In recent years, retinal diseases have increasingly contributed to the global burden of visual impairment. Age-related macular degeneration (AMD), diabetic retinopathy (DR) and retinal vein occlusion (RVO) are the most prevalent conditions under this category. The fundamental basis of pathology involves oedema of the macular region and neovascularisation that eventually leads to irreversible loss of central vision. A mitogen known as vascular endothelial growth factor (VEGF) is at the crux of the pathological process, responsible for initiating a pro-inflammatory cascade and promoting angiogenesis. Treatment strategies aim to reduce macular oedema (MO) and neovascularisation through intravitreal injections that provide a suitable method for localised drug delivery. The main classes of drugs used are anti-VEGFs and steroids, targeting the angiogenic and inflammatory components of the pathology respectively. Ranibizumab, bevacizumab and aflibercept are the most commonly used anti-VEGFs, with ranibizumab and aflibercept recommended as first-line therapy because they show superiority over bevacizumb. Bevacizumab is not licensed for ocular conditions but is widely used off-label due to relatively similar efficacy profiles to other anti-VEGFs and significantly reduced cost. Anti-VEGFs have good safety profiles however are a burdensome method of treatment as monthly injections are required to achieve therapeutic effects. Dexamethasone, triamcinolone acetonide (TA) and fluocinolone acetonide (FA) are the most commonly used steroids, primarily for MO secondary to DR and RVO. They have longer half-lives than anti-VEGFs, allowing longer intervals between treatments. However, they have inferior efficacy profiles and significantly increased rates of side-effects such as cataract progression and raised intraocular pressure (IOP), making them second-line options. Combination therapy to address multiple aspects of the underlying pathology and research into longer-acting anti-VEGFs and different dosing regimens are potential strategies to achieve better results for all three conditions.
Posterior segment, or retinal diseases, are major contributing factors to the global burden of visual impairment and are likely to become more important due to the rapidly burgeoning ageing population. Globally, 285 million people of all ages are visually impaired, 39 million of whom are blind1. This is the first time that the proportion of visual impairment and blindness attributed to retinal diseases is greater than that credited to infective causes such as trachoma and corneal opacities. Therefore, it has become increasingly important to improve screening measures for early diagnoses and develop efficacious treatment strategies to tackle this growing problem. The most prevalent retinal diseases include age-related macular degeneration (AMD), diabetic retinopathy (DR) and retinal vein occlusion (RVO). All three share common underlying pathological mechanisms featuring a surge of pro-inflammatory mediators responsible for the degenerative sequelae that can largely be grouped under macular oedema (MO) and neovascularisation. A crucial component responsible for these changes is a mitogen known as vascular endothelial growth factor (VEGF). VEGF contributes greatly in the maintenance of ocular homeostasis. Loss of vascular endothelial integrity and subsequent hypoxic conditions augment VEGF production by approximately 3-fold from retinal endothelial cells, pigment epithelial cells and pericytes, which can then bind to VEGF receptors 1 and 22. The primary purpose of this is to enhance angiogenesis and thereby restore oxygen supply. VEGF-A is the main isoform involved in physiological and pathological angiogenesis. In the context of hypoxia, any neovascularisation that occurs is aberrant and results in pathology. VEGFR-2 is particularly responsible for the regulation of vascular endothelial function and its activation results in the disruption of cell adhesion molecules that protect endothelial integrity and leads to MO3. VEGF is also crucial to the inflammatory cascade that is initiated during retinopathy and enhances adhesion of leukocytes and macrophages to the vascular wall, thereby increasing vascular permeability and blood retinal barrier (BRB) dysfunction4.
Until the start of the last decade, focal/grid laser was the treatment of choice for its safety and efficacy profiles, however, this is only a temporary solution as it does not tackle the molecular basis of pathology. Therefore, other treatment strategies were sought leading to the advent of intravitreal injections. Intravitreal injections have revolutionised the management of retinal conditions as they provide a logical method for physicians to overcome the BRB and ensure that therapeutic levels of a drug are delivered to the right tissue, without systemically being absorbed and thereby cause drug toxicity.
