Comparison of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: The EVEREST II Randomized Clinical Trial.

Importance: The 2-year efficacy and safety of combination therapy of ranibizumab administered together with verteporfin photodynamic therapy (vPDT) compared with ranibizumab monotherapy in participants with polypoidal choroidal vasculopathy (PCV) are unclear. Objective: To compare treatment outcomes of ranibizumab, 0.5 mg, plus prompt vPDT combination therapy with ranibizumab, 0.5 mg, monotherapy in participants with PCV for 24 months. Design, Setting, and Participants: This 24-month, phase IV, double-masked, multicenter, randomized clinical trial (EVEREST II) was conducted among Asian participants from August 7, 2013, to March 2, 2017, with symptomatic macular PCV confirmed using indocyanine green angiography. Interventions: Participants (N = 322) were randomized 1:1 to ranibizumab, 0.5 mg, plus vPDT (combination therapy group; n = 168) or ranibizumab, 0.5 mg, plus sham PDT (monotherapy group; n = 154). All participants received 3 consecutive monthly ranibizumab injections, followed by a pro re nata regimen. Participants also received vPDT (combination group) or sham PDT (monotherapy group) on day 1, followed by a pro re nata regimen based on the presence of active polypoidal lesions. Main Outcomes and Measures: Evaluation of combination therapy vs monotherapy at 24 months in key clinical outcomes, treatment exposure, and safety. Polypoidal lesion regression was defined as the absence of indocyanine green hyperfluorescence of polypoidal lesions. Results: Among 322 participants (mean [SD] age, 68.1 [8.8] years; 225 [69.9%] male), the adjusted mean best-corrected visual acuity (BCVA) gains at month 24 were 9.6 letters in the combination therapy group and 5.5 letters in the monotherapy group (mean difference, 4.1 letters; 95% CI, 1.0-7.2 letters; P = .005), demonstrating that combination therapy was superior to monotherapy by the BCVA change from baseline to month 24. Combination therapy was superior to monotherapy in terms of complete polypoidal lesion regression at month 24 (81 of 143 [56.6%] vs 23 of 86 [26.7%] participants; P < .001). Participants in the combination group received fewer ranibizumab injections (median, 6.0 [interquartile range (IQR), 4.0-11.0]) than the monotherapy group (median, 12.0 [IQR, 7.0-17.0]) up to month 24. The combination group required a median of 2.0 (IQR, 1.0-3.0) vPDT treatments for 24 months, with 75 of 168 participants (44.6%) requiring only 1 vPDT treatment. Conclusions and Relevance: The 24-month data findings confirm that ranibizumab therapy, given as monotherapy or in combination with vPDT, is efficacious and safe for treatment of PCV. Combination therapy with vPDT added to ranibizumab achieved superior BCVA gain, increased odds of complete polypoidal lesion regression, and fewer treatment episodes compared with ranibizumab monotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01846273.

EVEREST study report 4: Fluorescein angiography features predictive of polypoidal choroidal vasculopathy.

IMPORTANCE: It is important to identify features of polypoidal choroidal vasculopathy (PCV) that differentiate it from typical neovascular age-related macular degeneration (nAMD) on various imaging modalities, including fluorescein angiography (FA). BACKGROUND: PCV was thought to be indistinguishable from nAMD using FA alone. In real-world practice, indocyanine-green angiography may often be unavailable or contraindicated. DESIGN: Analysis of FA images from a prospective, multicentre study. PARTICIPANTS: Study images of both PCV and nAMD patients from the EVEREST study. METHODS: FA features at baseline were independently graded by masked graders (fellowship-trained ophthalmologists) using standardized diagnostic algorithms. MAIN OUTCOME MEASURES: Predictive indicators (sensitivity, specificity, positive and negative predictive values) for PCV. RESULTS: Of the 95 patients screened, 61 had PCV. Of the 34 screening failures, 15 were diagnosed as nAMD. Hyperfluorescent nodules on FA were observed in 80% of patients with PCV vs 20% with nAMD (P < 0.001). Blocked fluorescence on FA, which corresponded to the presence of subretinal haemorrhage, occurred more frequently among patients with PCV vs nAMD (61.7% vs 13.3%, P = 0.001). Similarly, the leakage characteristic of occult choroidal neovascularization occurred more frequently among patients with PCV vs nAMD (95.0% vs 73.3%, P = 0.026). The positive predictive value for PCV was 94.1% for hyperfluorescent nodules, 94.9% for blocked fluorescence, 83.8% for occult choroidal neovascularization and 82.0% for pigment epithelial detachment. CONCLUSIONS AND RELEVANCE: This study demonstrated that certain FA features can be predictive of PCV and may be considered as an indication for retina specialists to perform indocyanine green angiography as confirmatory test.

