Topical Valganciclovir for the Treatment of Hypertensive Anterior Uveitis

CASE REPORT

Anton Delwig, PhD,* Jeremy D. Keenan, MD, MPH,*† and Todd P. Margolis, MD, PhD*†

The main mode of antiviral therapy is oral valganciclovir, Purpose: To report the use of topical valganciclovir for the which shows very good efficacy.4 Additional approaches treatment of hypertensive anterior uveitis associated with clinical include intravenous ganciclovir, intravitreal ganciclovir, and signs of cytomegalovirus (CMV) iritis. topical ganciclovir.4 However, repeat injections of intravitreal Methods: A case report and review of the literature. ganciclovir has obvious limitations, as does the long-term use of intravenous ganciclovir or oral valganciclovir, whose Results: A 37-year-old man was referred with a unilateral hyper- long-term side effects include bone marrow suppression tensive anterior uveitis with keratic precipitates suggestive of CMV and impairment of fertility.5 Although an ophthalmic gel as the causative agent. After institution of oral valganciclovir and formulation of ganciclovir (0.15%, Zirgan; Bausch & Lomb, topical corticosteroids, the patient’s ocular inflammation resolved Bridgewater, NJ) has been reported to control some patients and intraocular pressure normalized. Therapy was eventually with CMV iritis,4 we have been relatively unsuccessful in changed from oral valganciclovir to ophthalmic 1% valganciclovir using this approach. Because CMV anterior uveitis may ointment, which was able to effectively control ocular inflammation require years of antiviral therapy, there is a need for a safe, and allow the patient to discontinue topical corticosteroids and effective, and less expensive approach for managing CMV antihypertensive medications. Topical application of valganciclovir iritis. We report the successful treatment of a case of presumed did not result in clinically evident ocular surface toxicity. CMV iritis by topical administration of valganciclovir. Conclusions: 1% valganciclovir ointment may prove to be an effective treatment of hypertensive anterior uveitis associated with CASE REPORT clinical signs of CMV iritis. An otherwise healthy 28-year-old white man with a 2-year history of intermittent episodes of elevated IOP in the right eye was Key Words: valganciclovir, CMV, endotheliitis diagnosed with Posner–Schlossman syndrome. Management con- sisted of short courses of topical corticosteroids and antihypertensive (Cornea 2015;34:1513–1515) medications with no systemic or topical antivirals. By his mid 30s, the frequency of attacks had increased to the point that long-term management was necessary. By this time, the patient had also ytomegalovirus (CMV) has been recognized as a cause of developed iris atrophy, heterochromia, and anisocoria. Chypertensive iritis in immunocompetent patients, includ- The patient was referred to us at the age of 37 with chronic low- ing cases of Posner–Schlossman syndrome and Fuchs grade iritis and IOPs that were not adequately managed with heterochromic iridocyclitis.1 Clinical features of CMV iritis medications (prednisolone acetate, brimonidine, and dorzolamide/timo- include stellate, circinate, or coin-shaped keratic precipitates, lol). Based on the history, pattern of keratic precipitates, mild anterior elevated intraocular pressure (IOP), and mild inflammation in chamber inflammation, iris atrophy, and elevated IOP (25 mm Hg in the the anterior chamber.1–3 Current management of CMV iritis right eye and 16 mm Hg in the left eye), we suspected CMV iritis. No consists of appropriate antiviral medications along with anterior chamber reaction was noted. The polymerase chain reaction (PCR) of the aqueous was negative for CMV, herpes simplex virus topical steroids and topical antiglaucoma agents as necessary. (HSV), and varicella-zoster virus (VZV) DNA.6 However, because we had previously observed false-negative PCR results in a substantial proportion of eyes suspected to have CMV iritis on clinical grounds, we Received for publication May 23, 2015; revision received June 30, 2015; accepted July 2, 2015. Published online ahead of print September 10, decided to start a course of oral valganciclovir (900 mg twice daily). His 2015. IOP returned to normal levels within 6 weeks, and all keratic precipitates From the *Department of Ophthalmology, University of California, San completely resolved after 3 months. Complete blood counts were tested Francisco, San Francisco, CA; and †Francis I. Proctor Foundation, periodically, and no leukopenia developed. The dose of valganciclovir University of California, San Francisco, San Francisco, CA; A. Delwig is was then reduced to 450 mg twice daily, and the disease remained quiet. now with SiteOne Therapeutics, San Francisco, CA; and T. P. Margolis is Nine months after the start of valganciclovir therapy, now with the Department of Ophthalmology, Washington University, Saint valganciclovir was discontinued and twice-daily ganciclovir gel, Louis, MO. 0.15%, was started. One month later, examination of the right eye A. Delwig has a US provisional patent covering the topical ophthalmic revealed new keratic precipitates in a circinate pattern (Fig. 1) and formulation of valganciclovir. As of now, it has no monetary value. The other authors have no funding or conflicts of interest to disclose. slightly elevated IOP (23 mm Hg). The patient refused to restart oral Reprints: Jeremy D. Keenan, MD, MPH, 513 Parnassus Avenue, Med Sci valganciclovir because of concerns about the toxicity of systemic S334, UCSF Box 0412, San Francisco, CA 94143-0412 (e-mail: jeremy. valganciclovir, and continued ganciclovir gel, topical corticosteroids, [email protected]). and topical antihypertensives. Within 6 months of discontinuing oral Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. valganciclovir, his IOP could not be controlled medically (topical

