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    Research Update 569


    Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy.

    JAMA. 2023 Feb 7;

    Maturi RK, Glassman AR, Josic K, Baker CW, Gerstenblith AT, Jampol LM, Meleth A, Martin DF, Melia M, Punjabi OS, Rofagha S, Salehi-Had H, Stockdale CR, Sun JK;

    Importance: Anti-vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown.

    Objective: To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported.

    Design, Setting, And Participants: Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME.

    Interventions: Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss.

    Main Outcomes And Measures: Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years.

    Results: Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P < .001). The mean (SD) change in visual acuity from baseline to 4 years was -2.7 (6.5) letters with aflibercept and -2.4 (5.8) letters with sham (adjusted mean difference, -0.5 letters [97.5% CI, -2.3 to 1.3]; P = .52). Antiplatelet Trialists’ Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants.

    Conclusions And Relevance: Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME.

    DOI: 10.1001/jama.2022.25029


    A Randomized Controlled Trial of opt-302, a vegf-c/d inhibitor For Neovascular Age-Related Macular Degeneration.

    Ophthalmology. 2023 Feb 6:

    Jackson TL, Slakter J, Buyse M, Wang K, Dugel PU, Wykoff CC, Boyer DS, Gerometta M, Baldwin ME, Price CF.

    Purpose: Neovascular (wet) age-related macular degeneration (nAMD) is driven by vascular endothelial growth factors (VEGF)-A, -C and -D, which promote angiogenesis and vascular permeability. Intravitreal injections of anti-VEGF-A drugs are the standard of care, but these do not inhibit VEGF-C and -D, which may explain why many patients fail to respond fully. This trial aimed to test the safety and efficacy of OPT-302, a biologic inhibitor of VEGF-C and -D, in combination with the anti-VEGF-A inhibitor ranibizumab.

    Design: Dose-ranging, phase 2b, randomized, double-masked, sham-controlled trial. PARTICIPANTS: Participants with treatment-naïve nAMD were enrolled from 109 sites across Europe, Israel, and USA.

    Methods: Participants were randomized to six, 4-weekly, intravitreal injections of 0.5 mg OPT-302, 2.0 mg OPT-302, or sham; plus intravitreal 0.5 mg ranibizumab.

    Outcome Measures: The primary outcome was mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) at 24 weeks. Secondary outcomes (comparing baseline to week 24) were the proportion of participants gaining or losing ≥15 ETDRS BCVA letters; area under the ETDRS BCVA over time curve; change in spectral-domain optical coherence tomography (SD-OCT) central subfield thickness (CST); and change in intra-retinal fluid and sub-retinal fluid on SD-OCT.

    Results: Of 366 participants recruited 1st December 2017 to 30th November 2018, 122, 123 and 121 were randomized to 0.5 mg OPT-302, 2.0 mg OPT-302 or sham respectively. Mean (± standard deviation) visual acuity gain in the 2.0 mg OPT-302 group was significantly superior to sham (+14.2 ± 11.61 versus +10.8 ± 11.52 letters; p=0.01). The 0.5 mg OPT-302 group was not significantly different to sham (+9.44 ± 11.32 letters; p=0.83). Compared to sham, the secondary BCVA outcomes favored the 2.0 mg OPT-302 group, with structural outcomes favoring both OPT-302 dosage groups. Adverse events were similar across groups, with 16 (13.3%), 7 (5.6%) and 10 (8.3%) participants in the lower dose, higher dose and sham group developing at least one serious adverse event. Two unrelated deaths both occurred in the sham arm.

    Conclusions: Significantly superior vision gain was observed with OPT-302 2.0 mg combination therapy, versus standard of care, with favorable safety.

    DOI: 10.1016/j.ophtha.2023.02.001


    Subretinal Lipid Globules an Early Biomarker of Macular Neovascularization in Eyes with Intermediate Age-Related Macular Degeneration.

    Retina (Philadelphia, Pa.) 2023 Feb 7.

    Fragiotta S, Parravano M, Costanzo E, De Geronimo D, Varano M, Fernández-Avellaneda P, Freund KB.

    Purpose: To explore the association between subretinal lipid globules (SLG) detected in eyes with intermediate age-related macular degeneration (iAMD) with the presence of non-exudative macular neovascularization (NE-MNV).

