The Evolution of Antiviral Therapy for External Ocular Viral Infections Over Twenty-Five Years

The Evolution of Antiviral Therapy for External Ocular Viral Infections Over Twenty-five Years

Y. Jerold Gordon, M.D.

Purpose. To review the past 25 years of the evolution of antiviral levels on the corneal surface. By 1975, IDU was the treatment of therapy for the treatment of common external ocular viral infec- choice for herpetic epithelial keratitis worldwide. However, the tions (herpes simplex virus type 1, varicella-zoster virus, and ad- shortcomings of topical IDU therapy: significant toxicity (super- enovirus). Methods. A broad-based literature review in the fields ficial punctate keratitis, chemical conjunctivitis, and punctal oc- of virology, antiviral research, and ophthalmology will be carried clusion) and frequent hypersensitivity reactions, limited its useful- out. The pathogenesis of the major external ocular viral infections ness. As an insoluble agent, it had no therapeutic effect on herpetic and history of antiviral development will be cited. Important con- ceptual breakthroughs as well as historical landmarks will be em- stromal keratitis or iritis. Today, IDU is used infrequently in de- phasized. Results. The successful development of effective anti- veloped nations because it has been replaced by better drugs. How- virals to treat the most common external ocular viral infections ever, it remains effective and is used in developing nations where have dramatically reduced morbidity and sight loss. The immune cost issues are critical. pathogenesis of herpetic stromal keratitis is better understood. In the mid-1970s, several promising strategies to treat HSV Conclusions. Remarkable progress in the development of antiviral epithelial keratitis failed. These approaches included interferon therapy has occurred over the past quarter century. Future needs inducers, long acting, slow-dissolving IDU inserts (Ocuserts; Alza include improved antivirals and immunomodulators and vaccines Corp, Palo Alto, CA, U.S.A.), cryotherapy, and photodynamic to prevent and treat herpetic ocular infections and adenovirus kera- inactivation with light-activated dyes.5,6 toconjunctivitis. In 1976, vidarabine (Ara-A) was introduced as the second an- Key Words: Antiviral—Herpes simplex virus—Varicella-zoster 6 virus—Herpes zoster ophthalmicus—Adenovirus—EKC. tiviral for topical therapy of HSV epithelial keratitis. It is a purine nucleoside analog to adenine (Fig. 2). The mechanism of action includes inhibition of TK, DNA polymerase, and DNA chain ter- HERPES SIMPLEX OCULAR INFECTIONS mination. Clinical trials demonstrated equivalent efficacy to IDU against HSV epithelial keratitis. Like IDU, it is relatively insoluble Herpes Simplex Epithelial Keratitis and demonstrates a similar toxicity profile. It is used mainly today By 1975, the antiviral treatment of live virus replication asso- by health maintenance organizations seeking cost-savings and in ciated with herpes simplex keratitis was well established. The rare cases of hypersensitivity reactions to trifluridine (TFT). major historical breakthrough had occurred in 1959 when William 1 In 1980, TFT was introduced as a major improvement over Prusoff first synthesized a new anticancer drug, idoxuridine previous topical antivirals.5,7 It is a thymidine analog similar in (IDU) (Fig. 1). Although it proved too toxic for systemic use in structure to IDU but has three fluorine atoms at the five methyl cancer patients, the antiviral strategy to differentially block DNA group of the pyrimidine base (Fig. 2). Its mechanism of action is synthesis of intracellular herpes simplex compared to its host cell similar to the other nucleoside analogs, IDU and Ara-A. Clinical proved to be “the magic bullet.” IDU became the first antiviral trials demonstrated superiority to IDU and Ara-A, especially in the drug to successfully treat a human viral infection when, in 1962, presence of topical steroid. After frequent topical instillation, TFT Herbert Kaufman demonstrated that topical therapy of herpetic penetrates the cornea to produce therapeutic levels in the aqueous. epithelial keratitis with IDU led to rapid healing of corneal lesions 2 3 Topical toxicity is mild and includes superficial punctate keratitis, in rabbits and patients. The mechanism of action was based on chemical conjunctivitis, punctal occlusion, and rare hypersensitiv- the uptake of IDU in place of the natural base, thymidine. Inhibi- ity reactions. For the past 20 years, TFT has proven successful as tion resulted from saturation of critical viral enzymes, thymidine the topical antiviral of choice in the United States for the treatment kinase (TK) and DNA polymerase (pol); incorporation of phos- of herpetic epithelial keratitis. TFT also provides excellent antivi- phorylated IDU to form abnormal viral DNA; and translation of 4 ral coverage when combined with a topical