SIRE: Short interval in real life Does intensive anti-VEGF treatment in the first year predict subsequent treatment burden in exudative age-related macular degeneration?

Abstract

Background

Anti-VEGF’s have changed the prognosis of exudative age-related macular degeneration (AMD). Ranibizumab and aflibercept have proven their functional efficacy, but their use has revealed in real life a wide variety of patient profiles with varied responses to treatment. This work focused on patients receiving “intensive” IVT treatment with a sustained injection rhythm, also referred to as having a high treatment burden.

Objective

The main objective of this work was to determine, in real-life conditions, the proportion of patients receiving “intensive” treatment among those being followed for exudative AMD. Secondary objectives were to analyse the long-term functional outcomes of these patients, their anatomical characteristics, and the evolution of their treatment regimen.

Method

A retrospective descriptive single-centre real-life study was conducted on patients treated for exudative AMD with intensive treatment (intervals of less than 8 weeks during the first year of treatment). A subgroup analysis compared patients who exceeded Q8 during follow-up (Group 1) versus patients remaining in intensive treatment (Group 2).

Results

A total of 301 records were analysed, with 24.9% of the eyes (n = 75) considered under intensive treatment. The mean age was 84 years ( ± 7.5), and 61% were men. Type 1 choroidal neovascularization (CNV) accounted for 64% of our cohort, type 2 CNV represented 29.3%, and type 3 was involved in 6.7%. The mean follow-up was 5.6 years ( ± 3.6), with an average number of 41 IVT ( ± 26.7). Visual acuity was maintained at 0.53 ( ± 0.2) baseline vs. 0.61 ( ± 0.2) after 5 years of follow-up (p = 0.02). Central retinal thickness (CRT) and subretinal fluid (SRF) were significantly reduced during our follow-up, and PED height remained stable. Almost half of the eyes (44%) had an extension of their interval ( > Q8) beyond the first year; however, this objective was achieved on average after 4.5 years of treatment. The visual acuity of Group 2 ( < Q8), despite receiving more injections, was superior to that of Group 1 ( > Q8) with baseline values of 0.57 ( ± 0.2) and 0.48 ( ± 0.2) (p = 0.161) respectively, and at 5 years 0.79 ( ± 0.2) and 0.54 ( ± 0.2) (p = 0.026). Similarly, CRT, PED height, and SRF were higher in Group 2. The distribution of neovascular types showed more type 2 in Group 1 (45.5% vs. 16.7%).

Conclusion

Patients requiring intensive treatment represent about ¼ of our AMD patient population. Despite the high treatment burden, these patients maintain their visual acuity at 5 years. An extension of intervals is observed in nearly half of the patients, occurring late. Intensive treatment during the first year appears to be predictive of a future hight treatment burden.

Introduction

Age-related macular degeneration (AMD) is the leading cause of legal blindness in people over 50 in developed countries [1]. The exudative form accounts for the major part of our medical retina activity, as it is managed with anti-VEGFs since 2007 [2]. Bevacizumab (off-label) [3], ranibizumab [4, 5] and then aflibercept have allowed stabilizing or even improving the visual acuity (VA) in patients with exudative AMD [6]. Other molecules or dosages (brolucizumab, faricimab, aflibercept 8 mg) open up new perspectives, particularly in terms of dosing interval, but the real-life experience remains limited. The response to first-generation anti-VEGFs remains very heterogeneous depending on the patient, with dosing intervals ranging from Q4W (intravitreal injection every 4 weeks) to Q20W. In this respect, a personalized management, most often based on a Treat & Extend (T&E) protocol, is proposed [7], to reduce the treatment burden for some patients, while maintaining optimal disease control [8, 9].

In recent years, the experience with anti-VEGFs has allowed distinguishing three patient profiles: very good responders or “Happy Few” (about 15–20% of treated patients), good responders requiring uninterrupted intravitreal injections every 2–4 months (about 50% of treated patients) [10, 11] and, finally, poor or suboptimal responders requiring sustained treatment at < 2-month intervals, referred to as “intensive” treatment in this study. The aim of our study was to analyse the latter profile of patients in whom the treatment burden has an impact on the quality of life [12].

