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1.  Pharmacogenetic Influence of LOC387715/HTRA1 on the Efficacy of Bevacizumab Treatment for Age-Related Macular Degeneration in a Korean Population 
The purpose of this study was to determine the pharmacogenetic effects of complement factor H (CFH) Y402H, LOC387715 and high-temperature requirement factor A1 (HTRA1) genotypes on the treatment of exudative age-related macular degeneration (AMD) by intravitreal bevacizumab injection in a Korean population.
Seventy-five patients diagnosed with exudative AMD were treated with intravitreal bevacizumab (2.5 mg) monotherapy. All patients received three initial intravitreal bevacizumab injections every four weeks and were then treated "as needed" based on clinical findings, optical coherence tomography and fluorescein angiography during the 12 month follow-up period after the third injection.
The difference in visual acuity improvement among the three genotypes of LOC387715 were statistically significant at six months post-treatment (logarithm of the minimum angle of resolution; TT, 0.346; GT, 0.264; GG, 0.188; p = 0.037). Among the LOC387715 genotypes, the number of additional injections was lower in patients who had the risk T allele (GG, 2.143; GT, 2.000; TT, 1.575; p = 0.064). There was no significant difference between visual acuity and central macular thickness change in the CFH Y402H polymorphism group during the 12 month follow-up period. However, the TC group of CFH Y402H required more additional bevacizumab injections than the TT group (TT, 1.517; TC, 3.363; p = 0.020).
This study demonstrated that different LOC387715/HTRA1 genotypes resulted in different bevacizumab treatment responses on exudative AMD. Patients with the risk allele had an improved treatment response and less need for additional injections. However, patients with the CFH Y402H risk allele needed more additional injections of bevacizumab in order to improve visual acuity. This study illustrates how pharmacogenetic factors may help determine treatment modality and dosing. This could ultimately provide basic data for 'personalized medicine' in AMD.
PMCID: PMC3506814  PMID: 23204795
Bevacizumab; Complement factor H Y402H; HTRA1; LOC387715; Macular degeneration
2.  Involvement of genetic factors in the response to a variable-dosing ranibizumab treatment regimen for age-related macular degeneration 
Molecular Vision  2010;16:2598-2604.
To determine whether gene polymorphisms of the major genetic risk factor for age-related macular susceptibility 2 (ARMS2 A69S) and the complement factor H Y402H influence the response to a variable-dosing treatment regimen with ranibizumab for age-related macular degeneration.
This prospective cohort study included 90 patients (90 eyes) with exudative age related macular degeneration (AMD) treated with ranibizumab. Patients underwent a 1-year treatment as in the Study of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (Mitchell et al.). Injections were administered monthly when a patient lost five letters on the Early Treatment Diabetic Retinopathy Study chart or gained 100 μm in central subfield retinal thickness (CSRT). Genotypes (rs10490924 and rs1061170) were analyzed using gene sequence analysis. Best-corrected visual acuity (BCVA) and CSRT values were compared between ARMS2 and complement factor H genotypes. Multiple regression analysis was used to assess the statistical significance.
Mean increase in visual acuity was 4.44±8.12 letters with a 103.63±94.7 µm decrease in CSRT. BCVA improvement was statistically significant in all genotype groups except in homozygous 69S in the AMRS2 gene. CSRT and BCVA changes were correlated (r=0.2521; 95% CI: 0.04746–0.4364, p=0.0165). Multiple regression analysis revealed a significant impact of 69S (p=0.015) on the change in BCVA.
Visual acuity did not improve during the study in patients homozygous for ARMS2 69S, despite a decrease in CSRT. Further investigation is needed to confirm our findings and understand the mechanisms involved.
PMCID: PMC3000236  PMID: 21151600
3.  A pharmacogenetics study to predict outcome in patients receiving anti-VEGF therapy in age related macular degeneration 
To ascertain whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth factor (VEGFA), Complement Factor H (CFH), and LOC387715 genes could predict outcome to anti-VEGF therapy for patients with age related macular degeneration (AMD).
Patients with “wet” AMD were identified by chart review. Baseline optical coherence tomography (OCT) and visual acuity (VA) data, and at least 6 months of clinical follow up after 3 initial monthly injections of bevacizumab or ranibizumab were required for inclusion. Based on OCT and VA, patients were categorized into two possible clinical outcomes: (a) responders and (b) non-responders. DNA was extracted from saliva and genotyped for candidate SNPs in the VEGFA, LOC387715, and CFH genes. Clinical outcomes were statistically compared to patient genotypes.
101 patients were recruited, and one eye from each patient was included in the analysis. 97% of samples were successfully genotyped for all SNPs. We found a statistically significant association between the LOC387715 A69S TT genotype and outcome based on OCT.
Genetic variation may be associated with outcome in patients receiving anti-VEGF therapy.
PMCID: PMC3797648  PMID: 24143065
age related macular degeneration; ARMS2; bevacizumab; complement factor H (CFH); LOC387715; ranibizumab; single nucleotide polymorphisms; vascular endothelial growth factor
4.  Effectiveness of ranibizumab intravitreal injections for exudative age-related macular degeneration treatment: 12-month outcomes 
The aim of this paper was to evaluate functional and anatomical results of intravitreal ranibizumab injections and the course of exudative age-related macular degeneration (AMD) treatment over a 12-month observation period.
