Dataset Information

Analysis of the association between CFH Y402H polymorphism and response to intravitreal ranibizumab in patients with neovascular age-related macular degeneration (nAMD).

ABSTRACT: Pharmacogenetic studies indicate that a variable response to anti-vascular endothelial growth factor (VEGF) therapy in patients with neovascular form of AMD (nAMD) may be due to polymorphisms in the complement factor H gene (CFH). This study is the first to investigate the association between CFH Y402H polymorphism and the response to ranibizumab therapy in Malaysian patients with nAMD. We included 134 patients with nAMD, examined between September 2014 and February 2016. The diagnosis of nAMD was confirmed by ophthalmologic examination, before ranibizumab therapy was started. Each patient received an intravitreal injection of 0.5 mg/0.05 ml ranibizumab following a treat-and-extend (TE) regimen. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were recorded after 3 and 6 months following the first injection and compared with the baseline values. Genotyping of Y402H (rs1061170) polymorphism was performed using PCR-RFLP and the amplified product was digested with MluCI restriction enzyme. Association between the Y402H genotypes and response to treatment was determined by a logistic regression analysis of responder (n = 49) and non-responder (n = 84) group. Significantly worse mean BCVA was observed for the CC genotype compared to the TT + CT genotype in the total sample after 6-month follow-up (p = 0.018). Comparing the baseline and 6-month point measurements, improved mean BCVA was observed in responder group, while worse mean BCVA was recorded for non-responder group. However, our regression analysis, adjusted for confounding factors, showed no significant association between the Y402H genotypes and response to treatment in nAMD patients under the recessive model (p > 0.05). Overall, our results suggest that factors other than Y402H polymorphism may be involved in the progression of nAMD after treatment with anti-VEGF agents, in Malaysian population.

SUBMITTER: Mohamad NA

PROVIDER: S-EPMC6087554 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Analysis of the association between CFH Y402H polymorphism and response to intravitreal ranibizumab in patients with neovascular age-related macular degeneration (nAMD).

Mohamad Nur Afiqah NA Ramachandran Vasudevan V Ismail Patimah P Mohd Isa Hazlita H Chan Yoke Mun YM Ngah Nor Fariza NF Md Bakri Norshakimah N Ching Siew Mooi SM Hoo Fan Kee FK Wan Sulaiman Wan Aliaa WA Inche Mat Liyana Najwa LN Hazmi Mohamed Mohd M

Bosnian journal of basic medical sciences 20180801 3

Pharmacogenetic studies indicate that a variable response to anti-vascular endothelial growth factor (VEGF) therapy in patients with neovascular form of AMD (nAMD) may be due to polymorphisms in the complement factor H gene (CFH). This study is the first to investigate the association between CFH Y402H polymorphism and the response to ranibizumab therapy in Malaysian patients with nAMD. We included 134 patients with nAMD, examined between September 2014 and February 2016. The diagnosis of nAMD w ...[more]

PMID: 29579408

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Project description:To examine if the gene encoding C-reactive protein (CRP), a biomarker of inflammation, confers risk for neovascular age-related macular degeneration (AMD) in the presence of other modifiers of inflammation, including body mass index (BMI), diabetes, smoking, and complement factor H (CFH) Y402 genotype. Additionally we examined the degree to which CRP common variation was in linkage disequilibrium (LD) within our cohort.We ascertained 244 individuals from 104 families where at least one member had neovascular AMD, and a sibling had normal maculae and was past the age of the index patient's diagnosis of neovascular AMD. We employed a direct sequencing approach to analyze the 5'-promoter region as well as the entire coding region and the 3'-untranslated region of the CRP gene. CFH Y402 genotype data was available for all participants. Lifestyle and medical factors were obtained via administration of a standardized questionnaire. The family-based association test, haplotype analysis, McNemar's test, and conditional logistic regression were used to determine significant associations and interactions. Haploview was used to calculate the degree of LD (r2) between all CRP variants identified.Six single nucleotide polymorphisms (SNPs; rs3091244, rs1417938, rs1800947, rs1130864, rs1205, and rs3093068) comprised one haplotype block of which only rs1130864 and rs1417938 were in high LD (r2=0.94). SNP rs3093068 was in LD but less so with rs3093059 (r2=0.83), which is not part of the haplotype block. Six SNPs made up six different haplotypes with > or = 5% frequency, none of which were significantly associated with AMD risk. No statistically significant association was detected between any of the nine common variants in CRP and neovascular AMD when considering disease status alone or when controlling for smoking exposure, BMI, diabetes, or CFH genotype. Significant interactions were not found between CRP genotypes and any of the risk factors studied. No novel CRP variation was identified.We provide evidence that if elevated serum/plasma levels of CRP are associated with neovascular AMD, it is likely not due to genetic variation within CRP, but likely due to variations in some other genetic as well as epidemiological factors.