steroid in the treatment defective viral proteins. Clinical success was achieved in the eye of the “immunogenic” herpetic stromal keratitis and iritis. True because frequent dosing of topical IDU delivered directly to the biochemical resistance is very rare, as trigeminal ganglionic la- target replicating herpes simplex virus (HSV) attained virucidal tency guarantees that each reactivation event produces “antiviral- naive HSV virions” at the peripheral ocular site. Failure to obtain a positive clinical response (i.e., resolution of corneal dendrites Submitted February 16, 2000. Accepted April 30, 2000. and/or geographic ulcer) with TFT usually means poor patient From the Department of Ophthalmology, The University of Pittsburgh compliance and/or an incorrect clinical diagnosis. The out-of- School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Address correspondence to Dr. Y. Jerold Gordon, the Department of pocket costs for uninsured patients ($79.00/5-mL bottle; U.S. dol- Ophthalmology, The University of Pittsburgh School of Medicine, 203 lars) is a major impediment to compliance. TFT will remain the Lothrop Street, Pittsburgh, PA 15213, U.S.A. topical agent of choice in the United States for the foreseeable

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FIG. 1. The evolution of antiviral therapy for external ocular viral infections over 25 years. The year indicates date of FDA approval. future as appropriate alternatives (topical acyclovir) will not be equivalent prodrugs, valacyclovir or famciclovir,9 may be admin- marketed in the United States for commercial reasons, and the istered orally as an alternative to topical therapy for the treatment development and Food and Drug Administration (FDA) approval of herpes epithelial keratitis. After systemic administration, toxic- of newer agents has become a slower, more expensive process over ity is rare but normal renal function is required to excrete the drug. the past 25 years. Therefore, patients on long-term ACV suppression therapy should In 1982, acyclovir (ACV), an exciting, breakthrough drug for have their renal function monitored (serial blood urea nitrogen, the treatment of all herpes simplex (HSV-1, HSV-2) and varicella- creatinine). zoster infections, became available in the United States.5,8 ACV is Ganciclovir (1989),5 foscarnet (1991), and cidofovir (1996)9 a purine analog to guanine with its deoxyribose ring broken open (Fig. 2) are other FDA-approved antiviral agents that are effective (Fig. 2). ACV represents a second generation antiviral that is spe- when administered systemically against HSV but that are not com- cific for HSV-infected cells only. This selectivity of antiviral ac- mercially available for topical therapy of HSV-1 epithelial kerati- tion significantly reduced host cell toxicity; and, for the first time, tis. Ganciclovir ophthalmic gel 0.15% is currently in clinical trials an antiviral agent could be administered orally and intravenously in Europe.10 Brivudin, another thymidine nucleoside analog (Fig. to treat serious systemic HSV simplex infections (encephalitis, 2), is also effective as a topical agent against HSV-1 epithelial genital herpes, etc.) in immunocompetent and immunosuppressed keratitis but is only available in Europe.11 patients. The mechanism of action of ACV is as a nucleoside After 25 years of antiviral development, we currently have ex- analog that blocks critical HSV enzymes (TK, DNA polymerase) cellent topical antivirals (TFT, ACV) for the treatment of HSV-1 and also functions as a DNA chain terminator. ACV readily pen- epithelial keratitis. Antiviral resistance is not a clinical problem etrates the cornea after topical administration to produce virucidal because of the role of HSV-1 ganglionic latency in recurrent kera- levels in the aqueous. ACV demonstrates significantly less ocular titis. Nevertheless, ophthalmology would be well served with the toxicity (superficial punctate keratitis, punctal occlusion) than any development of newer topical antivirals that are more potent, less other topical antiviral (TFT, Ara-A, and IDU). ACV ointment, 3% toxic, and cheaper. Infrequent dosing would provide for improved five times a day, is an extremely effective topical antiviral for the patient convenience and better compliance. Finally, research to treatment of herpes epithelial keratitis; and, outside of the United develop antivirals other than nucleoside analogs to inhibit States, it remains the drug of choice. ACV (400 mg T.I.D.) or HSV-1 is worthwhile and ongoing (e.g., ribonucleotide reductase

Cornea, Vol. 19, No. 5, 2000 ANTIVIRAL THERAPY FOR EXTERNAL OCULAR VIRAL INFECTIONS 675

FIG. 2. The chemical structures of antivirals used in ophthalmology. The single letter within the parentheses represents the natural base (A, adenine; T, thymine; G, guanine; U, uracil) for each antiviral nucleoside analog. The year indicates date of FDA approval.