In 25 patients with active dominantly classic exudative AMD, treatment was performed according to the following schedule: 3 intravitreal injections of 0.5 mg ranibizumab at monthly intervals (saturation phase); further injections were based on activity of the neovascular process. Changes in VA and central retinal thickness (CRT) during treatment were evaluated with ANOVA testing.
Mean pre-treatment best corrected visual acuity was 0.73±0.27 logMAR. After the third ranibizumab injection the best results, 0.54±0.27 logMAR, were seen; 12-month results were 0.58±0.26 logMAR. Patients had a mean improvement of 10.6 letters at 12 months. In 92% of patients stabilization or improvement of vision was observed. The mean number of injections in the 12-month period was 6.
Baseline mean CRT was 351.12±74.15 μm. After the first ranibizumab injection it decreased significantly to 221.96±60.85 μm, after the third injection it was 200.80±47.63 μm, and after 12 months it was 213.16±44.37 μm. Mean correlations between baseline average CRT and baseline average VA measured in ETDRS letters (p=0.017) and in logMAR scale (p=0.033) and between average CRT after the third injection and average VA in logMAR scale after the third injection (p=0.047) were noted.
Treatment with intravitreal ranibizumab injections according to the presented scheme provides AMD patients with a chance of stabilization and improvement of the topical state, with a lower number of injections and preserved topical and general safety. Our results suggest that regular monthly controls are necessary to be able react rapidly to the smallest signs of deterioration, not only in visual acuity, but also in OCT images.
PMCID: PMC3560504  PMID: 21873944
exudative AMD; ranibizumab; central retinal thickness
5.  Bevacizumab vs ranibizumab for neovascular age-related macular degeneration in Chinese patients 
To compare the clinical efficacy of intravitreal injections of bevacizumab and ranibizumab for treating Chinese patients with neovascular age-related macular degeneration (AMD).
Among 60 Chinese patients with exudative AMD (60 eyes), 28 received intravitreal bevacizumab injections (1.25mg) and 32 received intravitreal ranibizumab injections (0.5mg), once a month for 3 months and were followed for a total of 6 months. Monthly optical coherence tomography (OCT) was used to determine whether the patients received additional treatments during the follow-up. We compared the baseline and 6-month follow-up values of mean best-corrected visual acuity (BCVA) and central retinal thickness (CRT) in both groups of patients. We also compared the occurrence of adverse events.
At the 6-month follow-up, the mean BCVA (logMAR) of the bevacizumab and ranibizumab treatment groups improved from the baseline measurements of 0.72±0.23 and 0.73±0.22 to 0.47±0.14 and 0.45±0.20, respectively (P<0.05 for both groups). However, the change was not significantly different between the two groups. As evaluated by OCT, CRT decreased from 366.71±34.72µm and 352±36.9µm at baseline to 250.86±41.51µm and 243.22±41.38µm in the bevacizumab and ranibizumab groups, respectively (P<0.05 for both groups). However, the change was not significantly different between the two groups. There were no severe local adverse reactions or systemic adverse events.
Intravitreal bevacizumab and ranibizumab have equivalent effects on BCVA and CRT and appeare safe over the short-term.
PMCID: PMC3633755  PMID: 23638418
age-related macular degeneration; choroidal neovascularization; bevacizumab (avastin); ranibizumab (lucentis)
6.  Pharmacogenetics for Genes Associated with Age-Related Macular Degeneration (AMD) in the Comparison of AMD Treatments Trials (CATT) 
Ophthalmology  2013;120(3):593-599.
To evaluate the pharmacogenetic relationship between genotypes of single nucleotide polymorphisms (SNPs) known to be associated with age-related macular degeneration (AMD) and response to treatment with ranibizumab (Lucentis) or bevacizumab (Avastin) for neovascular AMD.
Clinical trial.
834 (73%) of 1149 patients participating in the Comparison of AMD Treatments Trials (CATT) were recruited through 43 CATT clinical centers.
Each patient was genotyped for SNPs rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3), using TaqMan SNP genotyping assays.
Main Outcomes Measures
Genotypic frequencies were compared to clinical measures of response to therapy at one year including mean visual acuity (VA), mean change in VA, ≥15 letter increase, retinal thickness, mean change in total foveal thickness, presence of fluid on OCT, presence of leakage on fluorescein angiography (FA), mean change in lesion size and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. To adjust for multiple comparisons, p≤0.01 was considered statistically significant.
No statistically significant differences in response by genotype were identified for any of the clinical measures studied. Specifically, there were no high-risk alleles that predicted final VA or change in VA, the degree of anatomical response (fluid on OCT or FA, retinal thickness, change in total foveal thickness, change in lesion size) or the number of injections. Furthermore, a stepwise analysis failed to show a significant epistatic interaction among the variants analyzed; i.e., response did not vary by the number of risk alleles present. The lack of association was similar whether patients were treated with ranibizumab or bevacizumab or whether they received monthly or pro re nata (PRN) dosing.
Although specific alleles for CFH, ARMS2, HTRA1 and C3 may predict the development of AMD, they did not predict response to anti-vascular endothelial growth factor (VEGF) therapy.