Two main types of intravitreal drugs have been used according to the primary mechanism of each pathology. Intravitreal anti-VEGF injections mainly tackle the neovascularization component, therefore were primarily used in AMD, but are now licensed for their efficacy in addressing MO secondary to DR and RVO. Ranibizumab (Lucentis) is a 48kDa recombinant humanized IgG1 kappa isotype antibody fragment that binds to all VEGF-A isoforms5. Bevacizumab (Avastin) is a 149kDa humanised murine monoclonal antibody that has FDA approval for use in metastatic colorectal cancer but is used off-label widely for ocular conditions6. It inhibits all isoforms of VEGF with high specificity and affinity for VEGF-A, reduced immunogenicity and a longer half-life. The newest addition to the class of anti-VEGF preparations is called aflibercept (VEGF TrapEye). It is a decoy receptor fusion protein made up of the second domain of human VEGF receptor 1 and the third domain of VEGF receptor 2, fused to the Fc domain of human IgG17. Aflibercept has a significantly higher binding affinity to all isoforms of VEGF and is distinct in its ability to inhibit placental growth factor (PlGF) which works in conjunction with VEGF-A to induce pathological angiogenesis. This implies a broader spectrum of action achieved by this drug.
Intravitreal steroid injections are the second class of drugs used to address the inflammatory component of the disease process. They stabilize the BRB, reduce exudation and are anti-angiogenic. Ozurdex is a biodegradable co-polymer of polylactic-co-glycolic acid containing 0.7mg dexamethasone that is delivered into the vitreous cavity for slow release of the active compound. Its levels peak within the first 2 months but effects last for 4-6 months on average after a single injection. Triamcinolone acetonide (TA) is a synthetic steroid from the glucocorticoid family. The preservative-free formulations of this compound such as Trivaris, are most commonly used. It is also insoluble in water, allowing extended time of action in the eye. Fluocinolone acetonide (FA) is another synthetic corticosteroid with comparable potency to dexamethasone, however possesses zero-order kinetics allowing slow release over a longer time period.
The purpose of this paper is to discuss the efficacy of current treatment strategies and shed light on future directions to combat the progression of retinal diseases. The parameters to be considered when comparing drugs include treatment efficacy, safety, frequency of dosing and cost. There are three defined treatment regimens for the use of intravitreal injections: fixed dosing, pro re nata (PRN) and treat-and-extend.
AGE-RELATED MACULAR DEGENERATION (AMD)
AMD ranks third among the global causes of visual impairment and is a leading cause of irreversible blindness in the developed world7. AMD is defined as changes occurring in the central region of the eye, the macula, which can be attributed to the ageing process and no other obvious pathology in people over the age of 55 years. This condition has been classified into non-exudative/dry/early AMD and exudative/wet/neovascular AMD: the latter being the more progressive form of the disease.
Dry AMD is characterized by lipid accumulation, known as drusen, below the retinal pigment epithelium (RPE), with associated pigmentary changes. At this stage, visual impairment is minimal, if any, and can often be missed due to compensation by the unaffected eye. A hallmark of progressing dry AMD is geographic atrophy (GA): sharply defined areas of depigmentation, reflecting RPE atrophy, often associated with severe impairment of visual acuity, contrast sensitivity, near vision and reading speed, all being functions of the macula (Fig 1)8. Dry AMD is slow progressing and is less likely to cause visual deficit, therefore is treated by reducing risk factors such as smoking or by antioxidants and laser therapy.
A small proportion of patients suffer progression to exudative AMD, diagnosed by the presence of choroidal neovascularization (CNV). New fenestrated vessels from the choroid break through the sub-pigment epithelial space, allowing leakage of fluid between retinal layers and separating them. The outcome of this is retinal thickening and misalignment of the underlying photoreceptors, eventually causing fibrosis and disciform scar formation that disrupts normal retinal architecture and leads to permanent central vision loss9.