The main objective was to determine, under real-life conditions, the proportion of exudative AMD patients receiving “intensive” treatment. Secondary objectives were to analyse the long-term functional outcomes of these patients, their anatomical characteristics and changes in their treatment regimen.

Materials and methods

This was a monocentric retrospective study conducted between November 2021 and May 2023. All patients actively treated with ranibizumab or aflibercept intravitreal injections for exudative AMD over the study period, exclusively as part of a T&E protocol, and followed since the time of diagnosis in our department were included, in order to have complete data from dose loading to the last visit available.

Eyes treated according to a T&E regimen requiring a dosing interval of less than 8 weeks during the first year of treatment (Q4W, Q5W, Q6W and Q7W maximum) were included. These patients were considered “intensively treated”. In this cohort, two patients’ subgroups were identified. Group 1 included patients for whom a dosing interval >Q8W was achieved after this first year of intensive treatment, and group 2 included the remaining “resistant” patients for whom a dosing interval <Q8W was required throughout their follow-up.

The T&E regimen was applied with dosing intervals that could be extended by 2-week increments. Criteria for exudative recurrence, and therefore dosing interval adjustment, were the presence of intraretinal fluid (IRF), subretinal fluid (SRF), increased retinal pigment epithelial detachment (PED) height, and the appearance of a grey spot. Eyes with AMD look-alike conditions, choroidal neovascularization (CNV) associated with the pachychoroid spectrum, polypoidal vasculopathy, and with associated diabetic macular oedema were excluded.

The following data were analysed: age, gender, weight, height, CNV type, anti-VEGF agent used, lens status, presence of an epiretinal membrane (ERM), history of vitrectomy.

Anatomical and functional data were analysed at the time of diagnosis, and at 1, 2, 3, 4, 5 and, in some cases, 10 years. Optical coherence tomography (OCT) and fluorescein and indocyanine green angiography were performed using the Spectralis angio-OCT device (Heidelberg Engineering Inc., Germany). OCT-angiography (OCT-A) was performed using the OCT Cirrus 5000 (Angioplex) device (Carl Zeiss Meditec AG, Germany) with a 3 × 3 mm pattern, except when a large neovascular membrane was present (6×6 mm). OCT data analysed included the central retinal thickness (CRT), the presence of a PED and its maximum thickness, IRF, SRF and its maximum thickness. Retinal pigment epithelium (RPE) atrophy was defined as the alteration of the RPE monolayer and the underlying hypertransmission at the choroid on spectral domain (SD)-OCT. The presence or absence of macular atrophy was then assessed in each patient, and its area was measured as described by Sadda et al. who have defined the complete RPE and outer retinal atrophy (cRORA) [13]. When OCTA-A images were available, the CNV surface area was also measured. CNV types were assessed based on multimodal imaging according to the classification of Freund et al. [14, 15].

Study objectives

The main objective of this study was to determine the proportion of patients receiving intensive treatment, i.e., not achieving a Q8W interval between intravitreal injections during the first year of treatment. Secondary objectives were to perform a descriptive analysis of the outcomes of these patients based on longitudinal, anatomical and functional data throughout their management. Finally, factors potentially associated with long-term dosing interval >Q8W in intensively treated patients were investigated.

Ethical and regulatory considerations

The study complied with Good Clinical Practice/International Council for Harmonization guidelines, the Declaration of Helsinki, and all applicable country-specific regulations governing the conduct of clinical research, depending on which one guaranteed the best protection for the individual. This study was approved by the institutional review board of the French Society of Ophthalmology (IRB 00008855 Société Française d’Ophtalmologie IRB#1).

