 24 hours after viral inoculation. In addition, aciclovir was not effective in eradicating established latent HSV infection,f'*^! Despite its inability to eradicate latent infection,[^'l therapeutic and/or prophylactic administration of aciclovir is considered a standard antiviral therapy for several manifestations of HSV infection. In addition to aciclovir, two second-generation antiviral agents, famciclovir
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(see section 2,3) and valaciclovir (see section 2,8), have recently been introduced in clinical practice for the treatment of viral conjunctivitis caused by herpesviruses, 2.2 Cidofovir

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Cidofovir, also known as HPMPC [(S)-l-(3hydroxy-2-phosphonylmethoxypropyl)cytosine], is an acyclic nucleoside phosphonate, which has been used for the treatment of cytomegalovirus retinitis in patients with AIDS. Maintenance therapy with cidofovir involves an infusion only once every 2 weeks, making it a convenient treatment option. Two case reports'-'--'and two clinical trials''^-^'*' assessing the effect of cidofovir in viral conjunctivitis were identified. The first case report involved a 31-year-old woman who was treated with cidofovir for adenoviral conjunctivitis. Cidofovir was used as a 0.2% solution four times daily for 8 days, resulting in resolution of clinical signs and symptoms in the infected eye, and preventing spread of infection in the uninfected eye.'-'' In the second case report, a 44-year-old man with haemorrhagic adenoviral keratoconjunctivitis was successfully treated with intravenous cidofovir 1 mg/kg three times weekly for 4 weeks.'"' In a clinical trial, cidofovir was used as 0.2% eye drops alone, or in combination with 1% ciclosporin eye drops four times daily for a period of 21 days, to treat 39 patients with acute adenoviral keratoconjunctivitis. The use of cidofovir and ciclosporin alone or coadministered did not accelerate the improvement of clinical symptoms of acute adenoviral keratoconjunctivitis compared with the natural course of the infection.'-^' In a second clinical study conducted by the same research team, 34 patients with recent onset of acute adenoviral keratoconjunctivitis were treated using a higher dose of topical cidofovir (1%) with or without 1% ciclosporin for 21 days. The higher dose of cidofovir lowered the frequency of severe corneal opacities, but was accompanied by local adverse effects, such as erythema of the lids and injection of the conjunctiva.'-'*' //) viiro. cidofovir and other nucleoside monophosphate analogues, such as HPMPA [(S)-9-(3hydroxy-2-phosphonomethoxypropyl)adenine]
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and 2'-nor-cyclic guanosine monophosphate, have demonstrated significant inhibitory activity against common clinical ocular isolates and standard adenoviral serotypes (1, 5, 8 and 19) related to viral conjunctivitis,!'^'*' In addition, in a series of experiments in the New Zealand rabbit ocular model, topical administration of cidofovir significantly reduced adenovirus serotype 5 (Ad5) ocular titres and shortened the duration of shedding in comparison with control eyes when administered prophylactically'""' or after an established Ad5 infection,l"''*'*'^! In one of these studies, combined treatment with corticosteroids significantly reversed the antiviral activity of cidofovir;!'*^' therefore, caution should be taken when treating symptomatic adenoviral ocular infection. In another study performed with the New Zealand rabbit ocular model, although topical cidofovir treatment demonstrated significant antiviral activity against the parental Ad5 strain, three cidolbvirresistant variants of this virus were identified.'*^' The antiviral effect of cidofovir was also tested using the cotton rat model for adenovirus serotypes 4, 8 and 37,'''^' and with primary ocular feline herpesvirus-1 infection in cats,''"*' where the inhibitory effect of cidofovir on viral replication was confirmed. Finally, another study examined the possible adverse effects from the use of cidofovir, as well as of zalcitabine and stavudine, which have been used for the treatment of HIV, in adenovirus infections; a solution containing 1% of each aforementioned agent was administered as eye drops to healthy female Japanese albino rabbits four times daily for 14 days. Redness of eyelids and conjunctival injection were observed in all study groups, while narrowing of the lacrimal canaliculus was observed in the cidofovir group.''*'*' 2,3 Famciclovir Famciclovir is a guanine analogue used for the treatment of various herpesvirus infections, most commonly for herpes zoster. It is a prodrug form of penciclovir with improved oral bioavailability, Famciclovir displays the same antiviral spectrum as aciclovir in regards to herpesviruses. Only one clinical study so far has reported famciclovir for the treatment of viral conjunctivitis.'-^-'
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Table III. Summary of antiviral regimens for viral conjunctivitis tested in in vitro experimental systems Study (year) Gordon et al.l^^' (1991) Langford etal.l^l(1988) Langford etal.l^'l(2003) Langford etal.l^2l(1983) Experimental system A549 human alveolar epithelial eells Chang's human conjunctival cells Human conjunctival and lens cells WISH human amniotic epitheliai cells. Chang's human conjunctival cells and RK-13 rabbit kidney cells Primary human conjunctival cells MRC5 human lung fibroblasts and primary human conjunctival cells Human rhabdomyosarcoma cells Infectious agent Adi, Ad5, Ada orAd19 Cox A24 EV70 Ad3, Cox A24, EV70 orHSV-i(F) Cox A24 Drug Cidofovir (HPMPC) or HPMPA or 2-nor-cyclic GMP Human IFNot or IFN Rabbit or human serum IFN Human I F N , IFN or IFNy antiviral antibodies siRNA against the cisacting replication element of Cox A24 siRNA against the virai polymerase 3D gene of both viruses siRNA against the viral polymerase 3D gene of EV70 Povidone-iodine Efficacy" Inhibition of viral replication; cidofovir was the least toxic Both equally reduced virus infection and production IFNa enhanced the protective effect of serum, observed only in conjunctival cells Synergistic effect of treatments in reducing viral production, which was dependent on the type of IFN Decrease of viral replication