    Methods: This was a retrospective analysis of 113 consecutive patients with bilateral iAMD (226 eyes) followed for a least 6 months. All eyes underwent multimodal imaging with fundus autofluorescence, spectral-domain optical coherence tomography (SD-OCT), and OCT angiography (OCTA). SLG were identified on SD-OCT as round hyporeflective lesions measuring 31-157 mm located between the ellipsoid zone and the retinal pigment epithelium /Bruch’s membrane complex. NE-MNV was detected with OCTA. The features of NE-MNV lesions detected in eyes with SLG were compared to those in eyes without SLG.

    Results: SLG were identified in 15 eyes of which 14/15 eyes (93.3%) demonstrated NE-MNV on OCTA. In the remaining 98 eyes without SLG, 18 (18.4%) displayed NE-AMD on OCTA. MNV area was larger in the SLG subgroup (+0.38 vs. +0.21 mm2, p=0.008) and showed faster horizontal growth (+727 μm, CI95% 250.4, 1205.4) than MNV in eyes without SLG (+ 64.9 μm, CI95%, 24.3, 154) on OCT B-scan. After a mean of 11.6 months, the conversion rate to exudative MNV was similar between eyes with SLG and those without SLG [8/26 (38.5%) vs. 3/13 (27.3%), p=0.56)].

    Conclusions: The detection of SLG in eyes with iAMD was strongly correlated with the presence of NE-MNV. While these MNV lesions were larger and grew faster than NE-MNV detected in eyes lacking SLG, rates of conversion to exudative MNV appeared similar.

    DOI: 10.1097/IAE.0000000000003760

    Photostress Recovery Time as a Potential Predictive Biomarker for Age-Related Macular Degeneration.

    Translational vision science & technology. 2023 Feb 1;

    Brandl C, Zimmermann ME, Herold JM, Helbig H, Stark KJ, Heid IM.

    Purpose: The purpose of this study was to assess recovery time following photostress and its association with age-related macular degeneration (AMD) cross-sectionally and longitudinally in an elderly population-based cohort.

    Methods: We analyzed photostress recovery time (PRT) and AMD in >1800 AugUR study participants aged 70+ years. On color fundus images from baseline and 3-year follow-up, presence of AMD was graded manually (Three Continent AMD Consortium Severity Scale). Visual acuity (VA) was assessed via Early Treatment Diabetic Retinopathy Study (ETDRS) charts. After a 30-second bleaching of the macular region via direct ophthalmoscope, PRT was measured as the seconds to regain VA.

    Results: First, we analyzed 1208 AugUR participants cross-sectionally (288 with early AMD, and 78 with late AMD). Prolonged PRT was associated with early and late AMD versus no AMD (median PRT = 119.5, 198.0 versus 80.0 seconds, respectively; logistic regression odds ratio [OR] = 1.109-1.165 per 10 seconds, P values < 0.0001). Sensitivity analyses using alternative models or restricting to participants after cataract surgery revealed similar ORs. Second, the association was confirmed in an independent cross-sectional AugUR sample (n = 486). Third, in longitudinal analysis of 233 AugUR participants without AMD, prolonged PRT was associated with incident AMD ascertained 3 years later (follow-up time = 3.2 ± 0.2 years, OR = 1.112-1.162 per 10 seconds, P < 0.05). Overall, we demonstrate a significant association of prolonged PRT with AMD cross-sectionally and longitudinally in elderly individuals.

    Conclusions: Prolonged PRT might capture retinal function impairment after cell damage before early AMD is visible via color fundus imaging.

    Translational Relevance: Our results suggest PRT as quantitative predictive biomarker for incident AMD, making it potentially worthwhile also for clinical care.

    DOI: 10.1167/tvst.12.2.15


    Changes in Retinal Sensitivity Associated with Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa with RPGR Gene Variations.

    JAMA Ophthalmology. 2023 Feb 9:

     von Krusenstiern L, Liu J, Liao E, Gow JA, Chen G, Ong T, Lotery AJ, Jalil A, Lam BL, MacLaren RE;

    Importance: X-linked retinitis pigmentosa (XLRP) is a severe cause of early-onset RP in male individuals, characterized by degeneration of photoreceptors, an extinguished electroretinogram, and vision loss.