Efficacy and Safety of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: A Randomized Clinical Trial.

Importance: Polypoidal choroidal vasculopathy (PCV) is a common subtype of exudative age-related macular degeneration among Asian individuals. To our knowledge, there are no large randomized clinical trials to evaluate intravitreal ranibizumab, with and without verteporfin photodynamic therapy (vPDT), for the treatment of PCV. Objective: To compare the efficacy and safety of combination therapy of ranibizumab and vPDT with ranibizumab monotherapy in PCV. Design, Setting, and Participants: A double-masked, multicenter randomized clinical trial of 322 Asian participants with symptomatic macular PCV confirmed by the Central Reading Center using indocyanine green angiography was conducted between August 7, 2013, and March 2, 2017. Interventions: Participants were randomized 1:1 to ranibizumab, 0.5 mg, and vPDT (n = 168; combination therapy group) or ranibizumab, 0.5 mg, and sham PDT (n = 154; monotherapy group). All participants received 3 consecutive monthly ranibizumab injections, followed by a pro re nata regimen. Participants also received vPDT/sham PDT on day 1, followed by a pro re nata regimen based on the presence of active polypoidal lesions. Main Outcomes and Measures: Step 1 assessed whether combination therapy was noninferior (5-letter margin) to monotherapy for change in best-corrected visual acuity from baseline and superior in complete polyp regression. If noninferiority was established, step 2 assessed whether combination therapy was superior to monotherapy measured by best-corrected visual acuity change at month 12. Results: Baseline demographics of the 322 participants were comparable between the treatment groups. Mean (SD) age of the patients was 68.1 (8.8) years, and overall, 69.9% of the patients were men. At baseline, the overall mean best-corrected visual acuity and mean central subfield thickness were 61.1 letters and 413.3 µm, respectively. At 12 months, mean improvement from baseline was 8.3 letters with combination therapy vs 5.1 letters with monotherapy (mean difference, 3.2 letters; 95% CI, 0.4-6.1), indicating that combination therapy met the predefined criterion for noninferiority as well as being superior to monotherapy (P = .01). Combination therapy was also superior to monotherapy in achieving complete polyp regression at month 12 (69.3% vs 34.7%; P < .001). Over 12 months, the combination therapy group received a median of 4.0 ranibizumab injections compared with 7.0 in the monotherapy group. Vitreous hemorrhage was the only ocular serious adverse event (combination therapy group, 1 [0.6%]; monotherapy group, 3 [2.0%]). Conclusions and Relevance: After 12 months, combination therapy of ranibizumab plus vPDT was not only noninferior but also superior to ranibizumab monotherapy in best-corrected visual acuity and superior in complete polyp regression while requiring fewer injections. Combination therapy should be considered for eyes with PCV. Trial Registration: clinicaltrials.gov Identifier: NCT01846273.

EVEREST study report 3: diagnostic challenges of polypoidal choroidal vasculopathy. Lessons learnt from screening failures in the EVEREST study.