PMCID: PMC3633658  PMID: 23337555
7.  Changing from bevacizumab to ranibizumab in age-related macular degeneration. Is it safe? 
To report our experiences in changing from intravitreal bevacizumab to ranibizumab in age-related macular degeneration (AMD).
Retrospective case series.
Participants and methods:
We retrospectively reviewed the records of 34 patients (36 eyes) who were treated with monthly injections of intravitreal bevacizumab for six months and then switched to monthly injections of ranibizumab for 12 months. Best-corrected visual acuity measurements (BCVA), contact lens biomicroscopy, optical coherence tomography (OCT), and fluorescein angiography were performed at the baseline examination and then monthly. Chi-square test was used for statistical analysis.
Following bevacizumab treatment, retinal thickness decreased (P = 0.033) while BCVA improved (P = 0.040). Changing from bevacizumab to ranibizumab resulted in a transient decrease in BCVA (P = 0.045) and an increase in retinal thickness (P = 0.042). In addition, three eyes presented with a large subretinal hemorrhage. However, final retinal thickness was better than the initial thickness and the value following the bevacizumab course. No major ocular or systemic side effects were noted.
Ranibizumab was clinically effective in the long term but the change of treatment from bevacizumab to a half-size molecule with less half-life in the vitreous such as ranibizumab contributed to a transient “instability” in the eye which may have triggered the large subretinal hemorrhage. There is insufficient experience reported in the literature in switching from one agent to another. A prospective study with controls is necessary to determine whether it is safe to change from one medication to another.
PMCID: PMC2801585  PMID: 20054410
age-related macular degeneration; bevacizumab; ranibizumab; subretinal hemorrhage
8.  CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration 
We determined whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and the response to treatment with a single intravitreous injection of bevacizumab for age-related macular degeneration (AMD). Eighty-three patients with exudative AMD treated by bevacizumab injection were genotyped for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, three SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and four SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. The CT genotype (heterozygous) of CFH-rs1061170 was more frequently represented in nonresponders in vision than TT genotypes (nonrisk allele homozygous) at the time points of 1 and 3 months, while there was no CC genotype (risk allele homozygous) in our study cohort (p = 7.66 × 10−3, 7.83 × 10−3, respectively). VEGF-rs699947 was also associated with vision changes at 1 month and PEDF-rs1136287 at 3 months (p = 5.11 × 10−3, 2.05 × 10−2, respectively). These variants may be utilized for genetic biomarkers to estimate visual outcomes in the response to intravitreal bevacizumab treatment for AMD.
PMCID: PMC3148139  PMID: 21811649
Age-related macular degeneration; Bevacizumab; Complement factor H; Genetic biomarker; High-temperature requirement A-1; Pigment epithelium-derived factor; Vascular endothelial growth factor
9.  Comparison of the effect between pegaptanib and ranibizumab on exudative age-related macular degeneration with small lesion size 
To compare the effect of pegaptanib versus ranibizumab on exudative age-related macular degeneration (AMD) with small lesion size.
This is a retrospective study of 81 eyes from 78 patients with exudative AMD treated and followed up over 12 months. Patients with baseline best corrected visual acuity (BCVA) under 20/400 and with a greatest linear dimension of lesion over 4500 μm were excluded from the study. Twenty-six eyes from 25 patients were treated with three consecutive intravitreal injections of pegaptanib (IVP group) and 55 eyes from 54 patients were treated with three consecutive ranibizumab injections (IVR group). Each therapy was repeated as needed. The alteration in BCVA was evaluated in the IVP and IVR groups.
No differences were detected in baseline parameters between the IVP and IVR groups. The mean BCVA (logMAR) at month 1, 3, 6 and 12 after the initial treatment was improved from baseline in the IVP group (−0.095, −0.17, −0.18 and −0.18, respectively) and in the IVR group (−0.077, −0.15, −0.17 and −0.11, respectively), which was statistically significant. There was no difference in the change in mean BCVA between IVP and IVR groups at the same time periods.
The visual outcome of IVP was equivalent with IVR in exudative AMD with small lesion size.
PMCID: PMC3299558  PMID: 22419857
pegaptanib; ranibizumab; age-related macular degeneration; small lesion size
10.  Current Smoking Is Associated with a Poor Visual Acuity Improvement after Intravitreal Ranibizumab Therapy in Patients with Exudative Age-Related Macular Degeneration 
Journal of Korean Medical Science  2013;28(5):769-774.
In this study, the risk factors that may influence visual improvement after intravitreal ranibizumab (IVR) treatment for exudative age-related macular degeneration (AMD) were examined. From 2008 to 2012, 420 patients (448 eyes) with exudative AMD were prospectively registered at Seoul National University Hospital. From this group of patients, 125 eyes were included in this study. All patients were treated with 3 consecutive IVR injections. The visual acuity (VA) was evaluated at baseline and 1 month after the third ranibizumab injection. To evaluate the risk factors associated with VA improvement after IVR, patient demographic data and systemic risk factors were analyzed. Patients were divided into a poor VA improvement group and a good VA improvement group, with reference to the median visual improvement in all eyes. Among 125 eyes, 66 eyes (52.8%) were included in the responder group and 59 eyes (47.2%) in the non-responder group. The median VA improvement after 3 monthly ranibizumab injections was -0.05 logMAR. Multivariate analyses revealed that current smoking (adjusted OR, 7.540; 95% CI, 1.732-32.823) was independently associated with poor VA improvement after IVR treatment for exudative AMD. In conclusion, cigarette smoking is an independent risk factor for lower VA gains with IVR treatment for exudative AMD.
