The Asia-Pacific Journal of Ophthalmology

  • Current Issue

    November/December 2017 - Volume 6 - Issue 6
    Special Issue on Latest Development in AMD and Ophthalmic Application of Anti-VEGF Therapy
    pp: 477-568
    Guest Editors-in-Chief: William Mieler, Timothy Lai
    Guest Editors: R.V. Paul Chan, Andrew Chang, Gemmy Cheung, Patricio Schlottmann


Latest Developments in the Management of AMD Chang, Andrew; Schlottmann, Patricio G.; Chan, R.V. Paul
Over the past decade, the treatment of neovascular age-related macular degeneration (nAMD) has led to a considerable reduction of blindness due to this disease. Vascular endothelial growth factor (VEGF), identified as a main factor in the development of a neovascular membrane, has become the main target of therapy blocking its action. Anti-VEGF therapies result in vision gains for many and prevent further vision loss in a large majority of patients affected by nAMD. Unfortunately, results from real-world data have been less positive. This difference in results from randomized controlled trial data to the real world is a significant unmet medical need. New treatment modalities for neovascular AMD aim to increase efficacy and reduce the burden of treatment. Brolucizumab is a humanized single-single chain antibody fragment that inhibits VEGF-A with the smallest molecular weight to date (26 kDa).1 The combination of a small molecular weight and high concentration gradient make it an attractive addition to the anti-VEGF therapy family. Phase 2 studies have shown that brolucizumab was noninferior to aflibercept when matched at therapy every 8 weeks (q8). A larger proportion of participants were without fluid at a majority of visits. Therapy with brolucizumab every 12 weeks may be a potentially viable option for a proportion of patients.
Ophthalmic Application of Anti-VEGF Therapy Lai, Timothy Y.Y.; Cheung, Chui Ming Gemmy; Mieler, William F.
The concept of ocular angiogenesis research originated in the 1940s when Michaelson hypothesized a diffusible “factor X,” which could result in retinal and iris neovascularization in response to retinal ischemia. “Factor X” was subsequently identified by Senger et al as a protein that causes vascular leakage and was named vascular perme-ability factor (VPF). Ferrara et al later discovered a molecule that can result in proliferation of endothelial cells and the molecule was called vascular endothelial growth factor (VEGF). Further research found that the VPF and VEGF were in fact the same molecule. Moreover, elevated VEGF levels were found in patients with ocular disorders including neovascular age-related macular degeneration (aMd) and diabetic retinopathy. Based on these findings, inhibitors of VEGF were developed in animal studies to suppress the development and growth of ocular neovascularization. Further translational research and clinical trials have led to the approval of various anti-VEGF agents for neovascular aMd and anti-VEGF agents such as ranibizumab and aflibercept are now the gold standard therapy for neovascular aMd. Over the past 2 decades, based on the positive results of various pivotal clinical trials, the use of ranibizumab and aflibercept have now expanded to cover indications including diabetic macular edema (dME), macular edema due to retinal vein occlusions (rVo), myopic choroidal neovascularization (CNV), along with CNV due to uncommon diseases such as angioid streaks, ocular inflammation, central serous chorioretinopathy, and idiopathic CNV. In addition, another ophthalmic anti-VEGF agent, conbercept (also known as KH902), has been approved by the China Food and drug administration for treatment of neovascular aMd.