inhibitors,12 antisense inhibitors,13 and others [n-docosanol, 1970s. The role of live HSV-1 in herpetic stromal disease and iritis SP-303]9). was debated because of the demonstration of HSV particles in necrotizing keratitis14 and the recovery of live virus from Herpetic Stromal Keratitis/Iritis the aqueous.15 However, there was general acceptance of Unlike herpetic epithelial keratitis with many therapeutic Jone’s Immunological Blotter Theory that HSK and iritis were options, herpetic stromal keratitis (HSK) remains the major blind- principally host immune and inflammatory responses to HSV an- ing form of herpetic ocular infection with fewer successful thera- tigens deposited in the stroma, endothelium, iris, and trabecular peutic options to date. The clinical distinction between herpetic meshwork after HSV-1 epithelial keratitis.16 Clinical observations epithelial disease (dendritic and geographical ulcers) and stromal of the day supported this theory of HSK/iritis—i.e., no concurrent disease associated with iritis was well understood by the early epithelial dendritic or geographic lesions, no live HSV-1 by tear

Cornea, Vol. 19, No. 5, 2000 676 Y.J. GORDON film culture, and a positive clinical response to topical steroid Prevention Strategies For Recurrent HSV therapy. Ocular Infections Research to better understand the pathogenesis of HSK has been aggressively pursued using animal models of HSV cor- Behavioral neal infection over the past quarter century. Important fac- tors appear to be immune complexes formed between HSV antigen In the mid-1970s, preventing recurrent herpetic keratitis was and circulating anti-HSV antibodies,17 cell-mediated immunity recognized as important to prevent sight loss from repeated corneal and a cytokine-mediated inflammatory cascade,17–20 and viral scarring. Topical antiviral prophylaxis with IDU and Ara-A was “molecular mimicry.”21 Although cell-mediated immunity is dem- limited by significant local toxicity and frequent hypersensitivity onstrated by the role of CD4+ helper T cells, interleukin-2, inter- reactions. A behavioral approach was favored in which each pa- leukin-10, and gamma-interferon,18–20 molecular mimicry is sug- tient was advised to discover and avoid his unique clinical trig- gested by a late HSV-1 structural gene (UL 6) that produces ger(s) (e.g., stress, ultraviolet exposure, fever, hormonal changes). a protein identical to a host cell protein with the same gene Unfortunately, for many patients, no specific triggers could be 6,14 sequence.21 identified. Despite the apparent clinical benefits of topical steroid therapy for HSK and iritis, the mid-1970s were characterized by a con- tinuation of the “The Steroid Wars,” which began in the 1950s Long-term Antiviral Suppression Therapy with the introduction of topical corticosteroids into ophthalmic The breakthrough therapy in the prevention of recurrent herpetic care. The influential West Coast School, led by Phillip Thygeson infections was spearheaded by successful long-term antiviral sup- of the prestigious Proctor Foundation (UCSF, San Francisco, CA, pression therapy with oral ACV to reduce the frequency and se- U.S.A.), was unalterably opposed to the use of topical corticoste- verity of episodes of genital32,33 and orolabial herpes.34 Long-term roids in any herpetic eye infection, including the “immunogenic” suppression proved to be safe and effective up to 5 years, with no HSK and iritis.14 In contrast, the East Coast School led by Kauf- emergence of resistant strains in immunocompetent patients.35 man, Pavan-Langston, Laibson, and Nesburn favored a judicious ACV suppression therapy (400 mg T.I.D.) also reduced the need use of topical steroids in conjunction with an antiviral cover for for Cesarean section in patients with recurrent genital herpes36 and “appropriate” cases of HSK and iritis.22 These scientific differ- prevented reactivation of orofacial HSV-1 after laser resurfacing ences were finally resolved 40 years later by the Herpetic Eye cosmetic plastic procedures.37 The success of ACV suppression Disease Studies (HEDS I & II) in favor of the East Coast School. therapy for genital herpes has been duplicated with the prodrugs The HEDS I study demonstrated the value of a 10-week course valacyclovir38 and famciclovir39 with more convenient dosing. of topical corticosteroid therapy (1% prednisolone phosphate) The value of ACV suppression therapy in preventing recurrent combined with topical antiviral cover (TFT) to treat HSK. Com- HSV-1 epithelial keratitis was suggested by natural history stud- pared to a placebo control, the