We read with great interest the article entitled “One-Year Outcomes of Aflibercept in Recurrent or Persistent Neovascular Age-Related Macular Degeneration” by Arcinue and associates. We would like to congratulate the authors for conducting such a thorough study exploring the effects of intravitreal aflibercept administered every 8 weeks in a pro re nata regimen in patients affected by neovascular age-related macular degeneration (nAMD) and showing resistance to ranibizumab or bevacizumab injections.

However, we have a few queries regarding the methodology. The question of the most appropriate definition of resistant patients has already been addressed in previous studies considering patients with refractory, persistent, and resistant conditions or eyes displaying a frequent recurrence of the condition during anti–vascular endothelial growth factor (anti-VEGF) treatment.

In the current study, Arcinue and associates defined patients with multiple recurrences or persistence of exudation as resistant. More specifically, they excluded patients who had responded excellently to anti-VEGF agents and included only eyes that they considered “truly resistant.” It is very difficult to tell the difference between patients who are “truly resistant” and simply resistant.

In our standard clinical practice we usually observe 3 different responses. First of all, as luck would have it, most of the eyes we deal with show a complete response to anti-VEGF, usually indicated by a complete resolution of the fluid after the treatment, which can recur over the follow-up both frequently and rarely. Then there are patients who do not respond to the treatment from the beginning and can truly be defined as “nonresponders.” Lastly, other patients may also display an absence of response after the initial success of the anti-VEGF therapy, and this can be ascribed to the tachyphylaxis phenomenon.

There is currently no clear agreement on the parameters to be adopted to define either the presence or the absence of response, including aspects such as visual acuity change, time or amount of fluid resolution, or a combination of functional and morphologic parameters.

Regarding anti-VEGF resistance, we propose that the concept be divided into 3 aspects: first, functional resistance, characterized by the complete resolution of fluid, with no visual acuity change within at least 2 Early Treatment Diabetic Retinopathy Study (EDTRS) lines ; second, anatomic resistance, characterized by visual acuity improvement of at least 2 lines, in which fluid is detected; and third, full resistance, with visual acuity deterioration and/or no visual acuity change of at least 2 EDTRS lines in association with persistence of fluid.

Arcinue and associates’ definition of resistance based on multiple recurrences is not clear enough, and in our opinion the median number of 2 recurrences does not seem to be a real sign of resistance.

In light of these assumptions, the 32 eyes with persistent fluid collection despite the at least 5-monthly consecutive ranibizumab/bevacizumab injections might also qualify as resistant. The remaining 31 eyes should be considered patients with recurrences and the effects of switching to aflibercept injections should be analyzed separately and compared with studies considering the switching therapy in patients with nAMD responders to other anti-VEGF agents, as for example in the ASSESS trial.