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The Effect of Topical Application of 0.15% Ganciclovir Gel on Cytomegalovirus Corneal Endotheliitis

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The Effect of Topical Application of 0.15% Ganciclovir Gel on Cytomegalovirus Corneal Endotheliitis Clinical science The effect of topical application of 0.15% ganciclovir gel on cytomegalovirus corneal endotheliitis Noriko Koizumi,1,2 Dai Miyazaki,3 Tomoyuki Inoue,4 Fumie Ohtani,3 Michiko Kandori-Inoue,3 Tsutomu Inatomi,1 Chie Sotozono,1 Hiroko Nakagawa,1 Tomoko Horikiri,1 Mayumi Ueta,5 Takahiro Nakamura,5 Yoshitsugu Inoue,3 Yuichi Ohashi,4 Shigeru Kinoshita5 ▸ Additional material is ABSTRACT immunocompetent individuals suffering from anter- published online only. To view Background/aims The aim of this study was to ior uveitis with ocular hypertension45and corneal please visit the journal online – evaluate the therapeutic efficacy and drug transfer of endotheliitis.368 Clinical evidence of CMV-related (http://dx.doi.org/10.1136/ 6–11 bjophthalmol-2015-308238). topical application of 0.15% ganciclovir (GCV) gel on endotheliitis has accumulated, and current 1 cytomegalovirus (CMV) corneal endotheliitis. emphasis is on the importance of early diagnosis Department of 12–14 Ophthalmology, Kyoto Methods This study is a multicentre, prospective, and treatment. Prefectural University of interventional case series. Seven eyes of seven Several studies, including ours, have reported the Medicine, Kyoto, Japan immunocompetent patients diagnosed with CMV corneal usefulness of the systemic and topical application 2 Department of Biomedical endotheliitis, based on clinical manifestations and of anti-CMV medications, such as GCV and valgan- Engineering, Faculty of Life and 36810–14 Medical Sciences, Doshisha qualitative PCR, were enrolled in this study. The patients ciclovir. Our recent study of 106 eyes University, Kyoto, Japan were treated with topical applications of 0.15% GCV gel with CMV endotheliitis in Japan involved the sys- 3Division of Ophthalmology six times daily for 12 weeks without concomitant temic administration of anti-CMV drugs in 67.9% and Visual Science, Faculty of systemic GCV. Clinical evaluations and quantitative PCR and topical administration of GCV prepared from Medicine, Tottori University, of CMV were performed, and GCV concentrations in intravenous infusion vials in 75.2% of the cases. Tottori, Japan 4Department of aqueous humour were measured by liquid Forty-eight per cent of the patients received both Ophthalmology, Ehime chromatography/tandem mass spectrometry. systemic and topical anti-CMV treatment; this com- University School of Medicine, Results Clinical improvement of coin-shaped lesions, bination resulted in improvement or complete Ehime, Japan 5 other types of keratic precipitates, corneal oedema, and remission of KPs and corneal oedema in the major- Department of Frontier fl fi 14 Medical Science and anterior chamber in ammation was con rmed at the ity of cases. Systemic GCV is recognised as an Technology for Ophthalmology, 4-week visit in all seven eyes. The GCV treatment effective treatment for acute inflammation in CMV Kyoto Prefectural University of significantly decreased the CMV copy numbers endotheliitis; however, the long-term use of sys- Medicine, Kyoto, Japan (p<0.0001). After 12 weeks of treatment, six eyes temic GCV is limited due to its systemic side recovered clear corneas with good vision, and effects. Topical GCV therapy has been considered Correspondence to Professor Noriko Koizumi, endothelial function was well maintained. Detectable as a combination therapy with systemic GCV or as Department of Ophthalmology, levels of GCV were confirmed in the aqueous humour of a prophylactic therapy. The clinical effect of 0.15% Kyoto Prefectural University of all the eyes. The mean GCV concentration in the anterior GCV gel, approved for herpes simplex virus (HSV) Medicine, 465 Kajii-cho, chamber was 162.0±202.4 ng/mL. The re-emergence of keratitis, has been suggested in some cases.13 15 Hirokoji-agaru, Kawaramachi- dori, Kamigyo-ku, Kyoto 602- CMV without symptoms was observed in one eye with However, because 0.15% GCV gel has not been 0841, Japan; norikoiz@koto. lower drug transfer. No side effects were observed. approved and marketed in Japan, GCV eye drops kpu-m.ac.jp Conclusions Clinical improvement and reduced CMV prepared in hospital dispensaries from vials copy numbers in the aqueous humour were confirmed in designed for intravenous infusion are often used Received 14 December 2015 the CMV corneal endotheliitis cases. Although the case instead, as clinical studies approved by local ethics Revised 13 March 2016 81014 Accepted 10 April 2016 numbers are limited and long-term follow-up is committees. Considering the heightened rec- Published Online First necessary, the topical application of 0.15% GCV gel ognition of CMV endotheliitis and the increasing 3 May 