combined therapeutic regimen dem- ies40,41 and after keratoplasty.41–43 Recent experimental studies onstrated reduced persistence or progression of HSK, shorter du- also suggest the value of valacyclovir prophylaxis in current re- ration of HSK, and no increased risk of recurrent HSV. Postponing fractive procedures in the rabbit HSV-1 latency model.44 the initiation of topical steroid therapy delayed the healing of HSK The definitive National Institutes of Health-sponsored HEDS II 23 but did not adversely affect the visual outcome at 6 months. The study proved the value of long-term ACV suppression therapy for HEDS I study also demonstrated no clinical benefit in treating any form of ocular HSV (19% ACV vs. 32% control; p < 0.001), HSK with a 10-week course of oral ACV as adjunct therapy to for HSV stromal keratitis (14% ACV vs. 28% control; p < 0.005), standard topical therapy of TFT and 1% prednisolone phosphate.24 and for nonocular herpes and (primarily) orofacial (19% ACV vs. Furthermore, the HEDS II study showed that after an episode of 36% control; p < 0.001).45 The most important result from the HSV-1 epithelial keratitis, a 3-week course of oral ACV (400 mg HEDS II study was the “paradoxical” finding that HSK, “an im- T.I.D.) failed to prevent the development of HSK (10% ACV vs. munogenic disease,” could be significantly reduced by ACV sup- 11% control) or iritis in a 12-month follow-up period. The risk of pression therapy (400 mg B.I.D.). This result provided, for the first HSK or iritis after HSV-1 epithelial keratitis was significantly time, a practical strategy to prevent this blinding form of ocular higher (26%) in patients with a prior history of HSK or iritis.25 herpes. Other smaller HSK treatment studies demonstrated flubi- How an antiviral could prevent recurrent HSK again raises the profen to be effective when combined with antiviral cover.26 question of the role of live virus in this “immunogenic disease.” Cyclosporine A, a T cell inhibitor, demonstrated efficacy Three possibilities include direct antiviral inhibition of live HSV in experimental HSK models27,28 and in patients.29 Antiviral cover restricted to the stroma after ganglionic reactivation, corneal la- with oral ACV was shown to be as effective as topical tency46–48 associated with limited viral replication and partial gene ACV when combined with topical steroids in the treatment expression with limited production of viral antigens,49 and a per- of HSK.30 sistent “low-grade” infection of HSV-1 sequestered in stromal For treatment of HSV-1 iritis, the HEDS I study demonstra- keratocytes and endothelial cells. Additional research is necessary .with a to clarify which mechanism is operative (0.06 ס ted a strong trend for clinical benefit (p 10-week course of oral ACV as adjunct therapy to standard Similarly, infectious HSV-1 may play a role in recurrent iritis topical therapy of TFT and 1% prednisolone phosphate. Unfortu- and trabeculitis as suggested by immunohistochemistry50 and nately, the iritis study was stopped because only 50 of a tar- positive cultures for aqueous samples.15,51 Replicating HSV-1 geted 104 patients were enrolled after 4 years of recruiting would explain the therapeutic role for ACV in the these “immu- nationwide.31 nogenic” herpetic ocular diseases. Clinically, ACV suppression

Cornea, Vol. 19, No. 5, 2000 ANTIVIRAL THERAPY FOR EXTERNAL OCULAR VIRAL INFECTIONS 677 therapy has been shown to be effective in herpetic iritis52 and was inhibitors. Alpha blockade with thymoxamine and corynanthine58 in the HEDS I study.31 and beta blockade with propranolol59 were effective inhibitors of (0.06 ס suggested by a strong trend (p induced reactivation and ocular shedding of latent HSV-1 in mu- rine and rabbit ocular models. The clinical application of gangli- Vaccination onic blockade as a successful strategy to prevent recurrent HSV infections remains to be demonstrated. This broad topic is beyond the scope of a limited review of antivirals. The reader is referred to two excellent recent reviews on the subject by Bernstein and Stanberry53 and Krause and Strauss,54 VARICELLA-ZOSTER OCULAR INFECTIONS which are summarized briefly. Prevention of recurrent herpetic disease by vaccination has been attempted since the 1920s. Early Over the past 25 years, significant gains have been made in the attempts included nonspecific stimulation of the immune system use of antivirals to treat systemic varicella, HZ and HZO. An using live vectors (vaccinia and BCG) and autoinoculation to aug- alarming increase in the incidence and prevalence of varicella ment the patient’s