PURPOSE: To describe screening failures in the EVEREST study by examining the imaging characteristics that enabled differentiation of polypoidal choroidal vasculopathy (PCV) from cases that were subsequently diagnosed not to be PCV. METHODS: Post-hoc analysis of 34 patients with PCV reported as screening failures from EVEREST study. Standardised confocal scanning laser indocyanine green angiography (ICGA) images were graded by the Central Reading Centre to confirm PCV diagnosis based on the presence of early focal sub-retinal hyperfluorescence on ICGA and at least one of the following six diagnostic criteria: (1) nodular appearance of polyp(s) on stereoscopic examination, (2) hypofluorescent halo around nodule(s), (3) presence of a branching vascular network, (4) pulsation of polyp(s) on dynamic ICGA, (5) orange sub-retinal nodules on colour fundus photography, or (6) massive sub-macular haemorrhage (≥4 disc areas in size). Additional detailed image grading was performed with stereo-imaging and dynamic early-phase ICGA. RESULTS: Of the 95 screened PCV cases, 34 were excluded: (1) cases not suitable for recruitment as per the study protocol (n = 14), (2) equivocal lesions on ICGA characterised by small hyperfluorescent dots (n = 9), and (3) cases that were definitely not PCV (non-PCV, n = 11), identified by definitive diagnoses which included one case each of micro-aneurysm, retinal angiomatous proliferation, retino-choroidal anastomosis, small type-2 choroidal neovascularisation, retinal pigment epithelial (RPE) window defect and disciform scar; two cases of lesions where the choroidal vessel changed its course; and three cases of late-onset RPE staining. CONCLUSIONS: Standardised image grading techniques used in EVEREST study enabled effective differentiation of non-PCV from actual PCV.

A Cytomegalovirus Retinitis Screening Program: Evaluation of Enrollment Criteria for HIV Patients in Singapore.

PURPOSE: Identification of optimal enrollment criteria for a CMVR screening program suitable for a resource-limited environment. METHODS: A prospective audit was performed on newly diagnosed HIV patients referred for CMVR screening with any of the following four criteria: (1) visual symptoms, (2) low CD4(+) counts (<50 cells/µL), (3) AIDS-defining illnesses (ADI), and/or (4) opportunistic infections (OI). Odds ratios for each of the demographic factors and enrollment criteria were calculated. Sensitivities, specificities, and workload reduction for the various combinations were determined. RESULTS: A total of 348 screening visits for 176 HIV patients were performed. While individually only ADI was statistically significant for increased CMVR risk, the combination of CD4(+) counts <50 cells/µL with either ADI or visual symptoms or all 3 criteria were also statistically significant. Two enrollment criteria, ADI and ADI with CD4(+) <50 cells/µL, demonstrated good sensitivities, specificities, and workload reduction. CONCLUSION: We propose ADI and possibly CD4(+) counts <50 cells/µL as enrollment criteria for CMVR screening.

Telemedicine screening for cytomegalovirus retinitis using digital fundus photography.

BACKGROUND: Screening for cytomegalovirus retinitis (CMVR) is important in patients with acquired immune deficiency syndrome and low CD4(+) counts. However, many human immunodeficiency virus (HIV) patients lack access to specialist ophthalmological care. Telemedicine screening is a cost-effective method for screening these patients. We aimed to report the use of composite nine-field digital fundus photography (DFP) images for CMVR screening. We report its sensitivity and specificity in detecting CMVR and the level of agreement with gold-standard binocular indirect ophthalmoscopy. MATERIALS AND METHODS: An audit was performed on our national CMVR screening program that screened all HIV patients referred to the Ophthalmology Department at Tan Tock Seng Hospital, Singapore. All patients underwent retinal screening with DFP. Images were categorized as CMVR-positive, CMVR-negative, suspicious, or unreadable by blinded retinal specialists. Patients subsequently underwent dilated gold-standard indirect ophthalmoscopy by a different retinal specialist. Diagnoses were categorized as CMVR-positive, CMVR-negative, or unreadable. Sensitivity and specificity of retinal findings on DFP and kappa values for level of agreement between the two screening methods were calculated. RESULTS: Three hundred seventy screenings on 188 patients were performed. Twenty-three eyes diagnosed with CMVR on indirect ophthalmoscopy were also identified on DFP (100% sensitivity). A 99.9% specificity was achieved. The fundus photograph of one eye without CMVR was read as CMVR-positive because of an artifact, accounting for a false-positive. Kappa values ranged from 0.739 to 0.987. CONCLUSIONS: DFP is a sensitive and specific method of screening HIV patients for CMVR and has a high level of agreement with indirect ophthalmoscopy.

EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy.

