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Abstract
Aims To investigate the long-term safety of intravitreal ziv-aflibercept in eyes receiving six or more intravitreal injections of ziv-aflibercept, an off-label substitute to the approved aflibercept.
Methods Consecutive patients with retinal disease receiving six or more of intravitreal 0.05 mL ziv-aflibercept (1.25 mg) injections were followed monthly in three centres. Outcome measures were best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution (logMar)) and central macular thickness (CMT) on spectral domain optical coherence tomography and monitoring for ocular inflammation, progression of lens opacities and intraocular pressure rise. Paired comparison was done using Wilcoxon signed-rank test calculator.
Results Sixty-five eyes of 60 consecutive patients received a mean of 8.4 (6–17) intravitreal injections with a baseline mean logMAR BCVA of 0.98±0.56 and CMT 432.7±163.0 μm and followed for a mean of 9.2 months (range 6–18 months). After the sixth injection, mean BCVA improved to 0.57±0.36 (p=0.001) and CMT decreased to 274.8±117.8 μm (p=0.0001). At the 9-month follow-up, mean BCVA improved to 0.62±0.37 (p=0.0004) and mean CMT decreased to 292.0±160.9 μm (p<0.01) in 19 eyes. At 1 year, mean BCVA was 0.73±0.52 and CMT 311.6±232.5 μm in seven eyes. Intraocular pressures did not increase after injections. One subject developed transient mild iritis at the fourth injection but not on subsequent injections. No lens opacity progression or endophthalmitis was noted. Systemic adverse effects were not registered.
Conclusions Repeated intravitreal injections of ziv-aflibercept appear tolerable, safe and efficacious in the therapy of retinal disease.
- Retina
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Introduction
Aflibercept (Eylea, Regeneron, Tarrytown, New York, USA) is the most recently approved vascular endothelial growth factor (VEGF) antagonist for the treatment of diabetic macular oedema (DME),1 neovascular age-related macular degeneration (nAMD)2 and cystoid macular oedema (CME) from retinal venous occlusion (RVO).3 Aflibercept took the lead among the available anti-VEGF in the USA due to good clinical efficacy, proven safety record and long duration of action.1 However, its use in the Third World has been very slow partly due to state regulations and more so due to the high expense of the drug and in unavailability in many countries.
de Oliveira Dias et al4 were the first to demonstrate that ziv-aflibercept is not toxic to the retina in rabbits. Malik et al5 added laboratory evidence to the safety of ziv-aflibercept on retinal pigment epithelium cells in culture. Mansour et al6 detected no loss of anti-VEGF activity in compounded ziv-aflibercept for a period of 1 month in the laboratory and in eyes with nAMD or DME. Chhablani et al7 detected no electroretinographic alterations 1 month after injection of ziv-aflibercept in eyes with nAMD. Three-month studies in DME8–11 or nAMD12 and case reports13–16 attested to the short-term safety of the drug. However, long-term safety data after multiple injections are still lacking.
In this study, we report the long-term outcome of safety and clinical efficacy of intravitreal ziv-aflibercept (1.25 mg) in a multicentre setting.
Materials and methods
This is a non-randomised three-centre study examining safety by standard ophthalmic examinations, intraocular pressure measurements and potential clinical complications, such as myocardial infarction and other thromboembolic events. All ocular or systemic adverse effects happening to the patients after enrolment were recorded at every visit.
This study was approved by the institutional review committees and adhered to the tenets of the Declaration of Helsinki. The study duration was from March 2015 to August 2016. After detailed explanation of the protocol and off-label use, all patients signed a formal consent. Inclusion criteria included eyes received minimum six injections of intravitreal ziv-aflibercept for naïve or previously treated conditions such as nAMD, DME, CME from CRVO and pseudophakic CME. Exclusion criteria included use of any other intravitreal anti-VEGF therapy during the study period, corneal scar, infectious conjunctivitis, vitreous haemorrhage, asteroid hyalosis, macular ischaemia, macular scar from subretinal fibrosis and prior vitreoretinal surgery.