PMCID: PMC3653092  PMID: 23678271
Exudative Age-Related Macular Degeneration; Ranibizumab; Cigarette Smoking
11.  Efficacy of treatment with ranibizumab in patients with wet age-related macular degeneration in routine clinical care: data from the COMPASS health services research 
To assess healthcare processes during treatment of neovascular age-related macular degeneration (AMD) in patients under real-life conditions and evaluate efficacy of monthly visual acuity (VA) assessment in a pro re nata treatment regime.
A multicentre, prospective, non-interventional study based in Germany included neovascular AMD patients treated with intravitreal ranibizumab. Patients completed a 3-month loading phase with monthly intravitreal injections of 0.5 mg ranibizumab, followed by a 12-month maintenance phase during which investigators documented VA, additional injections, metamorphopsias, routine ophthalmological examinations and adverse events at monthly follow-up visits. Efficacy analysis included change from baseline in best-corrected VA (BCVA) based on descriptive statistics.
A total of 2,232 patients were enrolled throughout Germany and 1,729 patients (mean age 77.8 years, 63.2 % women) comprised the efficacy population with a complete set of data. In the clinical setting recorded in our study, only a minority of patients underwent optical coherence tomography during the maintenance phase (71 of 1,729 patients). Patients received a mean total of 4.5 injections; three injections during upload phase and 1.5 additional injections during maintenance phase. Over half of the patients (51.4 %) did not receive additional injections. Mean decimal BCVA increased during the upload phase, (from LogMAR mean of 0.201 at baseline to 0.219 at Month 4) but displayed a decline over time (0.192 at Month 15).
Ranibizumab treatment in a real-life setting demonstrated efficacy in neovascular AMD patients, as shown by initial gains in BCVA. However, maintenance and improvement of these gains during the maintenance phase in a clinical routine setting remained below those expected compared with MARINA, ANCHOR and CATT trials, most likely due to a low number of retreatments, and the high number of patients with a poor response in regard to improvements of VA who were not investigated in these studies.
Trial registration number
This phase IV non-interventional health services research study was conducted under the Novartis internal registration code, CRFB002ADE10.
PMCID: PMC3968520  PMID: 24424409
Age-related macular degeneration; Intravitreal injections; Non-interventional study; Ranibizumab; Visual acuity; Neovascular age-related macular degeneration
12.  Effectiveness of intravitreal ranibizumab in exudative age-related macular degeneration (AMD): comparison between typical neovascular AMD and polypoidal choroidal vasculopathy over a 1 year follow-up 
BMC Ophthalmology  2013;13:10.
The effects of intravitreal ranibizumab (IVR) against exudative age-related macular degeneration (AMD) may be different associated with the lesion phenotype. This study was conducted to compare the outcomes of IVR between two different phenotypes of exudative AMD: typical neovascular AMD (tAMD) and polypoidal choroidal vasculopathy (PCV).
This is a retrospective cohort study of 54 eyes from 54 subfoveal exudative AMD patients (tAMD 24, PCV 30 eyes). Three consecutive IVR treatments (0.5 mg) were performed every month, followed by re-injections as needed. Change in the best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were then compared between the tAMD and PCV groups over 12 months of follow-up.
The mean BCVA was significantly improved (-0.11 logMAR units) at month 3 after the initial IVR (p <0 .001, Wilcoxon signed-rank test), and was sustained up to 12 months in all AMD patients (p =0.02). In the subgroup analysis, the tAMD group showed a significant improvement in their mean BCVA (-0.06, -0.17, -0.15 and -0.16 logMAR units at 1, 3, 6 and 12 months, respectively), but there was only a slight but non-significant improvement in the PCV group. The improvement in the BCVA was significantly greater in the tAMD group than in the PCV group (p = 0.043, repeated measures ANOVA) over 12 months. Both phenotypes showed significant improvements in the CRT during 12 months after the initial IVR.
IVR is an effective therapy for tAMD and PCV in the BCVA improvement in Japanese patients over 12 months of follow-up. The phenotype of tAMD showed a significantly better outcome with IVR than PCV in terms of BCVA improvement.
PMCID: PMC3627626  PMID: 23557322
Intravitreal ranibizumab; Polypoidal choroidal vasculopathy; Typical neovascular age-related macular degeneration; One-year outcome
13.  Ranibizumab Combined With Low-Dose Sorafenib for Exudative Age-Related Macular Degeneration 
Angiogenesis is a common factor in the pathogenesis of cancer and in exudative age-related macular degeneration (AMD). Therefore, angiogenesis inhibition has been developed as a therapeutic strategy. We report 2 cases of recurrent exudative AMD in which oral sorafenib, a tyrosine kinase inhibitor approved for cancer, was added to intravitreal ranibizumab, an antibody to vascular endothelial growth factor. These 2 patients were followed up by determination of visual acuity, fluorescein angiography, fundoscopy, and optical coherence tomography. The visual acuity of 1 patient improved from 20/70 to 20/60 while he was receiving sorafenib therapy; that of the other did not. Marked improvement was noted in both patients on optical coherence tomography. Additionally, both patients appeared to receive some benefit when low-dose oral sorafenib was used as monotherapy after its initial addition to ranibizumab therapy. Randomized trials of adding sorafenib to standard therapy for patients with neovascular AMD should be considered.