Due to the fact that the primary pathology in this case is neovascularisation, anti-VEGFs are recommended as first-line therapy. Ranibizumab was first discovered in 2006 in the ANCHOR (n=430) and MARINA (n=716) clinical trials for neovascular AMD. Monthly injections of 0.3mg and 0.5mg ranibizumab caused marked regression of CNV and prevented moderate vision loss in 90% of patients in both trials10. The ANCHOR trial revealed superiority over verteporfin photodynamic therapy (PDT) in improving mean best corrected visual acuity (BCVA; Fig 3). The MARINA trial depicted a dose-response effect of the drug, with maximal efficacy from 0.5mg11. The mean gain in visual acuity was maintained over a 2-year period in eyes receiving the injection in both trials and remained stable in 50% of the cohort at 7 year follow up12. Both trials indicated low rates of adverse ocular reactions including endophthalmitis,
cataract progression and raised intra-ocular pressure (IOP)10,11.
Efficacy of bevacizumab was compared to ranibizumab in the Comparison of AMD Treatment trial (CATT; n=1208). Similar results were achieved with both drugs using monthly and PRN dosing regimens13. A similar study called IVAN with the primary outcome of BCVA at 2 years produced analogous results14. This promoted the use off-license use of bevacizumab. The VIEW protocols (n=2419) tested aflibercept by randomising patients into aflibercept groups (0.5mg monthly, 2mg monthly or 2mg every 2 months). 95% and 90% of patients achieved maintenance of vision and at the end of 1 and 2 years respectively, had excellent retinal morphological outcomes15 and this was non-inferior to treatment with 0.5mg ranibizumab.
DIABETIC RETINOPATHY (DR)
Diabetes is a global epidemic with continually rising rates. This multi-system disease has lasting effects on the retina, a highly metabolically active tissue, to the extent that a third of all diabetics have signs of retinopathy16. DR is the leading cause of blindness in working-age individuals in industrialised countries, diabetic macular oedema (DMO) accounting for 75% of DR-related visual impairment. DR can be divided into non-proliferative (NPDR) and proliferative (PDR), neovascularization being a hallmark of the latter.
At the onset of diabetes, the retina resets its high metabolic activity to a lower set point to reduce energy demand. In the face of persistent hyperglycaemia however, a biochemical and physiological cascade involving advanced glycation end-products, sorbitol, oxygen free radicals and inflammatory cells is initiated17. The retinal microvasculature is particularly vulnerable to the influx of proinflammatory mediators, and lose their autoregulation mechanism, resulting in weakness, permeability and fluid leakage. The consequences of this include venous dilation, breakdown of inner BRB, retinal haemorrhages, microaneurysms, cotton wool spots and most importantly, MO. To cope with this, repair mechanisms are set in motion, however are aberrant and result in
neovascularization, gliosis, fibrosis and eventually, loss of visual acuity.
Ranibizumab has been employed for use in the treatment of DMO in DR as well. The DRCR.net study (n=854) displayed long-term maintenance of visual gain for up to 5 years and reduced risk of DR progression with IV ranibizumab18. This was substantiated by the RISE and RIDE trials that tested the efficacy of monthly 0.3 or 0.5mg ranibizumab injections in patients with DMO19. On a structural level as well, ranibizumab significantly reduced central retinal thickness (CRT) as compared to laser therapy, resulting in reduced MO and vascular leakage, enhanced retinal sensitivity and stabilised bioelectrical macular function measured using pattern, full-field and multifocal electroretinogram20,21. Ranibizumab also showed non-inferiority to panretinal photocoagulation (PRP) in patients with PDR over 2 years, providing a useful adjuvant for PRP to achieve maximal efficacy with reduced number of injections22. The DRCR.net protocol T (n=660) carried out a head-to-head comparison of the three anti-VEGFs (Fig 7). There was relatively small but clinically significant benefit of using aflibercept compared to bevacizumab in improving visual acuity, however this was comparable with ranibizumab using the same number of injections23. 2mg IV aflibercept treatment has also shown superiority against macular laser for DMO in the VISTA and VIVID clinical trials, specifically for patients with lower baseline visual acuity (below 20/50)24 and unresponsive MO. For this reason, aflibercept and ranibizumab are gold standard of treatment for patients with DMO and aflibercept is recommended for use in this
As the underlying pathology also features a large inflammatory component, steroid treatments have been trialled as well. The PLACID study revealed superiority of Ozurdex over macular laser for DMO with the primary end-points of reducing CRT and MO25. The MEAD study compared 0.35mg and 0.7mg doses of Ozurdex over 3 years and showed maintenance of improved vision and retinal morphology in the long term26. The primary advantage of Ozurdex highlighted by this study was the significantly fewer number of required injections (4-5 over 3 years) to achieve therapeutic effects as compared to anti-VEGF therapy (7-10 injections in the first year for ranibizumab). Ozrudex treatment however resulted in cataract progression in 67.9% and 64.1% from both doses respectively as opposed to 20.4% in the sham group for phakic eyes. This is a significant disadvantage that must be considered prior to commencement of therapy. The BEVORDEX study (n=88) comparing Ozurdex with bevacizumab revealed similar visual improvement, however superior anatomic outcomes and fewer required injections in the Ozurdex arm27. Combination therapy with Ozurdex and bevacizumab showed superiority in patients with refractory DMO compared with bevacizumab monotherapy as well, providing a potential cost-effective option in patients unresponsive to other treatments28. Therefore, Ozurdex treatment is recommended in subsets of patients with pseudophakic eyes, refractory DMO or in combination
particular subset of people.
