{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T18:35:15Z","timestamp":1762281315581,"version":"build-2065373602"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To identify predictors of extension of the injection interval beyond 8 weeks at the 24-month visit after switching to brolucizumab in aflibercept-resistant polypoidal choroidal vasculopathy (PCV).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Retrospective observational study<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>17 eyes of 16 patients with persistent or recurrent exudation on aflibercept were switched to intravitreal brolucizumab and managed with a treat-and-extend (T&amp;E) regimen with a minimum 8-week interval after loading. The primary outcome contrasted extension (&gt;8 weeks) versus non-extension (\u22648 weeks) at month 24. Prespecified predictors were early central choroidal thickness (CCT) change from baseline to the switch visit (A0 to A1;\u2009\u2265\u200940% reduction) and pachychoroid. Associations were tested with Fisher\u2019s exact tests and Firth-penalized logistic regression with the event defined as extension.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At 24 months, 6 of 17 eyes (35%) achieved extension. A\u2009\u2265\u200940% early CCT reduction occurred in 0 of 6 extension eyes versus 7 of 11 non-extension eyes (Fisher exact two-sided P\u2009\u2248\u20090.035). In the Firth model (event\u2009=\u2009extension),\u2009&lt;\u200940% CCT reduction strongly predicted extension (odds ratio 38.5; profile-likelihood 95% CI 2.0\u201310,000; LR P\u2009=\u20090.004). Non-pachychoroid showed the same direction with wide CIs (odds ratio 14.3; 95% CI 0.99\u20132,174; LR P\u2009=\u20090.006). Model fit was significant (LR \u03c7\u00b2\u2009=\u200915.19, P\u2009=\u20090.0005) and discrimination was good (apparent AUC\u2009\u2248\u20090.97). We prespecified a parsimonious two-predictor model to limit overfitting; adding age, sex, prior photodynamic therapy, or number of prior aflibercept injections did not materially change coefficients or improve AICc (\u0394AICc\u2009&lt;\u20092).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec005\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Eyes without marked early choroidal thinning (&lt;40% CCT reduction at A1) were more likely to extend, whereas marked thinning (\u226540%) signaled difficulty extending under T&amp;E regimen after switching to brolucizumab. Given the small sample and few events, estimates should be interpreted cautiously and considered hypothesis-generating, and warrant prospective external validation studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0326018","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T18:31:06Z","timestamp":1762281066000},"page":"e0326018","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Predictive factors for the efficacy of brolucizumab in refractory polypoidal choroidal vasculopathy following aflibercept resistance"],"prefix":"10.1371","volume":"20","author":[{"given":"Akie","family":"Yoshinaga","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohdai","family":"Kitamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1766-4773","authenticated-orcid":true,"given":"Shuichiro","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6182-4343","authenticated-orcid":true,"given":"Ryo","family":"Terao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Obata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9998-7448","authenticated-orcid":true,"given":"Keiko","family":"Azuma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"issue":"1","key":"pone.0326018.ref001","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ophtha.2007.03.008","article-title":"The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis","volume":"115","author":"TY Wong","year":"2008","journal-title":"Ophthalmology"},{"issue":"9827","key":"pone.0326018.ref002","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1016\/S0140-6736(12)60282-7","article-title":"Age-related macular degeneration","volume":"379","author":"LS Lim","year":"2012","journal-title":"Lancet"},{"issue":"12","key":"pone.0326018.ref003","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1038\/s41433-020-0799-y","article-title":"Association between visual acuity, lesion activity markers and retreatment decisions in neovascular age-related macular degeneration","volume":"34","author":"U Chakravarthy","year":"2020","journal-title":"Eye (Lond)"},{"key":"pone.0326018.ref004","article-title":"Optimizing Anti-VEGF Treatment Outcomes for Patients with Neovascular Age-Related Macular Degeneration","volume":"24","author":"CC Wykoff","year":"2018","journal-title":"J Manag Care Spec Pharm"},{"issue":"1","key":"pone.0326018.ref005","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1136\/bjo.2011.203893","article-title":"Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab","volume":"96","author":"MS Egh\u00f8j","year":"2012","journal-title":"Br J Ophthalmol"},{"key":"pone.0326018.ref006","first-page":"1857","article-title":"Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review","volume":"10","author":"S Yang","year":"2016","journal-title":"Drug Des Devel Ther"},{"key":"pone.0326018.ref007","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.2147\/OPTH.S50634","article-title":"Intravitreal aflibercept for polypoidal choroidal vasculopathy after developing ranibizumab tachyphylaxis","volume":"7","author":"M Miura","year":"2013","journal-title":"Clin