PMCID: PMC2763274  PMID: 18241635
14.  Association of CFH, LOC387715, and HTRA1 polymorphisms with exudative age-related macular degeneration in a northern Chinese population 
Molecular Vision  2008;14:1373-1381.
Variants in complement factor H (CFH), the hypothetical LOC387715, and the high-temperature requirement A-1 (HTRA1) genes have been reported to be associated with age-related macular degeneration (AMD). The purpose of this study was to investigate the association of reported common single-nucleotide polymorphisms (SNPs) in CFH, LOC387715, and HTRA1 with exudative AMD in a northern Chinese population.
A cohort of 121 unrelated patients with exudative AMD and 132 control subjects were enrolled in this study. Genomic DNA was extracted from blood leukocytes. Genotyping for SNPs rs1061170:T>C in CFH (Y402H), rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1 was performed using a polymerase chain reaction (PCR) method followed by allele-specific restriction enzyme digestion and direct sequencing.
The Y402H variant in CFH was not associated with exudative AMD in our study population. Frequencies of Y402H was 10.3% in AMD cases and 8.0% in controls (p=0.353). Significant associations were detected for exudative AMD with SNPs rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1. The risk T-allele frequency of rs10490924 in LOC387715 was 64.9% in cases versus 43.2% in controls (p<0.001). The odds ratio for risk of AMD was 1.56 (95% CI; 0.80–3.03) for the GT genotype and 5.45 (95% CI; 2.59–11.49) for the TT genotype. The A allele frequency of rs11200638 in the HTRA1 promoter was 67.8% in cases versus 42.4% in controls (p<0.001). The odds ratio was 2.75 (95% CI; 1.34–5.64) for the GA genotype and 7.90 (95% CI; 3.61–17.26) for the AA genotype. An odds ratio of 7.94 (95% CI; 3.49–18.04) was obtained for carriers with both TT genotype in LOC387715 and AA genotype in the HTRA1 promoter.
Our data suggest that the LOC387715 and HTRA1 polymorphisms are associated with a higher risk of exudative AMD in northern Chinese. We found no association of CFH Y402H with exudative AMD. The low frequency of CFH Y402H variant was further confirmed in this study population.
PMCID: PMC2493029  PMID: 18682812
15.  Treatment of age-related macular degeneration: focus on ranibizumab 
Ranibizumab, a humanized antigen-binding fragment (Fab) that binds all isoforms of VEGF-A, significantly slows down loss of vision and causes significant visual improvement in many patients with choroidal neovascularization (CNV) due to exudative age-related macular degeneration (AMD). These benefits of intravitreal ranibizumab apply to all angiographic subtypes of neovascular AMD and across all lesion sizes when the drug is injected at monthly intervals as shown in two pivotal phase III trials (ANCHOR and MARINA). The results from the PrONTO study suggest that less frequent treatment with ranibizumab through a variable dosing regimen dependent on optical coherence tomography (OCT) findings is a treatment option that results in comparably favorable visual outcomes. Currently, it is unclear whether combination therapy of ranibizumab with photodynamic therapy (PDT) provides any significant advantage over ranibizumab monotherapy (FOCUS trial); however, the combination of PDT and ranibizumab may decrease the need for frequent retreatment. This question will be addressed in the SUMMIT trial. Therapy with ranibizumab is generally very well tolerated with a low rate of seriously adverse ocular events or systemic side-effects. The advent of vascular endothelial growth factor (VEGF) inhibitors has revolutionized the therapy of neovascular AMD. Ranibizumab at the moment appears to be the most effective approved treatment for neovascular AMD.
PMCID: PMC2698673  PMID: 19668384
Lucentis; ranibizumab; vascular endothelial growth factor (VEGF); age-related macular degeneration (AMD); neovascular; exudative AMD; treatment
16.  Effect of ranibizumab on serous and vascular pigment epithelial detachments associated with exudative age-related macular degeneration 
To report the effect of intravitreal ranibizumab therapy for serous and vascular pigment epithelial detachments (PED) associated with choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD).
In a prospective study, best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) data were collected for 62 eyes of 62 patients, with serous or vascular PED associated with CNV secondary to AMD. Intravitreal ranibizumab 0.5 mg was administered with a loading phase of three consecutive monthly injections, followed by monthly review with further treatment, as indicated according to the retreatment criteria of the PrONTO study. The change in visual acuity and PED height from baseline to month 12 after the first injection was determined.