PURPOSE: To assess the effects of verteporfin photodynamic therapy (PDT) combined with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. METHODS: In this multicenter, double-masked, primarily indocyanine green angiography-guided trial, 61 Asian patients were randomized to verteporfin PDT (standard fluence), ranibizumab 0.5 mg, or the combination. Patients were administered with verteporfin PDT/placebo and initiated with three consecutive monthly ranibizumab/sham injections starting Day 1, and re-treated (Months 3-5) as per predefined criteria. The primary endpoint was the proportion of patients with indocyanine green angiography-assessed complete regression of polyps at Month 6. Secondary endpoints included mean change in best-corrected visual acuity at Month 6 and safety. RESULTS: At Month 6, verteporfin combined with ranibizumab or alone was superior to ranibizumab monotherapy in achieving complete polyp regression (77.8% and 71.4% vs. 28.6%; P < 0.01); mean change ± standard deviation in best-corrected visual acuity (letters) was 10.9 ± 10.9 (verteporfin PDT + ranibizumab), 7.5 ± 10.6 (verteporfin PDT), and 9.2 ± 12.4 (ranibizumab). There were no new safety findings with either drug used alone or in combination. CONCLUSION: Verteporfin PDT combined with ranibizumab 0.5 mg or alone was superior to ranibizumab monotherapy in achieving complete regression of polyps in this 6-month study in patients with symptomatic macular polypoidal choroidal vasculopathy. All treatments were well tolerated over 6 months.

Intravitreal ganciclovir maintenance injection for cytomegalovirus retinitis: efficacy of a low-volume, intermediate-dose regimen.

OBJECTIVE: To report the clinical outcomes of highly active antiretroviral therapy (HAART)-naïve, human immunodeficiency virus (HIV)-positive patients with newly diagnosed cytomegalovirus (CMV) retinitis receiving intravitreal injections of a low-volume intermediate maintenance dose (1.0 mg/0.02 ml) of ganciclovir. DESIGN: Nonrandomized, retrospective, interventional series. PARTICIPANTS: A consecutive cohort of 34 eyes from 24 HAART-naïve patients with AIDS and diagnosed with CMV retinitis by retinal specialists at the Singapore Communicable Disease Centre. INTERVENTION: Patients received a maintenance dose of 1.0 mg/0.02 ml of intravitreal ganciclovir once weekly after standard induction therapy with 2.0 mg/0.04 ml of twice weekly intravitreal ganciclovir. MAIN OUTCOME MEASURES: Time to progression, visual acuity, and complications. Progression was observed using photographic documentation. RESULTS: The median time to progression was 152 days (mean, 380.1 days, 95% confidence interval, 240.8-519.4). The median follow-up was 95 days (mean, 207.9 days). Three eyes developed rhegmatogenous detachments, but there was no endophthalmitis after 1858 injections. Contralateral involvement of CMV retinitis occurred in 17.6% of the patients. The cost estimate for intravitreal injections over a 6-month period was 11.7% that of sustained-release implants for unilateral treatment and 11.1% that of daily continuous intravenous infusions and oral valganciclovir compared with bilateral treatments. CONCLUSIONS: Weekly low-volume, intermediate-dose (1.0 mg/0.02 ml) ganciclovir is an efficacious option in developing countries where newer options of sustained-release implants and oral valganciclovir are unavailable or prohibitively expensive. The regimen maintains a long time to progression, preserving vision while minimizing retinal toxicity complications.

Ophthalmic complications of dengue.

We report 13 cases of ophthalmic complications resulting from dengue infection in Singapore. We performed a retrospective analysis of a series of 13 patients with dengue fever who had visual impairment. Investigations included Humphrey automated visual field analyzer, Amsler charting, fundus fluorescein angiography, and optical coherence tomography. Twenty-two eyes of 13 patients were affected. The mean age of patients was 31.7 years. Visual acuity varied from 20/25 to counting fingers only. Twelve patients (92.3%) noted central vision impairment. Onset of visual impairment coincided with the nadir of serum thrombocytopenia. Ophthalmologic findings include macular edema and blot hemorrhages (10), cotton wool spots (1), retinal vasculitis (4), exudative retinal detachment (2), and anterior uveitis (1). All patients recovered visual acuity to 20/30 or better with residual central scotoma by 12 weeks. These new complications suggest a widening spectrum of ophthalmic complications in dengue infection.