Project description:BackgroundAnti-vascular endothelial growth factor (anti-VEGF) agents have become the standard of care in neovascular age-related macular degeneration (nAMD). Despite generally excellent response rates to anti-VEGF therapy, some patients do not respond or may respond suboptimally. In the case of refractory or rapidly recurring fluid in nAMD, clinicians may switch to another anti-VEGF agent. TITAN was an observational study that assessed the effectiveness and safety of intravitreal aflibercept (IVT-AFL) in patients with nAMD refractory to ranibizumab who switched to IVT-AFL after less than 12?months of ranibizumab treatment in routine clinical practice in France.MethodsTITAN was an observational, retrospective and prospective 12-month study conducted at 28 centres in France. Patients with nAMD refractory to ranibizumab were enrolled. Patients who were switched from ranibizumab to IVT-AFL were followed for 12?months. Data were obtained from medical records for retrospectively included patients, and at routine follow-up visits for those included prospectively. The main outcome measure was percentage of patients who achieved treatment success (gain of ?1 Early Treatment Diabetic Retinopathy Study letters in best-corrected visual acuity [BCVA] and/or any reduction in central retinal thickness [CRT]) from baseline to 12?months after switching. A sample size of 225 patients was determined based on a 2-sided 95% confidence interval with a width equal to 0.12 when the sample proportion was 0.70.ResultsWe analysed safety data (N =?217) and clinical outcomes from patients in the per-protocol population (n =?125). The mean (standard deviation) number of IVT-AFL injections was 7.5 (2.6). Treatment success was achieved in 68.8% of patients. Mean BCVA change from baseline to Month 12 was +?1.5 letters (P =?0.105) and the mean CRT change was -?45.0??m (P <? 0.001). In a subgroup analysis, in patients who received three initial monthly IVT-AFL injections, mean BCVA gain was 3.3 letters at Month 12 (P =?0.015). Excluding lack of efficacy and inappropriate scheduling of drug administration, the most common adverse event was eye pain (2.3%).ConclusionsSwitching ranibizumab-refractory patients with nAMD to IVT-AFL may improve visual outcomes in some patients, particularly those who receive three initial monthly injections.Trial registrationClinicalTrials.gov , NCT02321241 . First posted: December 22, 2014; Last update posted: July 2, 2018.

Project description:BackgroundClinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data.MethodsIn a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart.ResultsBevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.ConclusionsAt 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.).

Project description:IntroductionNeovascular age-related macular degeneration (nAMD) is the leading cause of vision loss among persons aged 65 years and older. Anti-vascular endothelial growth factor (anti-VEGF) treatment is the recommended standard of care. The current study compares the effectiveness of ranibizumab in routine clinical practice in two countries that generally apply two different treatment regimens, treat-and-extend (T&E) in Australia or pro re nata (PRN) in the UK.MethodsThis retrospective, comparative, non-randomised cohort study is based on patients' data from electronic medical record (EMR) databases in Australia and the UK. Treatment regimens were defined based on location, with Australia as a proxy for analysing T&E and UK as a proxy for analysing PRN. The study included patients with a diagnosis of nAMD who started treatment with ranibizumab between January 2009 and July 2014. A total of 647 eyes of 570 patients in Australia and 3187 eyes of 2755 patients in the UK with complete 12-months follow-up were analysed.ResultsBaseline patient characteristics were comparable between the two cohorts. After 1 year of treatment, T&E-treated eyes achieved higher mean (±SE) visual acuity (VA) gains (5.00 ± 0.54 letters [95% confidence interval (CI) 3.93-6.06]) than PRN-treated eyes [3.04 ± 0.24 letters (95% CI 2.57-3.51); difference in means 2.07 ± 0.69 (95% CI 0.73-3.41), p < 0.001]. Non-inferiority of T&E compared to PRN was concluded based on the change in mean visual acuity gains at 12 months. Over the 12-month follow-up, T&E-treated eyes received a higher mean [±standard deviation (SD)] number of injections (9.29 ± 2.43) than PRN-treated eyes (6.04 ± 2.19) (p < 0.0001). Australian patients had a lower mean (±SD) number of total clinic visits (10.29 ± 2.90) than UK patients (11.47 ± 2.93) (p < 0.0001).ConclusionThe higher injection frequency in the T&E cohort may account for the trend toward improved vision.FundingNovartis Pharma AG, Basel, Switzerland.