therapy due to its efficacy yet increased risk of side effects.
Multiple clinical trials have indicated efficacy of IVTA using a 1mg or 4mg dose, however have shown no significant difference between the two doses. In fact, treatment with either dose showed inferiority to laser at the end of 2 years when comparing CRT and BCVA, with 50% of patients developing glaucoma and/or cataracts29. Interestingly however in pseudophakic eyes, results with fewer IVTA injections were similar, if not better than treatment with anti-VEGFs. This opens up a new treatment option for a particular subset of people that is more effective and less burdensome to adhere to. Furthermore, IVTA therapy has been beneficial in patients with PDR and refractory DMO, 4mg IVTA treatment achieving greater reduction in CRT as compared to 1.25mg bevacizumab30.
Iluvien is a non-biodegradable intravitreal implant for sustained FA (0.2ug or 0.5ug) delivery that has anti-oedematous effects for up to 3 years25. The FAME trial tested FA insert at different doses for patients with DMO and revealed significant visual gain following a single injection that was maintained at the end of 2 years. Similar to TA therapy, this effect was more exaggerated in patients with refractory DMO.
RETINAL VEIN OCCLUSION (RVO)
RVO is a common retinal disorder that causes sudden, profound visual loss. 16.4 million adults are affected with RVO worldwide31. It can be categorized according to the site of the occlusion i.e. central retinal vein occlusion (CRVO) features an obstruction in the central retinal vein, whereas branch retinal vein occlusion (BRVO) implicates one of the branches of the retinal venous tree. BRVO is the more common subtype, with a global prevalence of 13.9 million31.
The pathogenesis of this condition is related to arterial disease, the strongest risk factors being systemic hypertension and hyperlipidaemia (48% and 20% association32,33). Other predisposing factors include age, diabetes, glaucoma and hypercoaguability states. The CRV and central retinal artery share a common adventitial sheath when exiting the optic nerve head and passing through a narrow opening in the lamina cribrosa. This anatomical compression may result in endothelial changes. Arterial wall changes due to HTN or arteriosclerosis cause it to become a rigid structure that impinges on the pliable vein. Alongside this, mechanical compression due to inflammation of the optic nerve; deficiency in thrombolytic factors and; haemodynamic changes leading to a sluggish circulation all contribute to thrombus formation in the retinal vein. The major downstream effect of this is impedance of blood flow, resulting in increased intravascular pressure upstream to the occlusion, fluid leakage in the extracellular space, retinal haemorrhage development and reduced perfusion. Fluid leakage in the macular region results in MO and contributes to loss of visual acuity.
The CRUISE study revealed a gain in visual acuity with fixed ranibizumab dosing followed by a monthly PRN dosage regimen for CRVO, however this was inferior to treatment with aflibercept and bevacizumab. On the other hand, the best improvement in patients with BRVO was achieved with monthly 0.5mg ranibizumab injections for 6 months, followed by monthly PRN dosage as indicated by the BRAVO study34. Aflibercept has also been recommended for treating MO secondary to CRVO and BRVO after promising results in the COPERNICUS and GALILEO trials35,36. Its longer half-life translates into fewer injections, being more practical for healthcare providers and patients37. Ranibizumab and aflibercept are first line treatment for RVO as well.