2016 appears to be a useful treatment option for CMV number of patients in university hospitals, extensive endotheliitis. and long-term use of hospital-prepared eye drops Trial registration number UMIN000012435. might raise concerns regarding its chemical stability and safety. The aim of this prospective study was to eluci- INTRODUCTION date the effects of the topical use of commercially Corneal endotheliitis, characterised by localised available 0.15% GCV gel on CMV endotheliitis corneal oedema with keratic precipitates (KPs), without concomitant systemic GCV.Clinical evalua- often results in severe corneal endothelial dysfunc- tions and quantitative PCR of CMV were per- tion.12In 2006, we reported the first case of cyto- formed, and GCV concentrations in aqueous megalovirus (CMV)-induced corneal endotheliitis in humour were measured by liquid chromatography/ which CMV DNA was detected in aqueous humour tandem mass spectrometry (LC-MS/MS). To cite: Koizumi N, by PCR and which showed a positive response to Miyazaki D, Inoue T, et al. systemic ganciclovir (GCV) treatment.3 Recently, METHODS Br J Ophthalmol attention has been focused on CMV as an aetio- A prospective clinical study of 0.15% GCV gel – 2017;101:114 119. logical factor of anterior segment inflammation in treatment for CMV endotheliitis was conducted at 114 Koizumi N, et al. Br J Ophthalmol 2017;101:114–119. doi:10.1136/bjophthalmol-2015-308238 Clinical science three university hospitals: Kyoto Prefectural University of sample size of seven was estimated to be necessary, assuming a Medicine, Tottori University, and Ehime University. The study within-subject variance of 1, a correlation between repeated protocol was approved by the institutional review boards of the measures of 0.2, and error variance of 2. This sample size pro- three hospitals before beginning the study, which was conducted vided a power of 80% for repeated-measures ANOVA, with a according to the tenets of the Declaration of Helsinki. The 0.05 significance of error rate. study subjects received complete information regarding the protocol, and written informed consent was obtained from each RESULTS participant prior to entry into the study. This study is registered Clinical manifestations of patients with CMV endotheliitis at http://www.umin.ac.jp as study no. UMIN000012435. Seven eyes of seven patients were enrolled in this study from December 2013 to December 2014. Patient demographic data Inclusion and exclusion criteria and clinical manifestations are summarised in table 1 and online The patients in this study were diagnosed with CMV endothelii- supplementary table s-1. Qualitative PCR examination of the tis based on clinical manifestations and viral examination using aqueous humour showed that all seven eyes were positive for qualitative PCR of their aqueous humour; all matched the diag- CMV but negative for HSV and varicella zoster virus (VZV). nostic criteria of CMV endotheliitis.14 Patients treated with any The patients were seven immunocompetent Japanese men, form of GCV therapy (topical or systemic) in the prior month 39–74 years of age (63.4±10.7 years). Six of the seven eyes had were excluded. previously been treated for anterior uveitis with ocular hyper- tension or Posner–Schlossman syndrome at other ophthalmol- Treatment protocol ogy clinics, and corticosteroid eye drops had been applied The patients were treated with 0.15% GCV gel (Virgan, routinely for more than 1 year. One case involved decompensa- Laboratoires Théa, Clermont-Ferrand, France) six times a day in tion of a corneal graft after a second penetrating keratoplasty combination with 0.1% fluorometholone and antibiotic eye (PK) with recurrent inflammation, which was resistant to steroid drops four times a day for 12 weeks. Anti-glaucoma medication and immunosuppressive treatment. Despite the topical steroid was continued for patients under treatment. To eliminate the treatment, these seven cases exhibited progressive corneal possible effect of steroids on the clinical evaluation, patients endotheliitis with corneal endothelial cell loss, and they were who had been treated with a stronger steroid, such as 0.1% referred to the university hospitals. betamethasone, had their medication changed to 0.1% fluoro- At the initiation of topical GCV therapy, coin-shaped lesions metholone for 4 weeks prior to being included in the study after were detected in four eyes (57.1%), other forms of KPs were obtaining informed consent. present in six eyes (85.7%), corneal oedema was observed in five eyes (71.4%) and mild anterior chamber inflammation was Clinical evaluation observed in five eyes (71.4%). Topical glaucoma medications Slit-lamp examinations were performed, and best-corrected were applied to five eyes (71.4%); acetazolamide tablets were visual acuity (BCVA), intraocular pressure (IOP), endothelial cell used concurrently for four of those eyes (57.1%).
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