    Objective: To assess the duration of improvements in retinal sensitivity associated with a single, subretinal injection of cotoretigene toliparvovec (BIIB112/AAV8-RPGR) gene therapy after vitrectomy surgery in the dosed eye over 12 months in part 1 of the Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) study, compared with untreated fellow eyes and eyes from the untreated subgroup from the Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) study.

    Design, Setting, And Participants: This was a post hoc analysis of the XIRIUS and XOLARIS studies. Part 1 of the XIRIUS study was a phase 1, dose-escalation study of 18 male participants 18 years or older enrolled between March 8, 2017, and October 16, 2018, with genetically confirmed RPGR-variant XLRP with active disease and best-corrected visual acuity better than or equal to light perception (cohort 1), 34 to 73 letters (20/40 to 20/200 Snellen equivalent; cohorts 2-3), or greater than or equal to 34 letters (better than or equal to 20/200 Snellen equivalent; cohorts 4-6). Participants from the noninterventional, multicenter, global, prospective XOLARIS clinical study who met the inclusion and exclusion criteria of part 1 of XIRIUS were included as a comparator group (n = 103). Safety assessments included all XIRIUS participants; post hoc associations of retinal sensitivity assessments in XIRIUS only included the 12 participants receiving the 4 highest doses of cotoretigene toliparvovec. Data were analyzed on June 30, 2021.

    Main Outcomes And Measures: Incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events, changes from baseline in retinal sensitivity (as assessed by macular integrity assessment microperimetry), retinal sensitivity response (achievement of ≥7-dB improvement from baseline at ≥5 of 16 central loci), and low-luminance visual acuity were assessed over 24 months.

    Results: A total of 18 participants (mean [SD] age, 31.9 [9.4] years; male, 100%) were enrolled and completed the XIRIUS study. A subgroup of 103 participants (mean [SD] age, 30.8 [11.4] years; male, 100%) from the XOLARIS study was included. Administration of the 4 highest doses of cotoretigene toliparvovec (n = 12) among the 18 XIRIUS participants was associated with early improvements in retinal sensitivity. One of 103 untreated participants (1%) in the XOLARIS subgroup achieved improved retinal sensitivity at month 12. No DLTs were noted at any dose, and serious adverse events of reduced visual acuity (n = 2) and noninfective retinitis (n = 1) occurred.

    Conclusions And Relevance: Results suggest that early and sustained improvements in retinal sensitivity and low-luminance visual acuity in some participants through 12 months support consideration of additional clinical trials.

    DOI: 10.1001/jamaophthalmol.2022.6254


    Genetic Variability of Complement Factor H Has Ethnicity-Specific Associations With Choroidal Thickness.

    Investigative ophthalmology & visual science. 2023 Feb 1;

    Fenner BJ, Li H, Gan ATL, Song YS, Tham YC, Jonas JB, Wang YX, Cheng CY, Wong TY, Teo KYC, Tan ACS, Fan Q, Cheung CMG.

    Purpose: To identify genetic alleles associated with differences in choroidal thickness (CT) in a population-based multiethnic Asian cohort.

    Methods: A population-based multiethnic Asian cohort without retinal pathology was subjected to spectral-domain OCT (SD-OCT) and genotyping of risk alleles in CFH, VIPR2, ARMS2, and CETP. Subfoveal choroidal thickness (SFCT) values were assessed from SD-OCT, and associations with the risk alleles were determined for each cohort.

    Results: A total of 1045 healthy Asian individuals (550 Chinese, 147 Indians, 348 Malays) were prospectively enrolled in the study. Several CFH alleles (rs800292, rs1061170, and rs1329428) were associated with increased SFCT in Indians (+18.7 to +31.7 µm; P = 0.001-0.038) and marginally associated with decreased SFCT in Malays (-12.7 to -20.6 µm; P = 0.014-0.022). Haplotype analysis of CFH revealed variable associations with SFCT among races, with the H6 haplotype being associated with a 29.08-µm reduction in SFCT in the Chinese cohort (P = 0.02) but a 35.2-µm increase in SFCT in the Indian cohort (P < 0.001). Finally, subfield analysis of the Chinese cohort identified associations between the CFH risk allele rs1061170 and reduced CT in the nasal and superior sectors (-20.2 to -25.8 µm; P = 0.003-0.027).