Review Article

Updates on the Epidemiology of Age-Related Macular Degeneration Jonas, Jost B.; Cheung, Chui Ming Gemmy; Panda-Jonas, Songhomitra
This meta-analysis reports on current estimates of the prevalence of age-related macular degeneration (AMD) based on a review of recent meta-analyses and literature research. Within an age of 45–85 years, global prevalences of any AMD, early AMD, and late AMD were 8.7% [95% credible interval (CrI), 4.3‒17.4], 8.0% (95% CrI, 4.0‒15.5), and 0.4% (95% CrI, 0.2–0.8). Early AMD was more common in individuals of European ancestry (11.2%) than in Asians (6.8%), whereas prevalence of late AMD did not differ significantly. AMD of any type was less common in individuals of African ancestry. The number of individuals with AMD was estimated to be 196 million (95% CrI, 140‒261) in 2020 and 288 million (95% CrI, 205‒399) in 2040. The worldwide number of persons blind (presenting visual acuity < 3/60) or with moderate to severe vision impairment (MSVI; presenting visual acuity < 6/18 to 3/60 inclusive) due to macular disease in 2010 was 2.1 million [95% uncertainty interval (UI), 1.9‒2.7) individuals out of 32.4 million individuals blind and 6.0 million (95% UI, 5.2‒8.1) persons out of 191 million people with MSVI. Age-standardized prevalence of macular diseases as cause of blindness in adults aged 50+ years worldwide decreased from 0.2% (95% UI, 0.2‒0.2) in 1990 to 0.1% (95% UI, 0.1‒0.2) in 2010; as cause for MSVI, it remained mostly unchanged (1990: 0.4%; 95% UI, 0.3‒0.5; 2010: 0.4%; 95% UI, 0.4‒0.6), with no significant sex difference. In 2015, AMD was the fourth most common cause of blindness globally (in approximately 5.8% of blind individuals) and third most common cause for MSVI (3.9%). These data show the globally increasing importance of AMD.
The Role of New Imaging Methods in Managing Age-Related Macular Degeneration Talks, Stephen James; Aftab, Akhunzada Muhammad; Ashfaq, Imran; Soomro, Taha
The use of imaging for age-related macular degeneration (AMD) depends on how it benefits clinical management and on reimbursement. The latter should relate to the former. This review assesses how different forms of AMD can be imaged and what information this provides. For nonneovascular AMD high-resolution optical coherence tomography (OCT), autofluorescence, and near infrared imaging can identify the type of drusen, such as reticular pseudodrusen, which influences prognosis, and the amount of atrophy, for which phase 3 trials are underway. Clarifying the correct diagnosis for late-onset Stargardt and macular telangiectasia, if treatment becomes available, will be especially important. Choroidal thickness can be measured and changes with anti‒vascular endothelial growth factor treatment, but how this influences management is less clear. The finding of a thick choroid may alter the diagnosis to pachychoroid neovasculopathy, which may have a different treatment response. Peripheral retinal changes are commonly found on ultrawide-field imaging but their importance is not yet determined. The mainstay of imaging is OCT, which can detect neovascular AMD by detecting thickening and be used for follow-up, as the presence or absence of thickening is the main determinant of treatment. Higher resolution systems and now OCT angiography are able to distinguish neovascular type, especially type 2 choroidal neovascularization but also polypoidal choroidal vasculopathy and retinal angiomatous proliferation. Fundus fluorescein and indocyanine green angiographies still have a role, although that partly depends on whether photodynamic therapy is being considered. Automated image analysis and machine learning will be increasingly important in supporting clinician decisions.
New Treatment Modalities for Geographic Atrophy Kandasamy, Rathika; Wickremasinghe, Sanjeewa; Guymer, Robyn
Age-related macular degeneration (AMD) is a significant cause of global visual morbidity and is projected to affect 288 million people by the year 2040. The advent of treatment with anti‒vascular endothelial growth factor (anti-VEGF) drugs has revolutionized the treatment of neovascular AMD (nAMD) but there have been no similar breakthroughs for the treatment of geographic atrophy (GA) to retard its progression. The advancements in imaging and new understanding of disease mechanisms, based on molecular and genetic models, have paved the way for the development of novel experimental treatment options for GA that aim to cater to a thus far largely unmet need. This review paper focuses on the recent clinical trials of new treatment options for slowing GA progression rates with emphasis on the agents that are currently undergoing, or have already undergone, significant clinical trial testing. Several new groups of drugs, including those targeting the complement cascade and agents considered as neuroprotective, have shown some promising results and could potentially pave the way forward in the treatment of this devastating disease.