Sixty-one eyes of 61 patients (one of the patients developed retinal pigment epithelial tear and was excluded from the study) were assessed at the 12-month follow-up examination. There were two types of PED, including vascular PED in 32 patients (Group A) and serous PED (Group B) in 29 patients. The mean improvement of mean BCVA from baseline to 12 months was 0.09 logMAR (Logarithm of the Minimum Angle of Resolution) in Group A and 0.13 logMAR in Group B. Both groups showed significant improvement of the mean BCVA 12 months after the first injection compared with the baseline value (P < 0.05). In relation to the PED height, the mean decrease of mean PED height from baseline to 12 months was 135 μm in Group A and 180 μm in Group B. Both groups showed significant reduction of the PED height during the follow-up period (P < 0.01). The PED anatomical response to ranibizumab was not correlated with the BCVA improvement in any of the groups. Apart from one patient who developed pigment epithelial tear no other complications were documented.
Ranibizumab is an effective and safe treatment for improving vision in patients with serous and vascular PED, although the anatomical response of the PED to ranibizumab may not correlate directly with the visual outcome.
PMCID: PMC3712738  PMID: 23874084
age-related macular degeneration; choroidal neovascularisation; intravitreal injection; pigment epithelial detachment; ranibizumab
17.  Switching from Intravitreal Ranibizumab to Bevacizumab for Age-Related Macular Degeneration 
ISRN Ophthalmology  2011;2011:916789.
Purpose. To report our experiences in patients with age-related macular degeneration (AMD) treated initially with intravitreal ranibizumab and then switched to bevacizumab. Methods. We retrospectively reviewed the records of 7 patients (7 eyes) who were treated with monthly injections of intravitreal ranibizumab and then switched to injections of bevacizumab (every 6 weeks) for six months. The best-corrected visual acuity measurements (BCVA) and optical coherence tomography (OCT) were performed at the baseline examination and then at each visit. The Wilcoxon signed-rank test was used for the statistical analysis. Results. Following three monthly ranibizumab treatments, there was no significant difference in the BCVA, while the foveal retinal thickness (FRT) significantly decreased (P < 0.01). Switching from ranibizumab to bevacizumab resulted in maintenance (57.2%) of the BCVA and a further decrease in the FRT (P < 0.01) after 6 months. Conclusions. Switching to intravitreal bevacizumab may be effective in patients who wish to discontinue intravitreal ranibizumab treatment due to the high cost.
PMCID: PMC3912580  PMID: 24555120
18.  Profile of ranibizumab: efficacy and safety for the treatment of wet age-related macular degeneration 
Wet age-related macular degeneration (AMD) causes severe vision loss due to the development of choroidal neovascularization (CNV). The critical role of vascular endothelial growth factor in the pathogenesis of CNV is well understood. Ranibizumab plays an inhibitory role with CNV and reduces vascular permeability by binding to vascular endothelial growth factor. Intravitreal ranibizumab reduces the risk of visual acuity (VA) loss and increases the chance of VA gain compared with no treatment or photodynamic therapy for CNV in AMD. Some high-quality research has shown that the optimal timing for ranibizumab treating wet AMD is the first 3 months. It is recommended that ranibizumab is intravitreally injected monthly in the initiation for at least 3 months. Subsequent managing of regimens should be made dependent on the VA change, fundus examination, and image of optical coherence topography. An individualized strategy or combined method with photodynamic therapy is beneficial to the active lesion in the consecutive treatment of ranibizumab for CNV, and may be a good choice in order to decrease injection times. Regarding the safety profile, ranibizumab has been well tolerated in clinical trials. The principal ocular adverse event detected in clinical trials is a low frequency of ocular inflammation. Key serious ocular adverse events occurred in <5% of ranibizumab-treated patients in large-scale clinical trials. It appears unlikely that treatment with ranibizumab increases the risk of vascular events significantly. Less frequent injections on an as-needed schedule, based on monthly monitoring may have the most optimal risk:benefit ratio.
PMCID: PMC3404592  PMID: 22911433
age-related macular degeneration; choroidal neovascularization; ranibizumab; efficacy; safety
19.  Initial non-responders to ranibizumab in the treatment of age-related macular degeneration (AMD) 
Patients with exudative age-related macular degeneration (AMD) who did not respond to ranibizumab at the induction phase were assessed and referred to as initial non-responders.
We retrospectively reviewed the medical records of 215 patients (218 eyes) with exudative AMD. For the initial treatments, patients received three intravitreal injections of ranibizumab (IVR) every 4 weeks. Minimum follow-up period was 12 months. We defined patients with no improvement of best corrected logMAR visual acuity (BCVA), and with no decrease of central retinal thickness (CRT) at the end of the initial treatment, as initial non-responders. Patients who had previous treatment history prior to this investigation were included, but patients who had photodynamic therapy (PDT) with IVR were excluded.
Twenty-two eyes (10.1%) were identified as initial non-responders. The mean BCVA of initial non-responders before IVR and after induction phase were 0.39 and 0.36, respectively. There was no significant difference between these values, however the mean BCVA decreased significantly to 0.55 at 12 months after the beginning of the induction phase (P = 0.021). The mean greatest linear dimension (GLD) of the lesion before IVR of initial non-responders was 4,121 μm. We found 16 eyes with typical AMD, and six eyes with polypoidal choroidal vasculopathy. One eye had predominantly classic choroidal neovascularization (CNV), and others had occult CNV of typical AMD. As additional treatments, twelve eyes received PDT, and in three of the eyes exudation remained after PDT.
Initial non-responders were more prevalent in patients with occult CNV than in patients with other CNV types. Some of the initial non-responders did not respond to PDT. This study suggested possible involvement of other factors, in addition to vascular endothelial growth factor, in the occurrence of CNV in initial non-responder patients.