Statistical analyses

A descriptive analysis of the age, gender, CVN type, VA, anatomical data and various data relating to the intervals between intravitreal injections and other calculated durations was first performed. Qualitative variables are presented as numbers and percentages and quantitative variables as means and standard deviations. For qualitative variables, comparisons between the groups were performed using the Chi-2 test or the Fisher’s exact test in case of small sample sizes (theoretical number at least < 5). For quantitative variables, comparisons between the groups were performed using the Student’s t-test in case of normal distribution or the non-parametric Mann-Whitney test in case of non-normal distribution or small sample sizes (n1 or n2 < 30). For each quantitative variable, normality was tested using the Shapiro-Wilk test. Data obtained at the time of diagnosis and at 5 years were compared using a paired t-test. The time to achieve a Q8W dosing interval was estimated using the Kaplan Meier method. Survival curves were compared using the log-rank test. Univariate and then multivariate Cox regression models were used to identify factors potentially associated with the achievement of a Q8W dosing interval. Variables with a p-value < 0.10 in the univariate analysis were tested using a multivariate Cox model to identify variables independently associated with the achievement of a Q8W dosing interval. Results are presented as hazard ratios (HR) with their 95% confidence intervals (95% CI).

A value of p < 0.05 was considered statistically significant. All analyses were performed using R software v. 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Between November 2021 and May 2023, 301 eyes of 199 patients, meeting the inclusion criteria, were actively treated for exudative AMD with anti-VEGF intravitreal injections (aflibercept or ranibizumab) according to a T&E regimen with complete record data. Among these eyes, 75 eyes of 70 patients meeting the criteria for intensive treatment were included; 4 eyes were excluded due to missing data on initial management. Thus, 75 eyes treated according to T&E regimens since their loading dose with 3 intravitreal injections, and with a dosing interval not exceeding 8 weeks ( < Q8W) during the first 12 months of treatment, were analysed (Fig. 1). The prevalence of intensively treated eyes was 24.9%. Regarding treatment, two thirds of the patients (68%) had received a loading dose of ranibizumab. Due to suboptimal treatment, they were switched to aflibercept and more than 80% of patients were treated with aflibercept at the last visit (Table 1).

Fig. 1.

Study flowchart for selecting patients receiving intensive treatment.

Table 1.

Baseline Characteristics of patients receiving intensive treatment.

Characteristics	Total N = 75	Group 1 ( > Q8W) N = 33	Group 2 ( < Q8W) N = 42
Age Mean ± SD (years)	84.35 ± 7.5	85.70 ± 6.3	83.29 ± 8.3
Gender	♂ 46
♂ n (%)	(61.3%)	♂ 25 (75.8%)	♂ 21 (50%)
♀ n (%)	♀ 29 (38.7%)	♀ 8 (24.2%)	♀ 21 (50%)
Pseudophakic
n (%)	64 (85.3%)	31 (93.9%)	33 (78.6%)
Vitrectomy
n (%)	5 (6.7%)	3 (9.1%)	2 (4.8%)
CNV type n (%)
1	48 (64%)	15 (45.5%)	33 (78.6%)
2	22 (29.3%)	15 (45.5%)	7 (16.7%)
3	5 (6.7%)	3 (9.1%)	2 (4.8%)
Mean max dosing interval (weeks)	10.17 ± 3.9	13.73 ± 3.2	7.38 ± 1.2
ERM n (%)	20 (26.7%)	11 (33.3%)	9 (21.4%)
Time to achieve a Q8W interval (months)	59.2 ± 37.15	59.2 ± 37.15	N/A
Macular hematoma n (%)	8 (10.7%)	3 (9.1%)	5 (11.9%)
Injection frequency (number of injections/week)	6.57 ± 1.6	7.71 ± 1.8	5.68 ± 0.8
Follow-up duration
Mean ± SD (years)	5.63 ± 3.6	7.44 ± 3.3	4.21 ± 3.1
Median (years)	4.40	7.04	3.17
CNV surface area
μm2	4.13 ± 4.9	4.29 ± 5.5	4.01 ± 4.4
Number of intravitreal injections
Mean ± SD	41.8 ± 26.7	48.82 ± 24.7	36.29 ± 27.2
Ranibizumab
loading dose n (%)	51 (68%)	22 (66.6%)	29 (69%)
Last follow-up visit n (%)	14 (18.6%)	6 (18.1%)	8 (19%)
Aflibercept	24 (32%)	11 (33.4%)	13 (31%)
loading dose n (%)	61 (81.4%)	27 (81.9%)	34 (81%)

Note all six patients demonstrating stereopsis at 10½ years also demonstrated stereopsis with the Frisby and Titmus tests at age 4½ years.