Consecutive patients with ocular vascular disease received six or more intravitreal injection of 0.05 mL ziv-aflibercept (1.25 mg) and were followed prospectively monthly. Ziv-aflibercept 0.05 mL (1.25 mg aflibercept) was prepared and injected monthly according to standard protocols (compounding under sterile conditions with storage at 4°C for 4 weeks).6 Intravenous fluorescein angiography was done at the initial exam as per physician discretion. The same operator (AMM) performed the vision exam, optical coherence tomography (OCT) test and intravitreal injection in the Lebanese series, while the certified ophthalmology associates participated in the care of the patients in both the Egyptian and Indian series. All patients underwent refraction on the initial visit. Best-corrected visual acuity (BCVA) was assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) R chart (Precision Vision, La Salle, Illinois, USA) in Lebanon and Snellen visual acuity chart in both Egypt and India. Macular changes using spectral domain OCT were done monthly using 3D-2000 Topcon FA plus (Topcon, Tokyo, Japan) in Lebanon, Spectralis (Heidelberg Engineering GmbH, Heidelberg, Germany) in Egypt and Cirrus (Carl Zeiss Meditec, Dublin, California) in India. Central macular thickness (CMT) measurements (mean thickness in the central 1000 μm diameter area) were corrected for machine use according to established formulae.9 ,12 Intraocular pressure was measured using applanation tonometry. Monitoring of intraocular inflammation and cataract progression was carried monthly using the slit lamp.
Injection pattern followed the protocol for DME set by initial five monthly injections then treat and extend (Lebanon and Egypt), or pro-re-nata (PRN) (India).17 For eyes with nAMD, three initial monthly injections were done followed by PRN therapy,18 or three initial monthly, then monthly till absence of activity by OCT, then treat and extend (Lebanon). Eyes with consistently incomplete clinical response received monthly injections till at least the first year of follow-up.
Statistical analyses were done using SPSS V.22 (IBM Corporation, Chicago, Illinois, USA). Paired comparison was done using Wilcoxon signed-rank test calculator to assess the change in both vision and macular thickening. Significance was set at p value of 0.05.
Results
A total of 65 eyes (34 right eyes and 31 left eyes) were treated for nAMD (32 eyes), DME (25 eyes), CRVO (6 eyes) and pseudophakic CME (2 eyes). A total of 55 consecutive patients included 7 Indians and 48 Caucasians (38 Lebanese and 10 Egyptians) with a mean age of 68.4 (range 42–92) and gender distribution as 28 male and 27 female. Ten patients received bilateral therapy. The mean number of injections was 8.4 (range 6–17) over a mean follow-up of 9.2 months (range 6–18 months). Nineteen eyes received monthly therapy over a period of 1 year. There were 31 treatment naïve eyes (all Caucasians) and 34 treatment non-naïve eyes. Prior intravitreal injections included a total of 160 bevacizumab, 29 ranibizumab, 3 aflibercept (Eylea), 3 triamcinolone and 8 dexamethasone implant. Forty-seven eyes had no prior laser therapy, while 11 eyes had prior focal (4 eyes) or panretinal photocoagulation (8 eyes) or photodynamic therapy (1 eye). There were 36 phakic eyes and 29 pseudophakic eyes.
CMT decreased significantly by 157.9±157.7 μm at the 6-month follow-up (p<0.001) and by 137.2±113.0 μm at the 9-month follow-up (p<0.001) (table 1). BCVA gain was 0.41±0.44 at the 6-month follow-up (p<0.001) and 0.58±0.46 at the 9-month follow-up (p<0.001) (table 1). There were no signs of lens opacification or cataract progression as well as no sign of posterior uveitis. A single patient developed transient iritis following the fourth injection but not thereafter. No patient withdrew from the study. All patients were monitored closely by the various treating ophthalmologists with no adverse systemic effects reported throughout the study period. The longest follow-up periods were 18 months in a patient with nAMD (figure 1) and 17 months in a patient with DME.
Visual and anatomic results following six or more intravitreal injections of ziv-aflibercept
This 84-year-old healthy Lebanese man presented with sudden visual drop of 1 day. He had an acute submacular haemorrhage with best-corrected visual acuity (BCVA) of 20/400. Optical coherence tomography (OCT) and infrared images (Top panel) show the subretinal haemorrhage at the macular area. Polypoidal choroidal vasculopathy was ruled out by indocyanine angiography. After a total of 13 intravitreal ziv-aflibercept injections, at 17 and a half months (bottom), his BCVA improved to 20/20. Infrared image and the OCT scan show resolution of the subretinal haemorrhage. There were no signs of toxicity on clinical examination or OCT scans.