own immunity. Later vaccine efforts (1930– zoster (VZV) infections and HZO is attributed to diminished cell- 1980) sought specific protection against HSV using heat, formalin, mediated immunity (natural immunosuppression) associated with and ultraviolet-inactivated whole virus vaccines: Eli Lilly vaccine an ever increasing aging population, the expansion of the world- (U.S.A.), Lupidon vaccines (Germany), Skinner vaccine (U.K.), wide acquired immune deficiency syndrome (AIDS) epidemic, and Dundarov vaccine (Bulgaria), Cappel vaccine (Belguim), Kutnova an overall increase in the number of cancer patients. Furthermore, vaccine (Czech Republic), and Ivanovsky vaccine (Russia). De- therapeutic immunosuppression associated with the explosive spite widespread uncontrolled trials with these inactivated whole growth of transplantation surgery, cytotoxic therapy for serious virus vaccines, a therapeutic benefit (while claimed by many) has autoimmune diseases, and chemotherapy for cancer patients all never been scientifically proven in controlled trials. diminish patient cell-mediated immunity and promote VZV infec- A promising approach to prevent recurrent HSV-1 would be to tions and HZO. In 1976, the ocular signs of acute and chronic VZV use a genetically engineered avirulent live vaccine to cause a pri- infections were well described as dermatomal skin vesicles, ulcer- mary infection and to specifically colonize the neuronal sites of ative blepharitis, conjunctivitis, epithelial dendrites, stromal infil- latency with an impaired virus that would occupy the biological trates, iridocyclitis, secondary glaucoma, cataract, neurotrophic niche of wild type HSV-1 but that would be genetically incapable cornea, and postherpetic neuralgia, but there were very limited of reactivation to produce recurrent disease. A similar approach therapeutic options.6 Varicella hyperimmune globulin was recom- has been undertaken for VZV with the Varivax vaccine (Merck & mended for at-risk patients with leukemia and other malignant Co. Inc., West Point, PA, U.S.A.), now part of a universal vacci- diseases. The early available topical antivirals 0.1% IDU and 3% nation program to prevent or reduce the frequency of varicella. The Ara-A demonstrated no therapeutic effect on the corneal dendrites success of this approach will be determined by the future incidence observed during acute varicella or HZO. Intravenous Ara-A was and severity of herpes zoster (HZ) and herpes zoster ophthalmicus used sparingly in high-risk immunocompromised patients to pre- (HZO) in today’s vaccinees.55 vent disseminated zoster, but its effectiveness was limited by its Alternatives to a genetically-engineered avirulent live virus vac- insolubility and systemic toxicity. Systemic and topical corticoste- cine include a single cycle replication-impaired HSV-1 mutant roids were the most used drugs for the treatment of HZ and HZO (e.g., disabled infectious single cycle virus vaccine), non-HSV live before effective antivirals. The medical community was divided vectors that express HSV genes (usually glycoproteins), subunit then as it is now as to the value of systemic steroids to reduce acute vaccines (HSV glycoproteins), and plasmid DNA vaccines that and chronic pain associated with inflammation. Topical steroids express HSV glycoproteins.53,54 were favored by some ophthalmologists to reduce ocular inflam- In summary, vaccine development (mostly for genital herpes) is mation associated with keratouveitis, but The West Coast School, ongoing by many pharmaceutical companies. Carefully performed in a doctrinaire manner, opposed the use of topical steroids to treat controlled clinical trials is the only way to evaluate the merits of HZO as it had for HSV-1 stromal keratitis in the previously de- the different vaccine approaches to prevent recurrent herpetic in- scribed “Steroid Wars.”6 fections. In 1982, the introduction of ACV antiviral therapy ushered in a dramatic new era of effective therapeutic options in the treatment of acute VZV systemic and ocular infections. Although there are Ganglionic Blockers conflicting claims about the value of topical ACV in the treatment of VZV epithelial keratitis,60,61 the use of oral ACV has revolu- Although antiviral suppression therapy and vaccination offer the tionized the treatment of HZO, a difficult and sometimes blinding best chances for control of recurrent HSV-1 ocular infections, disease. In 1986, a landmark controlled clinical trial by Cobo et ganglionic blockers represent a novel approach. Once ganglionic al.62 established specific guidelines for the successful