    Conclusions: CFH variants are variably associated with CT among Asian ethnic groups. This has broad implications for the pathogenesis of common diseases such as age-related macular degeneration and central serous choroidopathy, the pathogenesis of which is associated with CT.

    DOI: 10.1167/iovs.64.2.10


    Associations with non-persistence with intra-vitreal therapy for neovascular age-related macular degeneration at 24 months.

    Ophthalmologica.journal international d’ophthalmologie. International Journal of ophthalmology. Zeitschrift fur Augenheikunde. 2023 Feb 6.

    Relton SD, Chi GC, Lotery AJ, West RM, McKibbin M;

    Aims: To investigate non-persistence with treatment for neovascular age-related macular degeneration (NvAMD) before day 720 (24 months) after initiation, explore associations with baseline characteristics and variation between sites.

    Methods: Anonymised demographic and clinical data were extracted from electronic medical records at treating National Health Service (NHS) Trusts for NvAMD eyes starting intra-vitreal therapy from 2017-2018. Time to non-persistence with treatment, defined as no recorded attendance for either monitoring or treatment for a period ≥6 months, was visualised with a Kaplan-Meier survival plot. Associations with treatment non-persistence were investigated using a Cox proportional hazards model.

    Results: Analysis included 7,970 eyes of 7,112 patients treated at 13 NHS Trusts. Censoring deaths and those eyes in which treatment was stopped permanently, the Kaplan-Meier analyses demonstrated survival figures of 77.7% for persistence with treatment to day 360 and 71.8% to day 720. Hazard ratios for non-persistence with treatment were reduced at 10 sites, relative to the reference, with first treated eye status and with baseline acuity ≤ LogMAR 0.5. Hazard ratios increased with younger age, in the presence of other ocular co-morbidities and with baseline acuity ≥ LogMAR 1.0. After an episode of non-persistence, visual acuity decreased by at least 0.1 and 0.3 LogMAR in 39% and 18% of eyes respectively.

    Conclusions: Non-persistence with treatment was common, especially in the first year of treatment, and was often associated with a decrease in visual acuity. Treatment site, baseline visual acuity and age were the strongest predictors of treatment non-persistence before day 720. Understanding and addressing reasons for non-persistence are important to ensure that effective but expensive treatments are used cost-effectively and to maintain acuity. Variation in non-persistence between sites, even after adjustment for other variables, suggests that local factors in treatment provision may be particularly important.

    DOI: 10.1159/000529446


    Birdshot chorioretinopathy in an HLA-A29 positive Asian patient.

    American journal of ophthalmol case reports. 2023 Jan 18;

     Regenold J, Ghoraba H, Akhavanrezayat A, Ongpalakorn P, Bazojoo V, Do DV, Nguyen QD

    Purpose: To present a case of birdshot chorioretinopathy (BCR) in a Chinese patient with HLA-A29 positivity.

    Observations: A 45-year-old Chinese female presented at a tertiary Ophthalmology Clinic with complaints of frequent headaches as well as blurred vision, photophobia, and pressure in the left eye (OS). The patient had a significant ocular history of left orbital cavernous hemangioma status post lateral orbitotomy and resection. Uncorrected visual acuity was 20/20 in the right eye (OD) and 20/40 in OS (pinhole 20/30). Funduscopic examination demonstrated optic disc edema, left eye worse than right eye, and vascular tortuosity in both eyes (OU). Late phase fluorescein angiography (FA) showed extensive perivascular and optic disc leakage and peripheral capillary leakage in OU. Laboratory evaluations were positive for human leukocyte antigen-A29 (HLA-A29). The patient was started on 40 mg prednisone daily; mycophenolate mofetil 500 mg twice daily was subsequently added.At the 3-month consultation visit to the Uveitis Clinic, dilated funduscopic examination revealed 1+ vitreous cells and improved optic disc edema in OU. FA showed improved vascular and optic disc leakage in OS but worsened leakage in OD. At this point, indocyanine green angiography (ICGA) was ordered which revealed hypocyanescent lesions throughout the choroid that were centered on the optic disc, supporting and confirming the diagnosis of BCR.

    Conclusions And Importance: The index patient is the first reported case of BCR in an HLA-A29 positive Asian patient.

    DOI: 10.1016/j.ajoc.2023.101802