Jun et al.i83i (2008) Jun et al.i"! (2011) Tan et al.'^] (2008)

Cox A24 or EV70 EV70

Cytoprotective effect; decrease in viral replication protein synthesis Prevention of viral replication when the SiRNA was added prophylactically; reduction of virai production when added after infection Effective against free adenovirus but not against intracellular adenoviral particles in already infected cell; low cytotoxicity for healthy cells Zaicitabine and stavudine reduced adenoviral replication Arildone reduced viral replication and did not affect IFN production; additive effect of arildone and IFN in reducing viral titres Inhibition of virus production and of the viral cytopathogenic effect Muitivalent sialic acid conjugated to HAS was more efficient in preventing infection of cells

Monnerat et al.l^l (2006)

A549 human alveolar epitheliai cells

Ad8

Uchio et al.l^ (2007) Langford etal.l8l(1985) Langford etal.l^l(1995) Johansson et al.''"! (2007)

A549 human alveolar epithelial cells WISH human amniotic epitheiial cells Chang's human conjunctival, Hep-2 laryngeal and glioma cells Human corneal epithelial cells

Ad3. Ad4. Ad8. Ad19 or Ad37 Cox A24 or EV70 Cox A24 or EV70 Ad37

Zaicltabine. stavudine. nevirapine, indinavir or amprenavir Arildone, IFN or Arildone + lFN Benzimidazoles

Muitivalent sialic acid conjugated to HAS or monosaccharidic sialic acid

Based on the statements of the authors.