treatment of latency has been established by wild type HSV-1, there is no acute HZO. Clinically, ACV promoted a rapid resolution of exist- known strategy (antiviral or otherwise) to eliminate the latent virus ing skin lesions, prevented new lesion formation, and facilitated from its neuronal reservoir. However, blockade of HSV-1 reacti- rapid resolution of VZV shedding and a rapid cessation of acute vation was achieved in the monkey56 and mouse57 using 9-(4- neuralgia. It reduced episcleritis, dendritic keratitis, and iritis dur- hydroxybutyl)-N2-phenylguanine, a drug that inhibits the enzyme ing the acute phase, as well as subsequent chronic stromal keratitis. TK deemed essential for the efficient reactivation of HSV-1. Gan- Unfortunately, ACV had no effect on neurotrophic keratitis or glionic blockade has also been achieved experimentally by ma- postherpetic neuralgia. Although a single study questioned its nipulation of the autonomic nervous system using pharmacologic value in HZO,63 others confirmed it.64 ACV has been over-

Cornea, Vol. 19, No. 5, 2000 678 Y.J. GORDON whelmingly endorsed by ophthalmologists and has become the ganglionic latency and can reactivate to produce a mild zoster. standard of care for HZO in the past 15 years. ACV plays an Important questions remain to be answered in the future. Will essential role in the treatment of HZO in patients with AIDS and Varivax significantly reduce the incidence and severity of HZ and other immunocompromised patients. The natural history of the HZO in future decades? Will future sporadic cases of wild type disease has been altered to create a chronic disease with persistent varicella be more severe as they occur later in life in an adult infectious VZV associated with dermatitis, keratitis, iritis, and fre- population? quent clinical recurrences.65 In immunocompromised patients, in- In summary, the important progress of the past quarter century travenous ACV has replaced the less effective and more toxic includes the successful development of effective oral antiviral vidarabine as the agent of choice.9,66 Chronic ACV therapy in therapy to limit the ravages of HZ and HZO. Antiviral therapy will AIDS patients has led to the emergence of TK-negative ACV- continue to play a vital role in the near future with an expected resistant VZV isolates that have been treated successfully with increase in the number of HZ and HZO cases, but universal vac- intravenous foscarnet.9,66 cination is likely to ultimately reduce the number and severity of The introduction of the prodrugs famciclovir (1994) and vala- HZ and HZO cases in future decades. cyclovir (1995) further enhanced the therapeutic options for the treatment of HZO. After oral administration, famciclovir is con- verted to its active form, penciclovir, and vacyclovir becomes ADENOVIRUS OCULAR INFECTIONS ACV (Fig. 2). Enhanced bioavailability for both drugs produces higher serum concentrations, which allows for more convenient By 1975, ophthalmologists were well aware of the challenges of dosing. Both valacyclovir (1 g T.I.D. ×7 days)67 and famciclovir treating local hospital- and office-based and community epidemics (500 mg T.I.D. ×7 days68 have demonstrated superiority to ACV of adenovirus (ADV) ocular infections. The pathogenicity of ADV in the resolution of acute pain in controlled clinical studies of HZ. ocular infections ranged from mild cases of follicular conjunctivi- Currently, the dosage regimens established in the zoster studies are tis (ADV serotypes 1–11 and 19) and pharyngeal conjunctival recommended for HZO. Although famciclovir is approved for use fever (ADV 3, 4, and 7) treated by primary care doctors and in AIDS patients, early studies with valacyclovir in very debili- pediatricians to serious cases of epidemic keratoconjunctivitis tated AIDS patients were associated with a number of deaths from (ADV 8, 19, and 37) treated mostly by ophthalmologists.72 In the thrombotic thrombocytopenic purpura/hemolytic uremic syn- acute stages of epidemic keratoconjunctivitis, patient signs include drome.69 However, current recommendations include the use of lid edema, pseudomembranes, follicular conjunctivitis, superficial valacyclovir in selected human immunodeficiency virus-infected punctate keratitis, and mild iritis. After several weeks, a subset of patients.66 epidemic keratoconjunctivitis patients will experience months of The most potent antiviral ever developed for the treatment of glare and visual disability secondary to multiple subepithelial im- varicella-zoster virus infections was sorivudine (50% inhibitory mune corneal infiltrates. The economic impact of ADV epidemics concentration 1,000× ACV) that was withdrawn from the Japanese is significant worldwide in time lost from work, school, and the market in 1993 after 18 deaths in patients concurrently receiving military. 