We thank Iacono and associates for their interest in our article, which included wet age-related macular degeneration (AMD) patients that had multiple recurrences or persistence of exudation owing to contingent negative variation (CNV) activity. We felt it important to exclude eyes that had responded excellently to anti–vascular endothelial growth factor (VEGF) agents in terms of CNV activity, and included only eyes that we considered “truly resistant.” There is a significant population of patients who respond well to anti-VEGF agents and remained dry on optical coherence tomography (OCT) and inactive on fluorescein angiography for years; we felt those should be excluded and may fall under Iacono and associates’ classification as “complete responders.” Eyes with multiple recurrences might be termed “transient responders.” We distinguished such eyes from eyes that had persistent fluid, or what Iacono and associates define as “nonresponders.” We agree that the terms “responder” and “nonresponder” for wet AMD patients are confusing and there is no consensus about the meaning of “resistance” to anti-VEGF therapy. In the HARBOR trial, some 20% of wet AMD patients required a large number of intravitreal ranibizumab injections before experiencing a response to the therapy. One may call them “nonresponders,” while others may call them “slow or delayed responders.”
In summary, patient responses to anti-VEGF agents are exceedingly varied, and it is hard to have set criteria when we are dealing with numerous parameters such as presence or absence of response, quality and degree of response, initial or delayed response, visual acuity gain, decrease in central retinal thickness, or a combination of functional and anatomic parameters. However, the response must be qualified and defined in more detail, whether complete, incomplete, or nonresponder, and whether the response is early or delayed, sustained or transient.
In our study, we did not analyze separately the eyes with recurrent vs persistent fluid. We thank Iacono and associates for their suggestion, but at this point we think that only a randomized controlled trial of switching among different anti-VEGF agents can prove whether tachyphylaxis is really the culprit behind resistance; but there does seem to be some benefit of aflibercept on bevacizumab or ranibizumab incomplete responders.