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

A large clinical study comprising of 454 patients with ophthalmic herpes zoster of the trigeminal nerve VI branch took place in 87 centres worldwide and compared the efficacy and safety of famciclovir with aciclovir. Famciclovir 500 mg was administered three times daily and aciclovir 800 mg five times daily, both orally for 7 days. The percentage of patients who experienced an
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ocular manifestation, such as conjunctivitis, keratitis and glaucoma, during the study was similar for the famciclovir and aciclovir groups, demonstrating that there was no difference between the two therapeutic agents. Nevertheless, as is the case with valaciclovir, famciclovir provides patients with a more convenient dosing regimen than

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In addition, in a small-scale study (n= 10) on feline herpesvirus-1-associated disease in cats, famciclovir was well tolerated and, in all cases, had a positive impact on the animal's condition; however, no untreated controls or animals that received another therapeutic regimen were included in the study.f^^l 2.4 Idoxuridine Idoxuridine, a modified form of deoxyuridine, is a nucleoside analogue, which is incorporated into viral DNA during replication and blocks base pairing. It is used as an anti-herpesvirus drug. Effective treatment of herpetic keratitis with idoxuridine was first reported in 1962,1^-' and for many years idoxuridine was the only antiviral agent available for its treatment. We identified a clinical trial involving 70 patients with conjunctivitis who were treated with 0.5% idoxuridine ointment or placebo, applied several times daily for 7 days. Idoxuridine treatment did not have any influence in the typical course of the disease.'-*' Idoxuridine treatment has been reported to be associated with high toxicity. The adverse effects arising from topical application of idoxuridine have been reviewed elsewhere.''-^' 2.5 interferons Interferons (IFNs) are natural proteins produced by cells in response to viral infection and aim to control viral spread. Our search identified six clinical evaluations of the effect of IFNs in viral conjunctivitis.'^^"-*'' Five of these were clinical trials'-^-^'^ and one summarized clinical data.'-^^' Plasmid-derived IFNa-2 or placebo was used to treat a total of 14 patients with adenoviral conjunctivitis. The authors found no statistically significant effect of the IFN used on disease duration or virus shedding, although they observed a tendency towards asymptomatic infection in the second eye in the IFN-treated group versus the control group.'-^' Topical application of human fibroblast-derived IFN (HuIFN) was used in the treatment of epidemic keratoconjunctivitis caused by an adenovirus. A total of l-2x lO' reference units daily, divided into eight to ten drops, reduced the length of the disease
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compared with corticosteroid- and placebo-treated groups.'^**' In another clinical trial involving 37 participants, HuIFN was again topically administered (7.5x 10'IU/mL, one drop five times daily for 1 week) to patients with adenoviral keratoconjunctivitis. Improvement with topical HuIFN compared with placebo was found to be statistically significant when left eyes were affected, but not when right eyes were involved, an observation that could not be explained by the authors.'-"^' In a larger-scale clinical trial, a total of 150 patients with keratoconjunctivitis, due to adenovirus serotype 8 (Ad8), were randomly treated with exogenous IFNa combined with other medications; however, this regimen proved less efficient than polyvinylpyrrolidone-iodine treatment. In the same study, no prophylactic effect of IFNa on uninflamed fellow eyes was observed.'^"' Of note, another large-scale clinical trial reported the prevention of highly contagious viral keratoconjunctivitis by an unidentified virus in 123 of 130 patients in total after topical IFN application. The treatment comprised of one drop per eye daily for a period of 12 days.'-"' Finally, clinical data collected from the use of HuIFN, either in the form of cream (200001 U/g) to treat HSV-1 and herpes zoster ophthalmicus, or in the form of eye drops (500000-1 000000 U) for the treatment of adenovirus infections, proved to be efficient in shortening the course of the disease when applied in the eyes of patients who were in the early stages of the viral infection.'^-' In animal models of hamster and rabbit cornea, IFN production was induced by treatment with the chemical compound tilorone dihydrochloride, used to treat HSV and vesicular stomatitis virus. This compound was reported to have promising results in improving conjunctivitis.'-*''' In a study comprised of //; vitro data, natural and recombinant human IFNs (rlFNa and rlFN) added to Chang's human conjunctival cell cultures, which were infected with epidemic isolates of Cox A24, were shown to inhibit Cox A24 infection with varying effectiveness depending on the Cox A24 isolate and the type of IFN used.'''"' In another study, IFNot enhanced the protective effect of rabbit and human sera with regards to EV70 infection of conjunctival epithelial cells.'''''
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The possibility of a synergistic antiviral effect of IFNoi, IFN or IFNy plus specific antibody against EV70, Cox A24, adenovirus serotype 3 (Ad3) and HSV was investigated in Chang's conjunctival cells. Combinations of 10 units of anti-EV70 and anti-Cox A24 with 50 units of IFNoi, IFN or IFNy resulted in an enhanced inhibition of virus yields, which was greater than the sum of the individual effects; the results were similar for Ad3.'"' In summary, the data existing from the use of IFNs in the treatment of viral conjunctivitis are encouraging. Nevertheless, there are reports that failed to observe a beneficial effect of IFNs. The site of infection, time of IFN application, dose and type of IFN, as well as viral sensitivity to IFN are critical to the efficacy of this type of treatment, 2.6 RNA Interference RNA interference is an emerging technology that aims to block gene expression. Three in vitro studies and one animal study evaluated the use of small-interfering RNA (siRNA) molecules for replication inhibition of viruses responsible for the development of viral conjunctivitis,'''--'''''^''' An siRNA targeting a conserved region of Cox A24 was assessed for its antiviral potential in an in vitro system of HeLa or primary human conjunctival cells infected with several variants and clinical isolates of Cox A24. Viral replication in these cells was decreased when the specific siRNA was administered.'''^' The same research team, 2 years later, developed a novel siRNA that targeted a conserved region of both EV70 and Cox A24, which was able to decrease replication and protein synthesis of both viruses in MRC5 and primary human conjunctival cells.'*"*' In addition, an siRNA against EV70 reduced viral RNA in a rhabdomyosarcoma cell line when administered prior to or shortly after infection.'^^' In a mouse model of respiratory syncytial virus (RSV) infection of the eye, synthetic anti-RSV siRNA, applied topically shortly before viral inoculation, prevented spread of infection in the eye and lung; in contrast, when siRNA was added at different timepoints after RSV infection, it offered little or no protection.'^^'

