The findings of the present study show that administering monthly injections of ranibizumab to patients with nAMD for 6 months results in improved anatomical outcomes in selected cases. The absorption rate of the SRF volume was faster in patients with shorter durations of previous anti-VEGF treatment. Moreover, our findings imply that quantitative SRF volume evaluations can affect the management strategy for patients with nAMD; for instance, here, we found that six eyes with residual SRF showed slow, but steady, decreases in SRF volume, which meant these patients may benefit from extended continuous anti-VEGF injections.
The development of drug tolerance owing to repetitive treatment with anti-VEGF agents has previously been found to reduce treatment efficacy. [18, 19] Several mechanisms may underlie the decreased drug response in patients with nAMD, including pharmacokinetic tolerance, for instance via the development of neutralizing antibodies for anti-VEGF agents, and pharmacodynamic tolerance, such as through alterations in the neovascular membrane and vessel walls, the increased expression of VEGF or VEGF receptors, alterations in signal transduction, and/or the involvement of other growth factors that stimulate CNV growth. [20] In our study, patients likely exhibited drug tolerance-induced decreases in anti-VEGF efficacy, because all patients demonstrated the fluid-free macula after the first three monthly injections, but some exhibited persistent SRF after repetitive anti-VEGF treatments.
There is no authoritative consensus on how to define the responsiveness to anti-VEGF agents in nAMD patients. Clinically, a patient’s responsiveness is estimated based on whether the fluid-free macula is achieved after three to six anti-VEGF treatments and if there is less or no effect after this numbers of injections, it is generally considered as refractory nAMD. [4–9] However, although easy to perform, this estimation method may not fully reflect the patient’s actual anti-VEGF response. For instance, even if the macula is not completely fluid-free at the end of the treatment period, the patient’s nAMD may be slowly improving (Fig. 3). Our study showed that, among the 13 eyes with persistent fluid at month 6, six eyes (46.2%) exhibited significant decreases in SRF volume during the 6-month study period. These patients would be considered to have refractory nAMD if the conventional qualitative method was applied since their SRF remained after six consecutive anti-VEGF injections. However, these patients likely still have an anti-VEGF response because their SRF volume significantly decreased over the 6-month period, and thus, the patients may still benefit from extended monthly fixed anti-VEGF injections. Hence, quantitative methods of determining a patient’s anti-VEGF response, such as with the volumetric segmentation analyses employed herein, may be more useful than the current qualitative method.
Similar to the findings in previous studies, [21, 22] the PED did not show any significant changes in the present study. However, it should be noted that our sample size was relatively small, and thus we cannot fully determine the changes in PED volume that occurred after six monthly anti-VEGF injections in patients with nAMD with SRF and PED.
Our regression analysis suggested that the SRF volume change rate was negatively related to the duration of previous anti-VEGF treatment. This finding can be interpreted as indicating that prolonged treatment with the anti-VEGF agent can yield drug tolerance as we mentioned above, leading to a decreased SRF absorption rate in patients with nAMD.
Several limitations of this study must be considered. First, our follow-up duration was short, and thus our results only reflect the short-term outcomes of the evaluated fixed-dose regimen. Other limitations of this study include the small sample size and absence of a comparison group. Furthermore, we demonstrated successful outcomes with a single anti-VEGF agent, and as such, it remains unclear whether switching to another anti-VEGF agent may have yielded similar or better outcomes. Although our results are encouraging, a larger randomized controlled trial with a longer follow-up period is necessary to determine if this treatment regimen is indeed beneficial for this subset of patients.