New Treatment Modalities for Neovascular Age-Related Macular Degeneration Schlottmann, Patricio G.; Alezzandrini, Arturo A.; Zas, Marcelo; Rodriguez, Francisco J.; Luna, José D.; Wu, Lihteh
Age-related macular degeneration (AMD) is considered one of the main causes of severe vision loss in older adults. The neovascular form (nAMD) is an advanced stage, which is responsible for the most severe vision loss. Vascular endothelial growth factor (VEGF) is at present the main factor that leads to the development of a neovascular membrane and the increased leakage from the membrane to the retina. At present, anti-VEGF therapy is the only treatment that achieves vision gains in many patients and halts progression in most of them. VEGF blockade can be achieved with several molecules and various treatment regimens, which have been studied with excellent results. Unfortunately, real-world data has shown to be far less efficacious than clinical trials. This gap between clinical trials and real-world results is an unmet medical need that supports the necessity of new treatment modalities for nAMD. Of the various treatments being studied, anti-VEGFs of higher efficacy and longer durability are those more advanced in their development. Brolucizumab and abicipar pegol are 2 new anti-VEGF drugs that had positive results in phase 2 studies and are being tested in phase 3 trials at present. Other promising therapies are antiangiopoietin 2 molecules, which are in phase 2 development. At earlier stages of development but with promising results are squalamine, anti–VEGF-C and -D, and gene therapy. The future will give retina specialists a broad armamentarium with which patients may achieve high visual gains for the long term with a low treatment burden.
Prevention of Age-Related Macular Degeneration Singh, Niharika; Srinivasan, Sangeetha; Muralidharan, Vinata; Roy, Rupak; V, Jayprakash; Raman, Rajiv
Age-related macular degeneration (AMD) compromises quality of life. However, the available therapeutic options are limited. This has led to the identification of modifiable risk factors to prevent the development or alter the natural course and prognosis of AMD. The identification and modification of risk factors has the potential for greater public health impact on reducing morbidity from AMD. Likewise, identifying the imaging clues and genetic clues could serve as a guide to recognizing the propensity for progression to severe and end stages of the disease. Several attempts, both successful and unsuccessful, have been made for interventions that could delay the progression of AMD. Of these, pharmacological interventions have shown promising results. The Age-Related Eye Disease Study 1 and 2 have shown the beneficial role of antioxidants in a selected group of patients.
Anti-VEGF Therapy for Neovascular AMD and Polypoidal Choroidal Vasculopathy Cheung, Gemmy Chui Ming; Lai, Timothy Y.Y.; Gomi, Fumi; Ruamviboonsuk, Paisan; Koh, Adrian; Lee, Won Ki
Anti‒vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the treatment of neovascular age-related macular degeneration (AMD). This review will summarize the current evidence of anti-VEGF therapy in neovascular AMD, including subtypes of retinal angiomatous proliferation and polypoidal choroidal vasculopathy (PCV). Importantly, 2 large multicenter randomized clinical trials evaluating the safety and efficacy of anti-VEGF monotherapy and combination with photodynamic therapy (PDT) have recently reported initial first-year outcomes. In this review, we summarize the latest updates in the efficacy and safety of anti-VEGF monotherapy and combination with PDT in common lesion subtypes. Remaining gaps in current understanding are highlighted where further research is needed.
Anti-VEGF Therapy for Diabetic Eye Diseases Bahrami, Bobak; Hong, Thomas; Gilles, Mark C.; Chang, Andrew
Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness in the working-age population. The identification of vascular endothelial growth factor (VEGF) as a key mediator in the pathogenesis of DR has revolutionized the management of this vision-threatening disease. There is now strong evidence supporting intravitreal anti-VEGF therapy as first line in the management of sight-threatening diabetic macular edema (DME), along with a growing body of evidence to support the use of anti-VEGF drugs for proliferative DR. This review summarizes the role of VEGF in DR, the evidence for anti-VEGF therapy, safety considerations, and the future of anti-VEGF therapy for the management of DR.