2.7 Trifluridine

Trifluridine (trifiuorothymidine) is also a pyrimidine nucleoside; however, it appears to be more effective and less toxic than idoxuridine. Our search found six evaluations on the treatment of viral conjunctivitis with trifluridine, two of which are clinical trials''"'-'-^' and four are case reports.'-''''"' In a clinical study that included 150 patients with Ad8 infection who were treated at random, trifiuorothymidine drops in combination with exogenous IFNa was less successful than povidoneiodine administration.'-"'' In addition, random treatment of 74 patients with epidemic keratoconjunctivitis did not show any beneficial effect of trifiuridine over treatment with dexamethasone or artificial tears.1^^-^' In a case series, six patients with a previous medical history of herpetic keratitis were treated with trifluridine early on the course of the HSV-1 conjunctivitis, showing a fast recovery,'^"*' Another case report involved a 26-year-old woman who was treated successfully with a 14-day course of topical trifiuridine in combination with a single dose of intravenous vaccinia immune globulin for conjunctival infection.'-'^l Sixteen confirmed or probable cases of ocular vaccinia infection occurred in the US Department of Defense's Smallpox Vaccination Program out of a total of 450 293 smallpox vaccinations and some of them were successfully treated with topical trifiuridine 1%.'-^*'' Finally, Wander'-"' proposed prophylactic trifiuridine treatment for patients with a history of ocular HSV who were to undergo immune suppression, although, according to the author, no therapy to date has significantly decreased the recurrence rate for HSV infections. In a study involving 17 cats with ocular herpesvirus disease, topical trifluridine treatment did not prove to be superior to idoxuridine or vidarabine.'-''^' In summary, trifiuridine treatment has been used to treat cases of conjunctivitis caused by adenoviruses, herpesviruses or smallpox. Nevertheless, current data in regards to its efficacy are ambiguous. 2.8 Valaciclovir Valaciclovir is the esterified prodrug of aciclovir, to which it is converted in vivo. As such, it
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has greater bioavailability than acyclovir and is used to treat HSV infections and herpes zoster. We found two studies in the literature in which valaciclovir was used for the treatment of viral conjunctivitis.'-^**"^''l In one of these articles, oral valaciclovir was administered at 1000 mg three times daily for 10 days. No placebo or other treatment group was included in this study and, therefore, conclusions regarding the efficacy of this drug cannot be drawn.'''^l In contrast, a study including 110 immunocompetent patients with herpes zoster ophthalmicus compared the efficacy and safety of valaciclovir with aciclovir. Valaciclovir was administered as two 500 mg tablets three times daily and aciclovir as one 800 mg tablet five times daily, both for 7 days. The two drugs were shown to be equally tolerable and effective in preventing ocular complications of herpes zoster ophthalmicus, including conjunctivitis, superficial and stromal keratitis, and pain. However, the authors considered valaciclovir to be advantageous versus aciclovir because it provides a better dosing regimen. This study was mainly descriptive and no statistical evaluation was performed.'