Two main steroids are used for the treatment of RVO. Dexamethasone was investigated in the GENEVA phase III clinical trial, where 0.35mg and 0.7mg doses significantly improved visual acuity and reduced CRT38. Similar results were observed in patients with lower baseline visual acuity39. Ozurdex has been approved for MO secondary to RVO and is especially recommended in patients with pseudophakic eyes and/or cardiovascular comorbidities. The SCORE (n=411) trial concluded 4mg IVTA had similar efficacy to grid laser photocoagulation in patients with BRVO but 1mg dose improved visual acuity in patients with CRVO. Both doses were however associated with the highest rate of cataract formation, cataract surgery and IOP elevation40.
For the last three decades, focal/grid laser treatment has been the standard of care for reducing MO and addressing the inflammatory processes occurring as part of retinal diseases. The Early Treatment of Diabetic Retinopathy study (ETDRS) depicted a 50% reduction in the risk of moderate vision loss in patients with clinically significant MO for up to 3 years41. However, this method only provides a temporary fix with patients progressing to lose their vision, and microperimetry assessments of retinal function showed exacerbation of macular dysfunction. In recent years therefore, new treatments have been sought with the goal of therapy shifting from preventing vision loss to maximising visual gain. Treatment for retinal diseases warrants a drug that is anti-oedematous, anti-inflammatory and anti-angiogenic, can be delivered directly to the retina where it has localised effects and has a half-life that allows for longer intervals between treatments. Anti-VEGF injections have superior efficacy profiles as compared to steroid implants in multiple trials and better safety profiles, with reduced rates of injection-induced complications, cataract formation and raised IOP. They have most dramatically reduced CRT as seen on OCT scans, implying a reduction in MO, and reduced neovascularisation seen by fluorescin angiography, altogether highlighting their ability to tackle both components of the underlying pathological mechanism. The overall risk of endophthalmitis from anti-VEGFs is 0.019-1.6%42 due to procedural and drug-related factors such as cold chain lapse during transport of drugs and counterfeit medication in the case of bevacizumab. These factors make anti-VEGFs the best candidates to treat the aforementioned conditions. Ranibizumab has been trialled using 0.3mg and 0.5mg doses however a dose of 0.3mg is preferred as it reduces potential risks associated with systemic VEGF suppression. This is particularly important in the context of DMO, as most patients have an increased risk of mortality and associated cardiovascular disease. The approved dose for treatment of AMD and RVO however, is 0.5mg/0.05ml43. Due to the fact that its primary use has been in colorectal cancer, bevacizumab has a longer half-life of about 20 days as compared to ranibizumab (2 hours). Although this allows for longer intervals between treatments, it implies a higher toxicity profile with a greater hazard ratio of hypertensive side effects as compared to ranibizumab. It also has 12-fold increased risk of severe ocular inflammation and 22% greater risk of stroke compared to ranibizumab. Regardless, bevacizumab is widely used worldwide due to its cost-effectiveness. It is 30 times cheaper than ranibizumab, a single IV injection costing $50 as compared to $120044. The recommended dose is 1.25mg with 3 initial injections at monthly intervals. Aflibercept has proven superiority over other anti-VEGFs and is more effective in patients with lower baseline VA, suggesting more practical use. It is also cheaper than ranibizumab and has a longer half-life, therefore is the ideal drug of choice from the pool of anti-VEGFs.