Discussion
The current data add evidence to the long-term safety of intravitreal ziv-aflibercept. Concern was raised about the risks of hyperosmolarity. Buffering solutions in ziv-aflibercept contain sucrose and produce a high osmolality (1000 mOsm/kg) that is toxic to most cells. Concerns regarding hyperosmolality-induced retinal toxicity due to intravitreal ziv-aflibercept have been largely dispelled by recent publications. Again, injecting 0.05 mL ziv-aflibercept (1000 mOsm/kg) will raise the vitreous cavity osmolarity by 4% that is within the physiological range.6 Electroretinogram analysis in 12 subjects with wet AMD revealed no alterations 1 month after a single intravitreal ziv-aflibercept injection.
In August 2012, US Food and Drug Administration approved ziv-aflibercept for the treatment of advanced colorectal carcinoma.9 ,12 Ziv-aflibercept is packaged at the same concentration of 1.25 mg/0.05 mL as 4 and 8 mL vials. The 4 mL single use ziv-aflibercept vial costs US$512, which is less than the cost of 4 mL bevacizumab (US$660) and much less than that of aflibercept. Cost analysis6 showed ziv-aflibercept to be the most cost-effective VEGF antagonist versus bevacizumab (Avastin, Genentech, South San Francisco, California, USA). Off-label bevacizumab has become most commonly used intravitreal anti-VEGF injection due to its affordability and almost equal efficacy. Similarly, off-label intravitreal ziv-aflibercept is cost effective and efficacious. Ziv-aflibercept could be a safe alternative option in countries with limited access or unaffordability to aflibercept.
The dose of ziv-aflibercept used was 1.25 mg, which is 62.5% of the standard dose of 2 mg aflibercept used in VIEW, VIVID and VISTA protocols;9 ,12 however, in the VIEW trials, 0.5 and 2.0 mg produced quite comparable outcomes.6 ,9 ,12
Although aflibercept and bevacizumab appear to have more immunogenic properties than ranibizumab from their larger molecules and extra Fc portion, various studies did not detect major differences between the three VEGF antagonists in terms of anterior chamber flare.19–21 We encountered only one instance of transient self-limited mild irirtis among the 55 patients treated with ziv-aflibercept.
Limitations of this study include small sample size and short follow-up to compare with studies like VIVID, VISTA and VIEW. The treatment was performed as-needed in many eyes (most commonly used protocol), with 19 eyes requiring monthly treatment over a period of 1 year, hence, we can attest to the safety of both monthly and as-needed protocols. We did not perform electroretinographic monitoring, the safety data are based on clinical examination and imaging.
In conclusion, we report safety and efficacy of multiple intravitreal ziv-aflibercept for various indications. Off-label intravitreal ziv-aflibercept could be a cheap alternative anti-VEGF therapy. Future studies with larger sample size and longer follow-up are warranted to support its addition in the armamentarium of VEGF antagonists in ophthalmology.
References
Footnotes
Twitter Follow Ahmed Souka @ahmedsouka
Collaborators ‘Ziv-aflibercept study group’ investigators: Rajeev Reddy Pappuru, Taraprasad Das, Padmaja Kumari Rani, Mudit Tyagi, Raja Narayanan, Vivek Dave, Subhadra Jalali, Divya Balakrishnan, Muchai Gachago, Bhushan Uplanchiwar, Kushal Agrawal, Hitesh Agrawal, Remya Paulose, Mahima Jhingan, Vishal Govindhari, Sumit Randhir Singh, Rushil Kumar and Komal Agrawal.
Contributors AMM and JC: design and CD, AMM, MA, JC, AC and AARS: conduct of the study. CD, AMM, MA, JC, AC and AARS: collection, JC, AMM and CD: management, AMM: analysis and AMM JC and MA: interpretation of the data. AMM, JC and AARS: preparation, CD, AMM, MA, JC, AC and AARS: review and CD, AMM, MA, JC, AC and AARS: approval of the manuscript.
Competing interests None declared.
Patient consent Obtained.
Ethics approval L V Prasad Eye Institute Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.