PMCID: PMC3726592  PMID: 23901256
AMD; anti-VEGF drug; ranibizumab; initial non-responders
20.  Tear of Retinal Pigment Epithelium following YAG Laser Posterior Capsulotomy in a Patient on Anti-VEGF Treatment for AMD: Six Months’ Follow-Up 
Case Reports in Ophthalmology  2012;3(2):221-225.
To present a rare case of retinal pigment epithelium (RPE) rupture following YAG laser posterior capsulotomy (YAG PC) in a patient with exudative age-related macular degeneration (AMD).
Materials and Methods
An 85-year-old pseudophakic male patient on ranibizumab 0.5 mg/0.05 ml treatment due to exudative AMD received YAG PC for dense posterior capsule opacification (PCO) in his right eye. The patient had received his last intravitreal ranibizumab injection 3 months before YAG PC; his macula appeared stable on fundoscopy and optical coherence tomography scans at repeated visits, but his vision deteriorated to counting fingers due to PCO.
Following left eye posterior YAG PC, his best-corrected visual acuity (BCVA) improved to 6/12 (Snellen chart). Despite satisfactory visual results, the patient developed a parafoveal inferotemporal RPE rupture. A decision for further treatment with ranibizumab (0.5 mg/0.05 ml) intravitreal injections was made. After a total of 7 injections, the patient was clinically stable and his BCVA was 6/18 (Snellen chart).
RPE rupture is a well-known, serious complication in patients with exudative AMD, which often has devastating results on patients’ vision. Offering YAG PC to those patients could lead to a rupture of the RPE even in cases which appear to be stable and well controlled. Clinicians should be aware of this complication and inform the patients accordingly.
PMCID: PMC3398079  PMID: 22807911
Retinal pigment epithelium tear; YAG Laser; Age-related macular degeneration; Pigment epithelial detachment rupture; Ranibizumab
21.  Impact of Loading Phase, Initial Response and CFH Genotype on the Long-Term Outcome of Treatment for Neovascular Age-Related Macular Degeneration 
PLoS ONE  2012;7(7):e42014.
Factors influencing the outcome of anti-VEGF treatment in neovascular AMD are still investigated. We analyzed the impact of a loading phase, the significance of an initial response for the long-term and the effect of the CFH polymorphism (p.His402Tyr) on treatment outcome.
Patients treated with ranibizumab for neovascular AMD were analyzed over a period of 24 months by assessing effects of loading phase, initial response and genotype of CFH rs1061170 (c.1204C>T, p.His402Tyr).
204 eyes were included. A change of +5.0 [−1;+11] letters and +1.5 [−5.5;+9.5] was observed with a median of 4 [3]; [7] and 10 [7]; [14] ranibizumab injections during 12 and 24 months, respectively. Loading phase was no significant predictor for treatment as VA outcome in eyes with and without loading phase was similar (p = 0.846 and p = 0.729) at 12 and 24 months. In contrast, initial response was a significant predictor for improving vision of 5 or more letters at 12 (p = 0.001; OR = 6.75) and 24 months (p = 0.01; OR = 4.66). Furthermore, the CT genotype at CFH rs1061170 was identified as a significant predictor for a favorable VA outcome at 12 and 24 months (OR = 6.75, p = 0.001 and OR = 4.66, p = 0.01).
Our data suggest that clinical decisions regarding treatment may be guided by observing patients’ initial response as well as their genotype of SNP rs1061170, while the criterion of loading phase may not bear the customary value.
PMCID: PMC3405003  PMID: 22848690
22.  Bevacizumab versus Ranibizumab on As-Needed Treatment Regimen for Neovascular Age-Related Macular Degeneration in Turkish Patients 
ISRN Ophthalmology  2013;2013:151027.
Purpose. To compare the efficacy of intravitreal bevacizumab versus ranibizumab in the treatment of neovascular age-related macular degeneration (nAMD). Methods. Retrospective, comparative study. The newly diagnosed nAMD patients who were treated with intravitreal bevacizumab or ranibizumab on an as-needed treatment regimen were included in the study. Main outcome measures were the change in best corrected visual acuity (BCVA), and central retinal thickness (CRT). Secondary outcome measures were the number of injections, and complications. Results. A total of 154 patients were included in the study. Bevacizumab group consisted of 79 patients, and ranibizumab group consisted of 74 patients. Mean follow-up time was 18.9 months, and 18.3 months in the bevacizumab and ranibizumab groups, respectively. There was not a significant difference between the two groups regarding the change in BCVA and CRT at all time points (P > 0.05 for all). The mean number of injections at month 12 was 4.8 and 4.7 in bevacizumab and ranibizumab groups, respectively (P > 0.05). No serious complications were detected in any of the groups. Conclusion. Both of the bevacizumab and ranibizumab found to be effective in the treatment of nAMD in regards of functional and anatomical outcomes with similar number of treatments and similar side effects.
PMCID: PMC3914220  PMID: 24558597
23.  Three-year follow-up of visual outcome and quality of life in patients with age-related macular degeneration 
The purpose of this study was to evaluate the visual outcome and self-reported vision-targeted health status in patients treated with intravitreal ranibizumab for wet age-related macular degeneration (AMD).
