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

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The Evolution of Antiviral Therapy for External Ocular Viral Infections Over Twenty-Five Years Cornea 19(5): 673–680, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia 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 The successful development of effective anti- veloped nations because it has been replaced by better drugs.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 673 674 Y.J. GORDON 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
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