Analysis of the whole cohort

The mean follow-up duration of the cohort was 67.5 ± 43 months, i.e. more than 5 years. Patients received a mean number of 41.8 ± 26 intravitreal injections during the follow-up. Patients’ mean age was 84 ± 7.5 years, and there was clearly a male predominance (38.7% of women, 61.3% of men). Most patients (85.3%) were pseudophakic and 6.7% had a history of vitrectomy. Regarding CNV types, 48 eyes (64%) had type 1 CNV, 22 eyes (29.3%) had type 2 CNV, and 5 eyes (6.7%) had type 3 CNV (Table 1). The mean VA was 0.53 ± 0.2 logMAR at the time of diagnosis and 0.61 ± 0.2 logMAR during the first 2 years of follow-up. A significant functional improvement was observed, with a stable mean VA of 0.61 ± 0.2 logMAR at 5 years (p = 0.04) (Fig. 2). The mean CRT was 376 ± 110 µm at the time of diagnosis. During the first two years of treatment, it decreased significantly, reaching a plateau below 300 µm until the end of our 5-year follow-up (295 ± 68 µm, p = 0.0003). The SRF height also decreased significantly from 122 ± 113 µm at the time of diagnosis to 23 ± 39 µm at 5 years (p = 7.4 10^e-6). In contrast, the mean PED height remained stable during the follow-up (200 ± 173 µm at time of diagnosis versus 171 ± 98 µm at 5 years, p = 0.43) (Fig. 2).

Fig. 2. Changes in the whole cohort.

A Visual acuity; B CRT, SRF, and PED height.

Atrophy was present from the time of diagnosis in 16% of eyes. The mean atrophy area was measured at 0.44 ± 2.3 µm² at the time of diagnosis and increased progressively to 2.54 ± 4 µm² at 5 years (p = 0.00048).

In our whole cohort, the mean dosing interval remained below the 8-week threshold throughout the follow-up period. However, a slight increase in dosing interval was observed over time: 5.9 ± 1.6 weeks, 6.6 ± 2.7 weeks, and 6.9 ± 2.6 weeks at 1, 2 and 3 years, respectively. Thereafter, the dosing intervals no longer increased (6.9 ± 3.6 weeks and 6.8 ± 2.8 weeks at 4 and 5 years, respectively).

A univariate analysis identified type 2 (HR = 2.24, p = 0.03) and type 3 (HR = 4.64, p = 0.02) CVN, as well as the atrophy area at the time of diagnosis (HR = 1.11, p = 0.01), as predisposing factors for switching to a ≥ Q8W dosing interval. The multivariate analysis was only significant for type 3 CVN (HR = 4.55, p = 0.02) and the atrophy area at the time of diagnosis (HR = 1.09, p = 0.04) (Table 2).

Table 2.

Analysis of clinical factors predisposing to achieve a Q8W dosing interval.

Cox model	HR	95% CI inf	95% CI sup	p
Univariate analysis
Age	1.01	0.95	1.06	0.69
Pseudophakic	1.21	0.28	5.21	0.79
Gender	0.68	0.30	1.53	0.35
Type 2 CNV	2.24	1.07	4.68	0.03
Type 3 CNV	4.64	1.26	17.10	0.02
VA at the time of diagnosis	0.23	0.05	1.04	0.05
ERM at the time of diagnosis	0.99	0.99	1	0.61
SRF height at the time of diagnosis	0.99	0.99	1	0.36
PED height at the time of diagnosis	0.99	0.99	1	0.10
IRF at the time of diagnosis	1.55	0.73	3.29	0.24
CNV surface area at the time of diagnosis	0.97	0.90	1.04	0.46
Atrophy area at the time of diagnosis	1.11	1.02	1.21	0.01
Vitrectomy	1.32	0.4	4.37	0.64
ERM	1.48	0.70	3.09	0.29
Macular hematoma	0.9	0.27	2.97	0.86
Multivariate analysis
Type 2 CNV	1.73	0.78	3.82	0.17
Type 3 CNV	4.55	1.22	16.89	0.02
VA at the time of diagnosis	0.33	0.06	1.71	0.18
Atrophy area at the time of diagnosis	1.09	1	1.20	0.04

Bold values are significant at p ≤ 0,05.