^^1 2.9 Other Compounds Tested in Humans Additional agents that do not directly block viral replication have also been used for the treatment of viral conjunctivitis. An endogenous agent that has been mainly characterized for its antimicrobial activity. N-chlorotaurine, has been tested for tolerability and efficacy in patients with epidemic keratoconjunctivitis. Treatment for 7 days with eye drops containing a 1% aqueous solution of N-chlorotaurine (n = 33) or the antibacterial gentamicin (n = 27) as a control was well tolerated and shortened the duration of illness in patients with infections caused by a variety of microbes, such as adenovirus types 3, 4, 8, 19 and 37, enteroviruses or staphylococci.'**"' The broad-spectrum bactricide povidoneiodine, which is a stable chemical complex of polyvinylpyrrolidone and elemental iodine, has been used as a 0.4% ophthalmic suspension in combination with 0.1% dexamethasone to treat adenoviral conjunctivitis. The suspension was given four times daily for 5 days. The results of
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the study were regarded as promising by the authors; however, no placebo control patients were included, thus precluding any definitive conclusions.''*'' In vitro, povidone-iodine was highly effective against free adenovirus but less effective against intracellular adenoviral particles in already infected cells.'''''' 2.1(D Other Compounds Tested in Animal or In Vitro Studies Many compounds that have not been used yet in clinics have been reported to have an antiviral effect against conjunctivitis-relevant viral strains. In one study, ocular instillation of 2-deoxy-Dglucose markedly reduced the severity of viralinduced conjunctivitis and keratoconjunctivitis in calves. Of note, the drug was effective both when given at the onset of the infection and after clinical conjunctivitis had already developed.'''"'' A peptidomimetic compound, named BILD 1263, which blocks the ribonucleotide reductase of HSV-1, was used to treat HSV-1 KOS-infected mice; the treatment was shown to prevent signs of conjunctivitis.'^^' The antiviral potency of topical cobalt chelate CTC-96 was tested in New Zealand white rabbits infected with Ad5, an in vivo model of adenoviral keratoconjunctivitis most similar to human disease; CTC-96 treatment resulted in milder inflammation of the conjunctiva compared with the placebo-treated group.''^''' Treatment with 3% ganciclovir reduced adenovirus titres in cotton rat eyes.'"' Finally, 3% and 2% 2',3'-dideoxycytidine treatments were significantly more efficacious than 0.5% cidofovir treatment against ocular Ad5 infection in the New Zealand white rabbit replication model.'^'*' In an in vitro study with A549 cells, which evaluated the efficiency of various anti-HIV agents against adenoviruses, zaicitabine and stavudine, two nucleoside reverse transcriptase inhibitors, showed significant activity for adenovirus serotypes 3. 4, 8, 19 and 37; in contrast, nevirapine, a non-nucleoside reverse transcriptase inhibitor, and indinavir and amprenavir, which are both protease inhibitors, were ineffective against adenoviruses.'''^' In addition, arildone inhibited the infectivity of acute haemorrhagic conjunctivitis
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viruses EV70 and Cox A24 in human amnionic WISH cells in virro.'*'^' The benzimidazoles enviroxime (LY 122772) and enviradene (LY 127123) inhibited EV70 and Cox A24 infection of conjunctival and laryngeal cells in v/'/ro.'^^' Finally, multivalent sialic acid conjugated to human serum albumin prevented adenovirus serotype 37 from binding to and infecting human corneal epithelial cells 1000-fold more efficiently than monosaccharidic sialic acid.''