A total of 51 eyes from 50 patients aged 76 ± 7 years, with wet AMD not previously treated, were included in this prospective study. Best corrected visual acuity was examined using Early Treatment Diabetic Research Study charts and near vision reading. All patients underwent an ophthalmological examination, including fluorescein and indocyanine green angiography (occult cases) and optical coherence tomography. The Visual Function Questionnaire test was completed before and 37 ± 7 months after the start of intravitreal injections.
The patients received a mean number of 7.8 ± 5.0 (range 2–22) injections. One month after the third intravitreal injection, significant improvement was seen in both visual acuity (53 ± 14 to 61 ± 14 letter, P = 0.001) and near vision (17 ± 9 to 11 ± 8 points, P = 0.001). During follow-up, mean visual acuity decreased from 53 ± 14 to 44 ± 24 letters (P = 0.011), and near vision decreased from 17 ± 9 to 20 ± 11 points (P = 0.048). Despite visual impairment, the quality of life test revealed no significant decrease in mental health (P = 0.529) or ability to read a newspaper (P = 0.21), but a decrease in distance activities (reading street signs, steps, going to the theater) from 57 ± 27 to 46 ± 31 points (P = 0.007) was documented.
Decreased visual acuity was related to a decrease in self-reported visual function for distance activities, while mental health items, such as worrying, were not influenced.
PMCID: PMC3589196  PMID: 23467557
visual outcome; quality of life; age-related macular degeneration
24.  Retinal ganglion cell function after repeated intravitreal injections of ranibizumab in patients with age-related macular degeneration 
The purpose of this study was to evaluate the safety of intravitreal ranibizumab injection in patients with age-related macular degeneration.
Materials and methods
We examined retinal ganglion cell function using the photopic negative response of the electroretinogram (ERG) in patients with age-related macular degeneration (AMD) treated with intravitreal injections of ranibizumab. We studied 32 eyes of 32 patients with AMD and aged 50–84 years with a mean of 71 years. An intravitreal ranibizumab injection was given three times at monthly intervals. Additional injections were given according to an optical coherence tomography-guided variable dosing regimen. ERG recordings were made before treatment (baseline) and at 3, 6, 9, and 12 months postoperatively. Full-field cone ERGs were elicited by red stimuli on a blue background. The focal macular ERGs were elicited by a 15 degree white stimulus spot centered on the macular region. We measured the amplitudes of the a and b waves, oscillatory potentials, and the photopic negative response of the full-field cone and focal macular ERGs.
Visual acuity was significantly better than the baseline acuity, and macular thickness was significantly reduced after the intravitreal injections of ranibizumab. The amplitudes and implicit times of each wave of the full-field cone ERGs were not significantly changed after intravitreal ranibizumab injections. However, the amplitudes of each wave of the focal macular ERGs were increased after the injections. The implicit times of the a and b waves of the focal macular ERGs were significantly shortened after intravitreal injections of ranibizumab. The ratio of the full-field and focal photopic negative response/b-wave amplitude was not significantly changed after the injections.
The amplitudes of the focal macular ERGs, including the photopic negative response improved after repeated intravitreal ranibizumab injections, accompanied by a recovery of visual acuity and macular structure. The results of the full-field cone ERGs indicate that retinal ganglion cell function was not altered by repeated intravitreal ranibizumab injection.
PMCID: PMC3413340  PMID: 22888205
age-related macular degeneration; retinal ganglion cell; photopic negative response; electroretinogram; ranibizumab
25.  Comparison of visual acuity outcomes between ranibizumab and bevacizumab treatment in neovascular age-related macular degeneration 
To compare visual acuity (VA) outcomes between intravitreal injection of bevacizumab and ranibizumab in the treatment of neovascular age-related macular degeneration (AMD).
We conducted a consecutive, retrospective case series study in patients with newly diagnosed all type choroidal neovascularization (CNV) secondary to AMD who received an intravitreal injection of bevacizumab (1.25mg) or ranibizumab (0.3mg) at Lions Eye Institute, Western Australia from Mar. 2006 to May 2008. All patients received injection at baseline with additional monthly injections given at the discretion of the treating physician. Main outcome measures were changes in VA.
There were 371 consecutive patients received injection at least in one eye with at least 6 months of follow up (median of 12.0 months). Bevacizumab treatment prevented 221 out of 278 (79.5%) patients from losing < 15 letters in VA compared with 79 out of 93 (84.9%) of ranibizumab treated patients (P=0.25). While 68 (24.5%) of bevacizumab treated patients gained ≥15 letters of VA compared with 24 (25.8%) of ranibizumab treated patients (P=0.79). 75.3% and 66.2% patients benefited from ranibizumab and bevacizumab respectively with final VA better than 6/60 (P=0.10). Multivariate analysis showed that pre-treatment VA was negatively associated with benefit outcome. Assignment of injection was not associated with VA outcome of benefit after adjusting the covariate (P=0.857).
There are no difference in treatment efficacy in terms of VA between bevacizumab and ranibizumab in routine clinical condition.
PMCID: PMC3340678  PMID: 22553617
age-related macular degeneration; anti-VEGF; bevacizumab; ranibizumab; choroidal neovascularization

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