Ophthalmol"},{"issue":"11","key":"pone.0326018.ref008","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1097\/IAE.0000000000001047","article-title":"Angiographic findings of ranibizumab-resistant polypoidal choroidal vasculopathy after switching to a treat-and-extend regimen with intravitreal aflibercept","volume":"36","author":"K Azuma","year":"2016","journal-title":"Retina"},{"issue":"11","key":"pone.0326018.ref009","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1007\/s00417-019-04456-2","article-title":"Tachyphylaxis during treatment of exudative age-related macular degeneration with aflibercept","volume":"257","author":"C Hara","year":"2019","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"7","key":"pone.0326018.ref010","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1007\/s00417-021-05547-9","article-title":"Comparison of agents using higher dose anti-VEGF therapy for treatment-resistant neovascular age-related macular degeneration","volume":"260","author":"GK Broadhead","year":"2022","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"1","key":"pone.0326018.ref011","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s00417-023-06222-x","article-title":"Six-month outcomes of switching from aflibercept to faricimab in refractory cases of neovascular age-related macular degeneration","volume":"262","author":"K Kataoka","year":"2023","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"3","key":"pone.0326018.ref012","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1159\/000351651","article-title":"Triple therapy for anti-vascular endothelial growth factor nonresponders in neovascular age-related macular degeneration: impact of different photodynamic therapy parameters","volume":"230","author":"D Veritti","year":"2013","journal-title":"Ophthalmologica"},{"issue":"1","key":"pone.0326018.ref013","doi-asserted-by":"crossref","first-page":"22546","DOI":"10.1038\/s41598-022-25860-5","article-title":"Comparison of 24-month treatment outcomes between as-needed treatment and switching to treat-and-extend in type 3 macular neovascularization","volume":"12","author":"JH Kim","year":"2022","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0326018.ref014","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.ophtha.2020.08.006","article-title":"Polypoidal Choroidal Vasculopathy: Consensus Nomenclature and Non-Indocyanine Green Angiograph Diagnostic Criteria from the Asia-Pacific Ocular Imaging Society PCV Workgroup","volume":"128","author":"CMG Cheung","year":"2021","journal-title":"Ophthalmology"},{"issue":"10","key":"pone.0326018.ref015","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1097\/IAE.0000000000002051","article-title":"Inner choroidal flow signal attenuation in pachychoroid disease: optical Coherence Tomography Angiography","volume":"38","author":"O Gal-Or","year":"2018","journal-title":"Retina"},{"issue":"8","key":"pone.0326018.ref016","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1007\/s00417-015-3221-x","article-title":"Subfoveal choroidal thickness as a predictor of treatment response to anti-vascular endothelial growth factor therapy for polypoidal choroidal vasculopathy","volume":"254","author":"H Kim","year":"2016","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"1","key":"pone.0326018.ref017","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.ophtha.2020.06.028","article-title":"HAWK and HARRIER","volume":"128","author":"PU Dugel","year":"2021","journal-title":"Ophthalmology"},{"issue":"1","key":"pone.0326018.ref018","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ophtha.2019.04.017","article-title":"HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration","volume":"127","author":"PU Dugel","year":"2020","journal-title":"Ophthalmology"},{"issue":"5","key":"pone.0326018.ref019","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/j.ophtha.2015.12.030","article-title":"Single-Chain Antibody Fragment VEGF Inhibitor RTH258 for Neovascular Age-Related Macular Degeneration","volume":"123","author":"FG Holz","year":"2016","journal-title":"Ophthalmology"},{"key":"pone.0326018.ref020","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.mehy.2018.02.024","article-title":"Clinical manifestations of pachychoroid may be secondary to pachysclera and increased scleral rigidity","volume":"113","author":"P Venkatesh","year":"2018","journal-title":"Med Hypotheses"},{"issue":"1","key":"pone.0326018.ref021","doi-asserted-by":"crossref","first-page":"21876","DOI":"10.1038\/s41598-023-49153-7","article-title":"Long-term visual outcomes in pachychoroid spectrum diseases and its associating factors of eyes with chronic central serous chorioretinopathy","volume":"13","author":"K Azuma","year":"2023","journal-title":"Sci Rep"},{"issue":"6","key":"pone.0326018.ref022","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1007\/s00417-020-04940-0","article-title":"Pachychoroid: current concepts on clinical features and pathogenesis","volume":"259","author":"V Castro-Navarro","year":"2021","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"12","key":"pone.0326018.ref023","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.ophtha.2012.09.006","article-title":"Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration","volume":"119","author":"JS Heier","year":"2012","journal-title":"Ophthalmology"},{"issue":"2","key":"pone.0326018.ref024","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1159\/000513048","article-title":"Brolucizumab: A Newly Developed Anti-VEGF