Update on the Use of Anti-VEGF Intravitreal Therapies for Retinal Vein Occlusions Jiang, Yi; Mieler, William F.
The use of anti–vascular endothelial growth factor (VEGF) therapy in ophthalmology has profoundly changed our management and treatment of conditions such as cystoid macular edema, diabetic macular edema, choroidal neovascularization, and other proliferative retinopathies. Although initially used for the treatment of choroidal neovascularization in neovascular age-related macular degeneration, their application has spread rapidly for other indications as their outcomes have often outperformed previously existing treatments. Retinal vein occlusion (RVO) continues to be one of the leading causes of vision loss secondary to macular edema, in addition to macular ischemia and neovascularization in more severe cases. Before the availability of anti-VEGF therapy, the use of macular grid laser and panretinal photocoagulation was the mainstay of treatment of macular edema and neovascularization, respectively, in patients with RVOs. Two landmarks studies established the guidelines of these treatments for nearly a quarter century. Since the availability of anti-VEGF agents, there has been a paradigm shift in the treatment of RVO. Most importantly, there has also been a significant improvement in visual outcomes in these patients. The goal of this article is to provide a review of the pertinent clinical studies that have investigated the use of anti-VEGF in patients with retinal vein occlusions.
Anti–Vascular Endothelial Growth Factor Therapy for Myopic Choroidal Neovascularization Ng, Danny S.C.; Lai, Timothy Y.Y.; Cheung, Chui Ming Gemmy; Ohno-Matsui, Kyoko
Myopic choroidal neovascularization (CNV) is one of the most vision-impairing complications in patients with pathologic myopia. It is also one of the most frequently encountered non‒age-related macular degeneration causes of CNV and affects young patients in the working age group. Fluorescein angiography (FA) and spectral domain optical coherence tomography (OCT) are generally indicated to confirm the diagnosis of active myopic CNV before initiation of treatment. Without treatment, natural history studies have shown that the vision outcome can be very poor. More recently, a number of retrospective, prospective and phase 3, multicenter, randomized controlled trials have established the safety and efficacy of intravitreal anti‒vascular endothelial growth factor (VEGF) agents for the treatment of myopic CNV. Long-term follow-up studies have found that some of the initial vision gained after intravitreal anti-VEGF therapy may not be maintained, owing to the presence and progression of chorioretinal atrophy (CRA) adjacent to the CNV. Further research on clinical and imaging characteristics may elucidate the prognostic factors that are crucial to optimizing the treatment and prevention of visual impairment associated with myopic CNV.
Intravitreal Ziv-Aflibercept: Clinical Effects and Economic Impact Singh, Sumit Randhir; Dogra, Avantika; Stewart, Michael; Das, Taraprasad; Chhablani, Jay
During the past decade, drugs that inhibit the actions of vascular endothelial growth factor (VEGF) have become standard-of-care treatment for a variety of chorioretinal vascular conditions. The off-label, intravitreal use of ziv-aflibercept (Zaltrap) has provided clinicians with an additional cost-effective drug. The commercial preparation of ziv-aflibercept contains the same aflibercept (VEGF-trap) molecule as Eylea but has a much higher osmolarity (1000 mOsm/kg vs 300 mOsm/kg). Initial concerns regarding cytotoxicity and long-term safety of intravitreal ziv-aflibercept have been largely negated after a series of publications failed to identify adverse ocular and systemic side effects. Both treatment-naive and anti-VEGF‒resistant cases of neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), retinal vein occlusion (RVO), and choroidal neovascular membrane (CNVM) may respond as well to ziv-aflibercept as to aflibercept. A higher dose of ziv-aflibercept (2 mg in 0.08 mL) does not cause any adverse effects during short-term follow-up period (1 month). Data from various sources suggest that ziv-aflibercept may be as cost effective as bevacizumab, thereby making it an attractive treatment option in low- and middle-income countries. However, problems with off-label use, compounding, and counterfeiting limit its availability in many countries. Data from prospective, randomized, multicenter clinical trials are still required to convince physicians and regulatory bodies of its clinical efficacy and potential as early therapy.

