Ophthalmology (Eye & Ear Hospital) - Theses

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    Predictors of outcome of anti-VEGF treatment in neovascular age-related macular degeneration
    ABEDI, FARSHAD ( 2013)
    Purpose: To identify the predictors of visual acuity (VA) outcome of intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment in neovascular age-related macular degeneration (nAMD). Methods: A review was conducted on all treatment naïve eyes (459 eyes of 398 patients >50 years old) that received intravitreal ranibizumab or bevacizumab injections for nAMD at the Royal Victorian Eye and Ear Hospital from 2006 to 2010. 201 consecutive patients treated with an as-required regimen were genotyped for seven tagged single nucleotide polymorphisms (SNPs) in VEGFA gene. 224 patients were also genotyped for seventeen AMD risk-associated SNPs in the CFH, CFHR1-5, LOC387715/ARMS2, C3, C2, CFB and F13B genes. Multivariate data analysis, adjusted for age, sex, baseline VA, lesion type and size, and patients‘ smoking status examined the role of genetic variants on VA outcome of treatment. 120 treatment naive patients were treated with an “Inject and Extend” regimen comprising three initial monthly injections, followed by an extension phase of 9 months, where the interval to the subsequent injection was extended by two weeks if the extension criteria were met. Results: Mean baseline VA of the 459 eyes was 46.5±19 Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores. Mean change in VA from baseline was +3.0±15.6, -1.0±18.3, -7.3±21.5 and -11.7±22.7 letters after 12, 24, 36 and 48 months, respectively. The mean number of injections was 5.6 ±2.6 in year one, 3.1±3.1 in year two, 2.9±3.2 in year three and 3.2±3.0 in year four. A higher number of injections and worse baseline VA led to significantly greater improvement in VA. Outcomes significantly improved for patients who commenced treatment after 2008. In 120 patients treated with an “inject and extend” protocol, mean change in VA from baseline after 12 months was +9.5±10.9 letters with a mean number of injections and clinic visits of 8.6±1 over 12 months. Of the seven examined SNPs in the VEGFA gene, SNP rs3025000 was the only SNP significantly associated (p value < 1x10-4) with visual outcome at 6 months. The presence of the T allele at this SNP predicted a better outcome of +7 letters at 6 months. Analysis of the seventeen AMD risk-associated SNPs revealed that the AA genotype at rs11200638 - HTRA1 promoter SNP (p =0.001) and GG genotype at rs10490924 (A69S) in LOC387715/ARMS2 (p=0.002) were significantly associated with poorer VA outcome at 12 months. The mean change in VA from baseline in patients with AA genotype at rs11200638 was -2.9±15.2 letters after 12 months, compared with +5.1±14.1 letters in patients with AG or GG genotypes at this SNP. SNPs rs11200638 and rs10490924 were in high linkage disequilibrium (LD, r2 = 0.92). Conclusion: Overall, patients with a lower baseline VA showed a greater increase in VA with treatment. An “inject and extend” regimen achieved significant improvement in VA over 12 months. Variants in VEGFA, HTRA1 and LOC387715/ARMS2 genes were significantly associated with treatment outcome. This may suggest a pharmacogenetic association and lead to a personalised treatment regimen, based on genotype to achieve optimal outcome in certain groups of patients.