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effects. Topical ganciclovir (0.15% gel, Zirgan; Bausch & Lomb) has been reported to be effective in a fraction of patients but has been ineffective in our experience, possibly because of poor corneal permeability.3,4,7 Besides the lack of efficacy, ocular surface toxicity is also a concern with long- term use of topical ganciclovir. Topical valganciclovir may prove to be an option for long-term treatment of hypertensive iritis. Valganciclovir is approximately 8-fold more permeable through the cornea than is ganciclovir.8 Valganciclovir may be less toxic to the corneal epithelium than is ganciclovir because to become active, valganciclovir needs to be hydrolyzed by esterases, which are located mostly inside the eye.9 Furthermore, a nonaqueous formulation of valganciclovir may be preferable to an aqueous formulation: first, because the nonaqueous base should prevent hydrolysis of valganciclovir, which has a half-life of only 11 hours in water at neutral pH,10 and second, because a nonaqueous base may not require preservatives. This case report is limited by the lack of a definite diagnosis of CMV by aqueous PCR testing. The morphology of the keratic precipitates was characteristic of CMV iritis, and the quick response to systemic valganciclovir was suggestive of CMV as the etiology. It is possible that FIGURE 1. Keratic precipitates on the corneal endothelium a different herpes virus (eg, HSV or VZV) was responsible during a flare of hypertensive anterior uveitis. Arrow points to for hypertensive iritis because we did not attempt a course of coin-shaped keratic precipitates. acyclovir. However, even if that were the case, our findings are still noteworthy for suggesting that topical therapy could antihypertensives and oral methazolamide), and a filtering procedure have a role in the treatment of hypertensive iritis. was scheduled. In conclusion, this single case report suggests that At the same time, the patient, who was a scientist at topical valganciclovir ointment could be an effective and safe a pharmaceutical company, began surreptitiously treating his condition long-term treatment for hypertensive anterior uveitis that is with self-compounded topical valganciclovir. He initially wore associated with clinical signs of CMV iritis. More cases are a contact lens soaked overnight in 5% valganciclovir and later fi fi formulated 5% valganciclovir eye drops, which he administered 2 to needed to con rm the ef cacy and safety of a topical 4 times per day. We discussed with the patient the risks of using formulation of valganciclovir. valganciclovir in a way not approved by the United States Food and Drug Administration and the risks of compounding medication on his own, yet he chose to continue this therapy. With this approach, the REFERENCES patient’socularinflammation and IOP improved and surgery was 1. Chee SP, Bacsal K, Jap A, et al. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol. 2008; postponed, but he still required topical corticosteroids and topical – antihypertensive medications. After 3 years of controlled inflammation 145:834 840. 2. Koizumi N, Suzuki T, Uno T, et al. Cytomegalovirus as an etiologic on valganciclovir eye drops, the patient became concerned about factor in corneal endotheliitis. Ophthalmology. 