Original Study - Clinical

The VEGF Treatment of AMD Switch Study (The vTAS Study) Curry, Beverley; Bylsma, Guy; Hewitt, Alex W.; Verma, Nitin
Purpose: To evaluate the effect of aflibercept on anatomic and visual outcomes in patients with choroidal neovascularization (CNV) previously treated with intravitreal ranibizumab with persistent fluid on optical coherence tomography (OCT).

Design: Prospective, open-label study.

Methods: Eighteen patients (19 eyes) with CNV being treated with monthly ranibizumab, with persistent fluid on OCT, were switched to intravitreal aflibercept injections at intervals of up to 8 weeks. The primary outcome was the proportion of patients maintaining vision [<5 letter loss in visual acuity (VA)] at week 48. Secondary outcomes included the change in VA and central macular thickness (CMT) and the frequency of treatment necessary along with the safety of intravitreal aflibercept.

Results: Forty-eight weeks after switching to aflibercept, 16/19 eyes had maintained VA. There was a median increase in vision of 5 letters [interquartile range (IQR): 0, 15; P = 0.06)] and median CMT was reduced from 313 µm (IQR: 214, 334) to 258 µm (IQR: 200, 299; P = 0.02). After stratification by fluid location the reduction in CMT was statistically significant for eyes with intraretinal fluid (IRF) at baseline [median change, -25 µm (IQR: -14, -64); P = 0.01]. Macular volume within 6 mm of the fovea (CMTVol) was significantly reduced in eyes with subretinal fluid (SRF) [-0.20 mm3 (IQR: -1.45, -0.05); P = 0.03].

Conclusions: In this small cohort of eyes, switching to aflibercept seemed beneficial. The majority maintained or improved vision and eyes with IRF or SRF had significant reductions in macular edema. However, visual improvement was not always indicative of anatomical improvement.
The ARMOUR Study: Anti-VEGF in Neovascular AMD—Our Understanding in a Real-World Indian Setting Jain, Nimesh; Yadav, Naresh Kumar; Jayadev, Chaitra; Srinivasan, Priya; Mohan, Ashwin; Shetty, Bhujang K.
Purpose: The aim of our study was to share our experience with anti‒ vascular endothelial growth factor (anti-VEGF) injections in the treatment of neovascular age-related macular degeneration (nAMD) in a realworld setting.

Design: A retrospective, observational study.

Methods: Patients of Indian origin with nAMD receiving anti-VEGF with a minimum follow-up of 12 months were enrolled in this study. In group 1, patients were treated on a pro re nata (PRN) basis; in group 2, patients received a loading dose (3 injections) and were then treated on a PRN basis. Main outcome measures were mean change in corrected distance visual acuity (CDVA) and central subfield thickness (CSFT) from baseline to months 3 and 12.

Results: Overall, we observed that 77.31% (92/119 eyes) of patients either maintained or had improved visual acuity at 12 months’ follow-up. Similar visual outcome was observed in both groups. The average number of injections given in group 1 was 4.98 and in group 2 was 3.7. CDVA at 12 months was significantly correlated with type of drug molecule, CSFT at 3 and 12 months, baseline visual acuity, and CDVA at 3 months.

Conclusions: PRN treatment with significantly fewer injections achieved similar anatomical and functional outcomes when compared with the loading dose group. The results of this study need to be validated with a larger study group and a longer follow-up. This real-world observation shows that an individualized PRN approach without loading dose can be considered in the treatment of nAMD.
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