5-fluorouracil.9,60 Bromovinyluracil (BVU), a metabolite of Since the 1970s, treatment of epidemic keratoconjunctivitis has sorivudine, inhibited the hepatic enzyme dihydropyrimidine dehy- been symptomatic with topical antibiotics and steroids used in drogenase, which normally catabolizes 5-fluorouracil. Without this unhappy patients with disabling signs and symptoms. The absence enzyme, 5-fluorouracil serum concentrations rapidly rose to fatal of an effective commercially available antiviral frustrates both the levels. Although a recent controlled clinical trial in the United doctor and patient. Strict epidemiologic measures are advised to States demonstrated that once a day dosing (40 mg) with sorivu- limit transmission within families and to prevent epidemic spread dine was superior to ACV in treating HZ in immunosuppressed at doctors’ offices, hospitals, and in the community. Available patients, the FDA has indicated that it will not approve this drug topical antivirals (IDU, Ara-A, TFT, and ACV) demonstrate no and Merck has discontinued its development.70 clinical efficacy in ADV ocular infections. Early studies with in- In 1995, the introduction of Varivax (Merck), a live, attenuated terferon suggested efficacy, but later studies failed to demonstrate VZV vaccine, represented the next major advancement (after oral a therapeutic effect. antivirals) in the management and prevention of varicella-zoster However, the past 25 years have not been without progress.72 systemic and ocular infections. Varivax was developed by Tagaha- The incidence of acute respiratory disease caused by ADVs 4 and shi55 in the 1970s from the Oka strain of VZV recovered from a 7 was significantly reduced in the military after successful vacci- 3-year-old child with natural varicella. The Oka strain was attenu- nation with live, oral vaccines. Several antivirals were shown to ated by serial passage through multiple cell lines and differs from have anti-ADV activity in vitro: cidofovir, HPMPA, 2Ј-nor-cyclic other wild type VZV in its capsid structure and assembly.55 It was GMP, and ganciclovir. Successful ocular models of ADV infec- widely tested in Asia and was found to be safe, immunogenic, and tions were developed for the first time in the New Zealand white highly protective (93–97% protection) against natural varicella.71 (NZW) rabbit and cotton rat and antiviral screening in vivo is now Universal vaccination is now recommended in the United States possible. Pre-clinical testing suggested that topical cidofovir is a and other countries for all children over 1 years of age and for potent, long-acting topical antiviral that could be administered at-risk adolescents and adults. Clinical trials are currently under- infrequently and would be effective against ADV and HSV-1 in way to determine whether therapeutic vaccination with Varivax the NZW rabbit models. Phase I/II clinical trials demonstrated can boost cell-mediated immunity and antibody levels high enough safety and efficacy at the doses tested (0.5% cidofovir B.I.D. ×7 to prevent zoster and HZO in the elderly with wild type VZV days). Compared to placebo, treatment of patients with topical ganglionic latency. Clinical studies have shown that 5–10% of cidofovir promoted rapid clearing of ADV and inhibited the for- Varivax vaccinees develop mild varicella. The vaccine establishes mation of subepithelial immune infiltrates.73 Further development

Cornea, Vol. 19, No. 5, 2000 ANTIVIRAL THERAPY FOR EXTERNAL OCULAR VIRAL INFECTIONS 679 of cidofovir will depend on encouraging results (efficacy and 24. Barron BA, Gee L, Hauk WW, et al. Herpetic Eye Disease Study: a safety) in future trials and a favorable marketing projection. controlled trial of oral acyclovir for herpes simplex stromal keratitis. In summary, when compared to HSV and VZV ocular infec- Ophthalmology 1994;101:1871–2. 25. Anonymous. A controlled trial of oral acyclovir for the prevention of tions, significantly less progress has occurred in the past 25 years stromal keratitis or iritis in patients with herpes simplex virus epithelial in the development of effective antivirals to treat ADV ocular keratitis. Arch Ophthalmol 1997;115:703–12. infections. However, a greater interest by pharmaceutical compa- 26. Vajpayee RB, Dhakal BP, Gupta SK, et al. 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