2008;115:292–297. medication stability and began formulating 1% valganciclovir ointment 3. Koizumi N, Inatomi T, Suzuki T, et al. Clinical features and management in an oleaginous base (80% white petrolatum and 20% mineral oil), of cytomegalovirus corneal endotheliitis: analysis of 106 cases from the again surreptitiously. Application of this ointment each night was Japan corneal endotheliitis study. Br J Ophthalmol. 2015;99:54–58. effective in controlling his disease with no clinical evidence of ocular 4. Chee SP, Jap A. Cytomegalovirus anterior uveitis: outcome of treatment. surface toxicity. With long-term use of topical valganciclovir ointment, Br J Ophthalmol. 2010;94:1648–1652. the patient was able to taper off topical corticosteroids and topical 5. Segarra-Newnham M, Salazar MI. Valganciclovir: a new oral alternative for fi antihypertensives and has remained stable since then (9 months). cytomegalovirus retinitis in human immunode ciency virus-seropositive individuals. Pharmacotherapy. 2002;22:1124–1128. 6. Cohen JI, Fahle G, Kemp MA, et al. Human herpesvirus 6-A, 6-B, and 7 in vitreous fluid samples. J Med Virol. 2010;82:996–999. DISCUSSION 7. Gunda S, Hariharan S, Mitra AK. Corneal absorption and anterior chamber We describe the successful use of topical valganciclovir pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV): for the treatment of hypertensive anterior uveitis. In our case, in vivo comparative evaluation of these prodrugs with Val-GCV and GCV in rabbits. J Ocul Pharmacol Ther. 2006;22:465–476. the decision to target CMV was based on the classic features 8. Majumdar S, Nashed YE, Patel K, et al. Dipeptide monoester ganciclovir of CMV iritis including coin-shaped keratic precipitate, prodrugs for treating HSV-1-induced corneal epithelial and stromal elevated IOP, and response to valganciclovir despite a single keratitis: in vitro and in vivo evaluations. J Ocul Pharmacol Ther. 2005; negative PCR-based assay for CMV DNA in the aqueous. 21:463–474. 9. Lee VH. Esterase activities in adult rabbit eyes. J Pharm Sci. 1983;72: Currently, there is no safe and effective long-term 239–244. maintenance therapy for CMV-associated anterior uveitis. 10. Stefanidis D, Brandl M. Reactivity of valganciclovir in aqueous solution. Systemic therapy is effective but has serious potential side Drug Dev Ind Pharm. 2005;31:879–884.

APPENDIX: FORMULATION OF 1% TOPICAL tablet) leading to precipitation of the valganciclovir. The precipitate was spun VALGANCICLOVIR OINTMENT down at 3000g, isopropanol was decanted, and remaining volatile solvents fi Valganciclovir was extracted from the tablet form (450 mg, Valcyte; were removed in the lyophilizer. The identity of valganciclovir was con rmed Roche). Briefly, tablets were dissolved in 0.001 N HCl (2 mL per tablet), the by liquid chromatography–mass spectrometry (LC-MS), and 1% (wt/wt) insoluble excipients were isolated by centrifugation at 16,000g, the solution valganciclovir ointment in the oleaginous base (20% mineral oil and 80% was then filtered through a 0.2-mm filter into ice-cold isopropanol (20 mL per white petrolatum) was made by following standard compounding practices.