Finally, in the whole cohort the cumulative incidence of patient achieving the Q8W threshold increased very slowly over time (13% at 2 years, less than 20% at 4 years and only 30% at 6 years) (Fig. 3). The analysis according to the CNV subtypes with cox model showed that eyes with type 1 CNV were the most resistant over time (Fig. 3).

Fig. 3. Q8W dosing interval incidence and Cox model analysis.

A Cumulative incidence of achieving a Q8W dosing interval during follow-up in the whole cohort. B Cox model analysis based on CNV type.

Subgroup analysis

The subgroup of eyes that achieved a > Q8W dosing interval during the follow-up (group 1) accounted for 44% of all eyes (n = 33). The mean time to achieve a > Q8W dosing interval was long: 236 ± 148 weeks, i.e., 4.5 years (median: 4.8 years).

The dosing interval distribution for patients in group 1 ( > Q8W) showed that they were able to achieve long dosing intervals (Q10W, Q12W and Q16W) after a first year of intensive treatment.

Group 2 accounted for 56% of eyes (n = 42), that never achieved or exceeded a Q8W dosing interval during their follow-up (min-max: 13.75-149 months). The mean VA was higher in group 2 at 4 and 5 years (Fig. 2). Anatomically, all criteria (CRT, PED height and SRF) were higher in group 2 including the most resistant eyes (Fig. 2). This difference was significant for PED and SRF at 2 years. New vessel distribution differed between both groups with more type 2 and 3 CNV in group 1 ( > Q8W dosing interval): 45.5% versus 78.6% for type 1, 45.5% versus 16.7% for type 2 and 9.1% versus 4.8% for type 3 (p = 0.008).

Discussion

We have recently reported in the LIRE study that long dosing intervals ≥Q12W were achieved in a real-life setting in 38% of eyes treated for exudative AMD [16]. Here, we focused on the other extreme, i.e., short intervals in a real-life setting, by defining an intensive treatment profile (first year of treatment without achieving a Q8W dosing interval) and analysing the outcomes. In our cohort, a quarter of our exudative AMD patients received intensive treatment according to a T&E regimen in the first year. This finding is consistent with the results of the ALTAIR study (30%) [11] and those of a recent real-life study of the Fight Retinal Blindness (FRB) registry based on European data showing a rate of intensively treated patients of 25%, although the definitions of intensive treatment may vary. Boudousq et al. had defined intensive treatment as patients maintaining a mean dosing interval of Q6W after more than 2 years of treatment [17], whereas in our study we chose the criterion <Q8W during the first year of therapeutic management. Despite this, we found the same rate. This could be explained by changes in the injection profiles we analysed, showing that less than half of these intensively treated patients (44%) were able to achieve the >Q8W dosing interval, but only after a very long mean time of 4.5 years of intensive treatment. This long time could be explained by the slow change in neovascular membrane, which was initially very active and eventually became fibrosed over time.

This rate of 25% of intensively treated patients therefore accounts for a non-negligible proportion of suboptimally treated patients, also referred to in the literature as poor responders, or even “recurrent” or “recalcitrant” patients [18, 19]. They largely contribute to the unmet needs currently under discussion. The use of new molecules could reduce this rate. Pivotal studies assessing treatment regimens sometimes limited to a minimum Q8W threshold can only partially answer this question, and new real-life studies are needed to improve our knowledge.