Despite all the benefits associated with anti-VEGFs, sustained inhibition of RPE-derived VEGF-A blunts its neuro-protective and trophic effects on choriocapillaries and photoreceptors. This can exacerbate GA, with an increased hazard risk score of 1.59 from monthly injections as opposed to a PRN dosing regimen13. Monthly injections also increase the ‘per patient’ risk of injection-induced side effects. Furthermore, after therapeutic levels of drugs are depleted from the body, patients remain at risk of forming new lesions, leaks, haemorrhages and eventually disciform scarring due to the chronic nature of the diseases in question. Another important aspect to consider is the real-world implementation of strategies defined by the aforementioned clinical trials, which is not as clear cut. Most people do not meet the exact inclusion criteria defined by these studies and monthly injections prove burdensome on healthcare providers, patients and carers. For this reason, in the real world patients receive fewer injections and have fewer follow up appointments, eventually obtaining a lower initial gain in visual acuity6. The burden of monthly injections also pushes patients to opt for discontinuous treatment regimens such as treat-and-extend i.e. where the interval between treatments is increased when the disease is stable with the aim of injecting just before reactivation or; PRN dosing i.e. patients are treated only when the lesion is active, the results of which are inferior to monthly dosing. Reflecting on these factors highlights the importance of looking into drugs with a longer half-life, thereby negating the need for continuous treatment, yet at the same time keeping the rate of ocular and non-ocular side effects low.
Steroid implants are advantageous in this regard where slow-release of drugs translates into fewer injections, which is more cost-effective and practical. Their primary disadvantage however, is the high rate of side effects that they induce upon long-term treatment, which when weighed against their relatively inferior efficacy profiles enables them to be the less likely choice of treatment. In some subsets of patients, such as those with pseudophakic eyes or unresponsive MO, steroid therapy is beneficial as the major side effect of steroid-induced cataract formation is no longer relevant. Time between injections is increased as well and because these patients have a worse prognosis than most others they are usually more willing to comply with a riskier option. This class of drugs is also useful for the subset of people that have systemic vascular comorbidities that bar the use of anti-VEGFs for fear of adverse systemic events. Alternatively, combination therapy can also be explored as a possible solution to achieve maximal efficacy, as multiple aspects of the underlying pathology would be addressed with minimal injections and side effects. This includes dual therapy with anti-VEGFs and steroids or anti-VEGF/steroid injections and laser therapy or even triple therapy with all three treatment methods. The READ-2 trial for DMO delivered promising results from combination therapy with laser and ranibizumab to reduce MO for up to 2 years with fewer injections45 and; RVO treatment with Ozurdex and bevacizumab revealed syngergistic effects on increasing VA and reducing CRT46. Another method of making treatments more cost-effective is ‘task-shifting’ whereby non-ophthalmic workers at a community level are given more responsibility for diagnosis and delivery of treatments. Optometrists, nurses and GPs showed over 60% specificity of detecting DR47 and can also be trained to administer relevant treatments. This would not only reduce the cost of therapy and the burden on ophthalmologists, but also allow stricter control on screening and follow ups, rendering better outcomes.
Another exciting avenue of research on intravitreal injections that is being explored is slower release steroid inserts for MO in DR and RVO. A new preservative and solvent-free corticosteroid implant called Cortiject (NOVA63035) is undergoing a phase I study for DMO and has provided promising results for sustained release over 6-9 months. Verisome, another IVTA implant is undergoing phase I clinical trials for MO secondary to RVO lasting 1 year48. The Iluvien (FA) insert is also currently in phase II clinical trials for the treatment of dry AMD and MO secondary to RVO.
Significant progress has been made in recent years to improve the treatment of retinal diseases. Anti-VEGFs have come out as the superior therapeutic approach, however pose real-world challenges with regards to implementation of monthly dosing regimens. Development of anti-VEGFs with longer half-lives would solve this issue and enable effective yet less burdensome treatment. Alternatively, conducting large scale clinical trials to explore different dosing regimens that are less taxing and more cost-effective is worth considering. Large scale clinical trials into combination therapies would also be beneficial as targeting different points of the pathological process can act synergistically to increase effectiveness and durability of therapies. Furthermore, research into other aspects of the pathophysiology of disease must be carried out to isolate potential factors contributing to pathology that can be inhibited to achieve good visual outcomes. To achieve sustainable management strategies however, it is most important to ensure that patients have adequate education about retinal diseases, are followed-up adequately and are compliant with treatment. This puts great emphasis on the community healthcare workers and highlights that along with improved medication, a shift in treatment administrators is required to achieve best results.
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