Molecule for the Treatment of Neovascular Age-Related Macular Degeneration","volume":"244","author":"R Tadayoni","year":"2021","journal-title":"Ophthalmologica"},{"issue":"2","key":"pone.0326018.ref025","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s00417-022-05793-5","article-title":"Switching to brolucizumab from aflibercept in age-related macular degeneration with type 1 macular neovascularization and polypoidal choroidal vasculopathy: an 18-month follow-up study","volume":"261","author":"T Ueda-Consolvo","year":"2023","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"15","key":"pone.0326018.ref026","doi-asserted-by":"crossref","first-page":"4375","DOI":"10.3390\/jcm13154375","article-title":"Switching to Intravitreal Brolucizumab after Ranibizumab or Aflibercept Using Treat and Extend Regimen for Neovascular Age-Related Macular Degeneration in Japanese Patients: 1-Year Results and Factors Associated with Treatment Responsiveness","volume":"13","author":"K Hirayama","year":"2024","journal-title":"JCM"},{"issue":"3","key":"pone.0326018.ref027","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1007\/s10384-022-00908-1","article-title":"Switching from aflibercept to brolucizumab for the treatment of refractory neovascular age-related macular degeneration","volume":"66","author":"H Ota","year":"2022","journal-title":"Jpn J Ophthalmol"},{"issue":"1","key":"pone.0326018.ref028","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.survophthal.2024.09.011","article-title":"Choroidal thickness after anti-vascular endothelial growth factor in typical neovascular age-related macular degeneration \u2013 A systematic review and meta-analysis","volume":"70","author":"E Hoven","year":"2025","journal-title":"Survey of Ophthalmology"},{"issue":"4","key":"pone.0326018.ref029","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1167\/iovs.18-24522","article-title":"Reduced Vessel Density of the Choriocapillaris during Anti-Vascular Endothelial Growth Factor Therapy for Neovascular Age-Related Macular Degeneration","volume":"60","author":"T Hikichi","year":"2019","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"3","key":"pone.0326018.ref030","article-title":"VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells","volume":"274","author":"JD Hood","year":"1998","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"issue":"10","key":"pone.0326018.ref031","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1016\/j.ophtha.2020.03.031","article-title":"Spectral-Domain OCT Analysis of Risk Factors for Macular Atrophy Development in the HARBOR Study for Neovascular Age-Related Macular Degeneration","volume":"127","author":"SR Sadda","year":"2020","journal-title":"Ophthalmology"},{"issue":"1","key":"pone.0326018.ref032","doi-asserted-by":"crossref","first-page":"29157","DOI":"10.1038\/s41598-024-79179-4","article-title":"Importance of fluorescein angiography as a predictor of treatment response in patients with pachychoroid neovasculopathy","volume":"14","author":"M Maruyama-Inoue","year":"2024","journal-title":"Sci Rep"},{"issue":"12","key":"pone.0326018.ref033","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1167\/tvst.12.12.17","article-title":"Intravitreal Brolucizumab for Pachychoroid Neovasculopathy Associated With Chronic Central Serous Chorioretinopathy","volume":"12","author":"M Carosielli","year":"2023","journal-title":"Transl Vis Sci Technol"},{"issue":"1","key":"pone.0326018.ref034","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1038\/s41598-024-51628-0","article-title":"Predicting treatment outcomes of intravitreal brolucizumab for polypoidal choroidal vasculopathy through noninvasive assessment of polypoidal lesion blood flow with optical coherence tomography angiography","volume":"14","author":"J Hoshino","year":"2024","journal-title":"Sci Rep"},{"issue":"1","key":"pone.0326018.ref035","doi-asserted-by":"crossref","first-page":"13674","DOI":"10.1038\/s41598-025-98402-4","article-title":"Comparison of one-year outcomes between aflibercept and brolucizumab for treatment-na\u00efve pachychoroid neovasculopathy","volume":"15","author":"A Jeong","year":"2025","journal-title":"Sci Rep"},{"issue":"5","key":"pone.0326018.ref036","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1038\/s41433-024-03253-4","article-title":"Pachychoroid disease: review and update","volume":"39","author":"CMG Cheung","year":"2024","journal-title":"Eye"},{"issue":"3","key":"pone.0326018.ref037","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/aos.16797","article-title":"Efficacy of intravitreal faricimab therapy for polypoidal choroidal vasculopathy: A systematic review and meta-analysis","volume":"103","author":"A Arnold-Vangsted","year":"2025","journal-title":"Acta Ophthalmol"},{"issue":"4","key":"pone.0326018.ref038","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1007\/s10384-025-01240-0","article-title":"Japanese clinical guidelines for neovascular age-related macular degeneration","volume":"69","author":"T Iida","year":"2025","journal-title":"Jpn J Ophthalmol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0326018","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T18:31:12Z","timestamp":1762281072000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0326018"}},"subtitle":[],"editor":[{"given":"Jiro","family":"Kogo","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11,4]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0326018","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]}}}