Therapeutic response in the HAWK and HARRIER trials using deep learning in retinal fluid volume and compartment analysis

Abstract

Objectives: To assess the therapeutic response to brolucizumab and aflibercept by deep learning/OCT-based analysis of macular fluid volumes in neovascular age-related macular degeneration.

Methods: In this post-hoc analysis of two phase III, randomised, multi-centre studies (HAWK/HARRIER), 1078 and 739 treatment-naive eyes receiving brolucizumab or aflibercept according to protocol-specified criteria in HAWK and HARRIER, respectively, were included. Macular fluid on 41,840 OCT scans was localised and quantified using a validated deep learning-based algorithm. Volumes of intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED) for all central macular areas (1, 3 and 6 mm) in nanolitres (nL) and best corrected visual acuity (BCVA) change in ETDRS letters were associated using mixed models for repeated measures.

Results: Baseline IRF volumes decreased by >92% following the first intravitreal injection and consistently remained low during follow-up. Baseline SRF volumes decreased by >74% following the first injection, while PED volume resolved by 68-79% of its baseline volume. Resolution of SRF and PED was dependent on the substance and regimen used. Larger residual post-loading IRF, SRF and PED volumes were all independently associated with progressive vision loss during maintenance, where the differences in mean BCVA change between high and low fluid volume subgroups for IRF, SRF and PED were 3.4 letters (p < 0.0001), 1.7 letters (p < 0.001) and 2.5 letters (p < 0.0001), respectively.

Conclusions: Deep-learning methods allow an accurate assessment of substance and regimen efficacy. Irrespectively, all fluid compartments were found to be important markers of disease activity and were relevant for visual outcomes.

Fig. 1. Adjusted mean fluid volumes.

A Brolucizumab 6 mg and B aflibercept 2 mg. Fluid volumes are presented over the 96-week follow-up in the central 1 mm, 3 mm and 6 mm macular fields for HAWK (upper row) and HARRIER (lower row). Error bars denote 95% CIs. CI confidence interval, IRF intraretinal fluid, SRF subretinal fluid, PED pigment epithelial detachment.

Fig. 2. Adjusted mean fluid volumes.

A Intraretinal fluid, B subretinal fluid, and pigment epithelium detachment C. Fluid volumes are presented over the 96-week follow-up in the central 1 mm, 3 mm, and 6 mm macular fields for HAWK (upper row) and HARRIER (lower row). Error bars denote 95% CIs. CI confidence interval, IRF intraretinal fluid, SRF subretinal fluid, PED pigment epithelial detachment.

Fig. 3. BCVA change for Low and High fluid volumes.

Adjusted mean BCVA change from week 12 for patient subgroups characterised by Low or High fluid volume in the central 6 mm in each of the three fluid compartments (IRF, SRF, and PED). Error bars denote 95% CIs. BCVA best corrected visual acuity, CI confidence interval, IRF intraretinal fluid, PED pigment epithelial detachment, SRF subretinal fluid.

Fig. 4. Mean BCVA change from week 12 until the end of the study.

The results are averaged over all visits and the two studies. Each box represents a patient subgroup characterised by a different combination of High/Low disease activity in each of the three fluid compartments (IRF, SRF and PED). Height of the boxes represents standard error; width of the boxes is proportional to the percentage of patients in the corresponding subgroup. BCVA best corrected visual acuity, IRF intraretinal fluid, PED pigment epithelial detachment, SE standard error, SRF subretinal fluid.