Regarding baseline characteristics, the mean age of our intensively treated cohort was 84.3 ± 7.5 years, which is higher than that of patients in other French studies such as the GEFAL study (79 years) [20], but closer to that reported in the Landscape study (81 years). In our study, there was a clear male predominance with 67% of men, whereas we have recently reported the opposite with a female predominance (64%) in the French Landscape epidemiological study [21]. Our study focuses exclusively on patients requiring intensive treatment, which might have a different gender representation than the general wet AMD population. However, our study is based on a relatively small sample of 70 patients and the difference may come from a sampling fluctuation. This potentially different gender distribution might be an interesting finding but should be validated in larger samples.

The VA remained stable or even improved in the long term after 5 years of treatment, confirming the efficacy of anti-VEGF therapy, even in this very specific profile of intensively treated patients. Due to the aggressiveness of neovascular membrane activity, poorer functional outcomes could have been expected. This is therefore a positive message for our intensively treated patients.

We could also highlight a better VA in group 2 ( < Q8W dosing interval). This could be explained by the lower rate of atrophy, as well as by the high frequency of intravitreal injections and patient adherence. The mean follow-up duration was longer for group 1 than for group 2 (7.4 and 4.2 years, respectively), and we compensated for this bias by analysing the VA and anatomical criteria at fixed timepoints (2, 3, 4 and 5 years).

We also investigated the impact of the CNV type. Initially intensively treated eyes with type 1 CNV were more likely to remain intensively treated in subsequent years.

Regarding anatomical biomarkers, only the SRF height was really impacted by intensive treatment, with a significant drop from the first year of treatment. Conversely, the PED height and the CRT remained fairly stable and unchanged from the second year of treatment.

The persistence of IRF over time, found in about 70% of our patients, could explain why the CRT did not decrease, although SRF resorbed. Exudative signs persisted 4 weeks after an intravitreal injection in 33% of anti-VEGF-treated AMD patients in a recent Greek study, highlighting the existence of poor responders to anti-VEGF [22]. In our study, this rate was higher, since we only analysed poor responders. We observed that the eyes of group 1 had significantly less fluid than the persistent eyes of group 2, showing a better response, albeit partial, and suggesting their potential future fluid extent.

The distribution of CVN in our study also showed a predominance of type 1 CVN, found in 64% of the whole cohort, and in 78.6% of eyes with persistent intensive treatment. This is consistent with the results reported by Mathis et al. indicating that type 1 CNV required more intensive treatment with anti-VEGF intravitreal injections than other CNV types [23], and were also associated with less atrophy [24]. The distribution of type 2 CVN was also very uneven, predominating in eyes of group 1 (45.5% versus 16.7%), which could explain the greater progression of macular atrophy observed (associated with type 2 CNV), but also the poorer functional prognosis. The area of atrophic patches increases over time, and this evolution is well known as a factor limiting the long-term visual prognosis [25, 26]. As indicated in Table 1, 68% of our sample received a loading dose of ranibizumab compared to only 32% for aflibercept. However, at the most recent recorded visit, only 20% of patients were still on ranibizumab, while a significant majority (80%) had switched to aflibercept. This shift likely reflects the fact that ranibizumab was introduced to the market earlier (2007 vs 2012) and our analysis includes patients with very long treatment periods (over 10 years).

Regarding dosing intervals, in group 1, the mean maximum dosing interval was 13 weeks. Furthermore, at the last follow-up visit, it was interesting to note that two thirds of the eyes achieved a ≥ Q12W dosing interval (40% at Q12W, and 27% at ≥ Q14W).

These results showed the emergence of 2 almost equally represented profiles among intensively treated patients: those whose regimen remained persistent, and those who were able to switch to longer dosing intervals, even if this lengthening was achieved late. The VA maintained at 5 years was another very good sign, as it is an important information to provide to our intensively treated patients, to encourage them to continue injections and maintain their adherence.

