Long-Term Results of Pro Re Nata Regimen of Aflibercept Treatment in Persistent Neovascular Age-Related Macular Degeneration ILKAY KILIC MUFTUOGLU, CHERYL A. ARCINUE, FRANK F. TSAI, MOSTAFA ALAM, RAOUF GABER, NATALIA CAMACHO, QISHENG YOU, AND WILLIAM R. FREEMAN  PURPOSE: To determine the 24-month results of pa- tients who had pro re nata (PRN) aflibercept treatment owing to recurrent or resistant neovascular macular degeneration.  DESIGN: Retrospective, interventional, consecutive case series.  METHODS: Eighty-one eyes of 78 patients with resis- tant or multiple recurrences of intraretinal or subretinal fluid while receiving monthly bevacizumab or ranibizu- mab injections and were switched to strict, as-needed afli- bercept treatment with every-8-weeks spectral-domain optical coherence tomography (SDOCT)-guided moni- toring were included. If there was a persistence of fluid despite this treatment, more frequent aflibercept injec- tions were considered. Anatomic outcomes including maximum retinal thickness, central macular thickness, maximum pigment epithelial detachment height, maximum fluid height, and visual acuity (VA) were assessed at given follow-ups.  RESULTS: All anatomic endpoints significantly improved following 3 consecutive aflibercept injections, which were maintained through 24 months (P < .05 for all endpoints at all visits). Thirty-seven eyes (45.6%) required more frequent injections with monthly SDOCT-guided monitoring at a median of 37 weeks (interquartile range, 30–62 weeks) to adequately treat the retinal fluid. Seventy-one of 81 eyes (87.7%) became completely dry on at least 1 follow-up visit; however, there was no significant improvement in VA during the study period.  CONCLUSION: Aflibercept injection with an as-needed regimen was effective in many eyes previously treated with monthly bevacizumab or ranibizumab injections that had persistent or recurrent fluid. Despite significant improvement in anatomic outcomes, vision remained stable throughout the 2-year follow-up, likely because this cohort of patients had advanced choroidal neovascular membrane upon enrollment (recurrent or resistant). (Am J Ophthalmol 2016;167:1–9. Ó 2016 Published by Elsevier Inc.) A GE-RELATED MACULAR DEGENERATION (AMD) IS the major cause of vision loss in people over the age of 65 years living in industrialized countries. 1,2 It is estimated that 1.2 million people in the United States have wet, or exudative, AMD which is characterized by the presence of choroidal neovascularization (CNV), retinal fluid, hemorrhage, and, eventually scarring. 2 Although anti–vascular endothelial growth factor (VEGF) therapy has revolutionized the treatment of wet AMD and is now the standard of care, some patients may have persistence of intraretinal fluid (IRF) or subretinal fluid (SRF). The Comparison of Age-Related Macular Degeneration Treatments Trial (CATT) demonstrated that the proportion of eyes with persistent fluid was 51.5% following monthly ranibizumab injections and 67.4% in eyes treated with monthly bevacizumab injec- tions, after 2 years. 3 Aflibercept (Eylea; Regeneron, Tarrytown, New York, USA) is a soluble decoy receptor fusion protein that has a high affinity to all VEGF isoforms, as well as to placental growth factor. 4 Theoretical models suggested that afliber- cept has a longer duration of action compared with other available anti-VEGF drugs. 5 In the VIEW 1–2 studies, afli- bercept intravitreal injections dosed monthly or every other month after 3 initial monthly doses were found to be noninferior to monthly 0.5 mg ranibizumab injections in terms of efficacy and safety outcomes in treatment-naı ¨ve wet AMD patients. 4 It has been suggested that aflibercept may have a longer duration of effect, allowing treatment in- tervals to be extended beyond what may be achieved by bevacizumab or ranibizumab. In eyes with persistent fluid or multiple recurrences while on bevacizumab or ranibizumab treatment, one strategy often employed is to switch anti-VEGF agents to see if there may be increased efficacy. 6–11 We previously reported in the same Journal the 6-month and 1-year out- comes of those eyes treated with aflibercept for resistance or recurrence of fluid and/or exudation despite having Supplemental Material available at AJO.com. Accepted for publication Mar 28, 2016. From the Department of Ophthalmology, Jacobs Retina Center at the Shiley Eye Institute, University of California San Diego, La Jolla, California (I.K.M., C.A.A., F.F.T., M.A., R.G., N.C., Q.Y., W.R.F.); and Department of Ophthalmology, Istanbul Training and Research Hospital, Istanbul, Turkey (I.K.M.). Inquiries to William R. Freeman, University of California San Diego, Jacobs Retina Center at the Shiley Eye Institute, 94093 Campus Point Dr, La Jolla, CA 92037; e-mail: freeman@eyecenter.ucsd.edu 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2016.03.038 1 Ó 2016 PUBLISHED BY ELSEVIER INC.