Project description:Neovascular age-related macular degeneration (nAMD) is a common world-wide cause of visual loss. Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents are an effective means to treat nAMD and reduce its impact on vision compared to either sham treatment or photodynamic therapy. Currently, the approved anti-VEGF drugs include ranibizumab, aflibercept and brolucizumab. In addition, bevacizumab, used as an off-label drug, and has been shown to be effective in treating nAMD. While anti-VEGF agents are effective, its limitations include the requirement for frequent, often monthly injections, and the need for long-term treatment of nAMD. These present significant burdens on the healthcare system and on the patients. In addition, reviews of patients with nAMD treated with anti-VEGF have reported deterioration of vision over time with progression of geographic atrophy. These limitations are partly addressed by exploring different treatment regimens that reduce the frequency of treatments. Newer anti-VEGF drugs have been shown in Phase III clinical trials to have injection intervals as long as 12 or even 16 weeks for a proportion of patients. There is research on newer drugs that affect other pathways, such as the angiopoietin pathway, which may impact nAMD by extending the treatment interval and reducing the burden of treatment. Other measures include the use of sustained-release implants that release the drug regularly over a period of time, and can be refilled periodically, as well as hydrogel platforms that serve to release the drug. The use of biosimilars will also serve to reduce the cost of treatment for nAMD. A new frontier of gene therapy, primarily targeting genes involved in the transduction of retinal cells to produce anti-VEGF proteins intraocularly, also opens a new avenue of therapeutic approaches that can be used for treatment. This review paper will discuss both current treatment options and the newer treatments under development.

Project description:PurposeThe purpose of this study is to evaluate the effect of complement factor H (CFH) Y402H CC and TT polymorphisms on treatment response to intravitreal ranibizumab injection in patients with wet age-related macular degeneration (AMD).MethodsOne hundred ninety-three patients with choroidal neovascularization (CNV) secondary to AMD who were monitored for at least 6 months of follow-up, and with at least three ranibizumab injections, were included in the study. At the final examination, an increase in visual acuity (VA) of five letters or more compared to the initial VA was regarded as a good response, and a decrease in VA of five letters or more compared to the initial VA was evaluated as a poor response. A genetic examination was performed with a PCR melting curve analysis. In the statistical evaluation, SPSS version 18 software was used.ResultsThe mean age of the patients was 71.01 (55-86) years, the mean follow-up was 13.34 (6-36) months, and the mean number of injections was 4.02 (3-15). There were 96 patients in the good response group (Group 1) and 97 patients in the poor response group (Group 2). The initial VA in Group 1 was 41.34 (10-64) letters, the initial central macular thickness (CMT) was 213.40 (126-494) µm, and the initial lesion width was 3760 (1430-6430) µm. The initial VA in Group 2 was 52.89 (26-82) letters, the initial CMT was 257.60 (115-882) µm, and the initial lesion width was 4460 (1000-7650) µm. There was no statistically significant difference between the two groups in terms of the initial VA and CMT (p=0.094, p=0.083). However, there was a statistically significant difference between the groups in the width of the initial lesion (p=0.003). In Group 1, 15 CC, 30 TT, and 51 TC alleles were found, and in Group 2, 49 CC, two TT, and 46 TC alleles were found, and the distribution was significantly different between the two groups (p=0.012). The change in the distribution of genotypes was not associated with either the lesion size or VA (p=0.841). Fibrosis developed in 12 patients who were all poor responders.ConclusionsCFH Y402H CC accompanied a poor response, and TT accompanied a good response in this series of patients with AMD undergoing ranibizumab therapy.

Dataset Information

Analysis of the association between CFH Y402H polymorphism and response to intravitreal ranibizumab in patients with neovascular age-related macular degeneration (nAMD).

Publications

Analysis of the association between CFH Y402H polymorphism and response to intravitreal ranibizumab in patients with neovascular age-related macular degeneration (nAMD).

Similar Datasets

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