3. Conclusion
We have systematically reviewed the available literature and summarized our findings concerning the use of antiviral medications for the treatment of viral conjunctivitis. Most of the antiviral medications currently in clinical use target DNA viruses; mainly herpesviruses, but also adenoviruses. Data on antiviral agents targeting RNA viruses as causes of conjunctivitis are mostly limited to animal and in vitro studies. Identification of the causative viral agent in clinical practice is thus of crucial importance. Subsequently, the type of treatment should be selected depending on the severity of symptoms and the magnitude of possible consequences, since severe conjunctivitis, as in the case of epidemic keratoconjunctivitis, requires aggressive management. Of note, reported cases of chronic conjunctivitis have been related to corticosteroid treatment that prolongs viral infection. Indeed, two studies of the Ad5/New Zealand white rabbit ocular model showed that corticosteroid treatment significantly enhanced viral replication and increased the duration of viral shedding,'^"-^^I In addition, topical application of NSAIDs was shown to be ineffective in controlling replication of adenovirus serotypes 1, 5, 8 or 19 in the New Zealand white rabbit ocular model.'' Corticosteroids are also contraindicated for the treatment of HSV-1 ocular infections. Treatment of conjunctivitis caused by HSV-1 with corticosteroids could lead to increased viral replication and, possibly, herpetic epithelial keratitis,'^'' Thus, caution is recommended in the use of this type of treatment in viral conjunctivitis, since it may lead to enhanced risk of viral transmission and epidemics.

Additional approaches have been used over the years for the management of conjunctivitis. Vaccination against viral strains causing conjunctivitis has been unsuccessfully used in the past. Military recruits were vaccinated for adenovirus serotypes 4 and 7 between 1971 and 1996, but the vaccine is currently unavailable after two fatal cases were reported,'^**' In recent years, a number of viruses have been shown to directly interfere with programmed cell death or apoptosis, an active process of cellular self-destruction that plays an important role during development. but also acts as a defence mechanism against viral infections.'^**' Viral products can either block apoptosis to prevent premature cell death and maximize viral progeny, or they can promote apoptosis to enhance their spread. Recently, it was shown that glycyrrhizic acid disrupts latent infection of HSV in Kaposi sarcoma by selectively inducing cell death of the HSV-infected cells.'**"' Study of the viral processes that block or induce apoptosis may provide opportunities for future drug interventions. Finally, significant advances in the treatment of viral conjunctivitis have been achieved over recent years with specialized medications that block viral proliferation, which are reported on in this review. Many of these are used in clinical practice, while others have proved their usefulness only in animal or in vitro models. Issues such as efficacy and toxicity still raise questions. Nevertheless, drugs such as aciclovir, triOuridine and valaciclovir are the main agents used for the management of conjunctivitis of herpetic origin. In a recent retrospective review on the effect of prophylactic oral antiviral treatment on HSV recurrences in a community-based cohort, oral antiviral prophylaxis was associated with a decreased risk of recurrence of several eye disorders caused by HSV,'*"' Further research is required in order to find efficacious yet tolerable dosage regimens of antiviral drugs.

Acknowledgements
No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interesi that are directly relevant to the content of this review.

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Correspondence: Dr Chrysanthi L. Skevaki, 41 Fidipidou str, 11527 Athens, Greece. E-mail: cskevaki@allergy.gr

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