In the future, these results could be further improved by the advent of two new molecules, faricimab and brolucizumab, as well as the new 8 mg dosage of aflibercept. The HAWK and HARRIER studies have indeed shown an anatomical superiority of brolucizumab over aflibercept 2 mg, but it is especially important to note that there is also a 50% reduction in poor responders with this new anti-VEGF [27]. The TENAYA and LUCERNE studies assessing faricimab have reported the efficacy of this multi-target molecule over long Q16W dosing intervals, although 21% of patients maintained a Q8W interval at 2 years. While these results are encouraging, they highlight the fact that some patients would still require intensive treatment [28]. Regarding the new dosage of aflibercept 8 mg, the PULSAR study has reported that 17% of patients maintained a Q8W dosing interval after 48 weeks [29, 30]. Real-life studies are needed to obtain additional results, overcoming the Q8W thresholds of pivotal studies.

Finally, 10% of these patients experienced a macular hematoma at 5 years, despite active treatment. Boudousq et al. have recently reported a lower incidence of 4% at 10 years. Matsunaga et al. have also reported that the occurrence of macular hematoma was not related to the extent of injection intervals but rather resulted from mechanical stress on the neovascular membrane [31]. In our cohort, hematomas occurred early: more than 60% during the first year of treatment and 40% during the second year. They were thus more common than in the FRB series (incidence of 1% and 1.6% respectively after 10 and 20 intravitreal injections). They could thus reflect the level of neovascular membrane activity, which was aggressive in our cohort. The high rate of vitrectomized eyes in our study sample can probably be explained by the occurrence of macular hematomas. These patients underwent surgery for subretinal injection of alteplase or washout procedure for an intravitreal haemorrhage. We explored the potential association between vitrectomy and a potentially reduced efficacy of anti-VEGF therapy, but the literature remains inconclusive. Some data suggest that vitrectomy accelerates the clearance of anti-VEGF agents, leading to a shortened intravitreal half-life and potentially reducing their pharmacokinetic efficacy [32]. On the other hand, clinical evidence indicates that intravitreal anti-VEGF injections remain effective in vitrectomized eyes, with favourable anatomical outcomes and vision preservation [33]. Further studies with larger samples remain needed to clarify this.

This study has some limitations, including its retrospective, monocentric design and its small sample size, with only 75 eyes studied. It nevertheless presents long-term results (up to more than 10 years) under a T&E regimen, a rarely reported dosing interval follow-up, and only complete cases were included. The literature data available on the 5-year outcome of these intensively treated patients is limited. This cohort allowed identifying two profiles among intensively treated patients: patients whose dosing interval could be extended late, and patients whose intensive treatment persisted (elderly men with predominantly type 1 CNV and significant PED at baseline). The important message for patients remains the good visual prognosis, since the VA was maintained or even improved at 5 years with this sustained injection interval.

Conclusion

Patients requiring intensive treatment accounted for about a quarter of all our current AMD patients. Treatment resistance raises the question of the involvement of other pro-angiogenic factors apart from VEGF. While waiting for other treatment options, a better understanding of these patients and the identification of a typical profile could allow guiding and arguing early our therapeutic choices, especially as new molecules are now available. Further larger studies are needed to confirm our results. In this real-life study, intensive treatment does maintain visual acuity: this is one of the key messages of this article, which carries significant hope for these high burden patients.

Summary

What was known before

• Ranibizumab and aflibercept have proven their functional efficacy.

• There are poor or suboptimal responders requiring intensive treatment.

What this study adds

• Patients requiring intensive treatment represent about ¼ of our AMD patient population.

• These patients maintain their visual acuity at 5 years.

• Intensive treatment during the first year appears to be predictive of a future hight treatment burden.

Author contributions

Conceptualized the study, supervised the project, and contributed to the manuscript’s final revision. (CD, CB, BM). Collected and analysed the data and contributed to the initial manuscript draft. (CD, JB, RC, IF, BM). Provided statistical analysis and critical review of the methodology section (CD, NC, IF, BM). Participated in writing, editing, and reviewing the manuscript. (CD, CB, IF, BM). Contributed to data interpretation and provided technical expertise. (CD, CB, BM).

Data availability

The data supporting the findings of this study have been compiled into an Excel spreadsheet, which is available for consultation. The statistical analyses and detailed results have also been included in tabular form in the supplementary documents attached to this manuscript.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s41433-025-03734-0.