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Two-year outcomes of intravitreal ziv-aflibercept
  1. Ahmad M Mansour1,2,
  2. Mohammed Ashraf3,
  3. Abdulrazzak Charbaji4,5,
  4. Muhammad H Younis1,2,
  5. Ahmed A Souka3,
  6. Avantika Dogra6,
  7. Hana A Mansour1,
  8. Jay Chhablani6
  9. On behalf of Ziv-aflibercept study group investigators
    1. 1 Department of Ophthalmology, American University of Beirut, Beirut, Lebanon
    2. 2 Department of Ophthalmology, Rafic Hariri University Hospital, Beirut, Lebanon
    3. 3 Department of Ophthalmology, Alexandria Faculty of Medicine, Alexandria University, Alexandria, Egypt
    4. 4 Department of Statistics and Research Methodology, Lebanese American University, Beirut, Lebanon
    5. 5 Department of Statistics and Research Methodology, Lebanese University, Beirut, Lebanon
    6. 6 Smt. Kanuri Santhamma Centre for Vitreoretinal Diseases, LV Prasad Eye Institute, Hyderabad, Andhra Pradesh, India
    1. Correspondence to Dr Jay Chhablani, Smt. Kanuri Santhamma Centre for Vitreoretinal Diseases, LV Prasad Eye Institute, Hyderabad, Andhra Pradesh 500034, India; jay.chhablani{at}gmail.com

    Abstract

    Aim To assess the two-year outcome of intravitreal ziv-aflibercept (IVZ) in eyes with macular diseases.

    Methods Consecutive subjects with various macular diseases that received six or more of 0.05 mL IVZ (1.25 mg) injections with at least 1 year follow-up were included. Outcome measures were best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution) and central macular thickness (CMT) on spectral domain optical coherence tomography. Paired comparison was done using Wilcoxon signed-rank test calculator.

    Results 107 eyes of 91 subjects received IVZ and were followed with mean±SD follow-up interval of 1.48±0.44 months following treat and extend or pro-re-nata protocol. The distribution included neovascular macular degeneration (42 eyes), diabetic macular oedema (32 eyes) and macular oedema secondary to retinal vein occlusion (11 eyes). Fifty eyes were naive, while 57 eyes were previously treated. Combining all disease categories, CMT decreased significantly by 133.0±153.0 µm at the 24-month follow-up (P<0.001) with BCVA gain of 0.35±0.37 at the 24-month follow-up (P<0.001) with mean number of injections of 8.5 at month 12, 2.4 between 12 and 18 month and 1.7 between 18 and 24 month. Ocular and systemic adverse effects included one episode of transient uveitis and one instance of central retinal artery occlusion after 1121 injections.

    Conclusions IVZ appears safe and efficacious in the therapy of macular diseases through 2 years.

    • retina
    • choroid
    • macula

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    Introduction

    Ziv-aflibercept (Sanofi and Regeneron Pharmaceuticals, Tarrytown, New York, USA) was approved by Food and Drug Administration on 3 August 2012 in combination with 5-fluorouracil, leucovorin, irinotecan for metastatic colorectal cancer resistant to oxaliplatin regimen. Being structurally identical, ziv-aflibercept is being used as off-label substitute to the approved (November 2011) aflibercept (Eylea, Regeneron, Tarrytown, New York, USA) for the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME) and cystoid macular oedema secondary to retinal venous occlusion (RVO-CME).1–6 The first ophthalmic report on ziv-aflibercept detailed the safety of intravitreal ziv-aflibercept (IVZ) in rabbits.1 Subsequently, a large number of clinical reports dealt with a short term of IVZ therapy (1–12 months),2–20 and one report dealt with longer follow-up of 18 months in inflamed pterygia.21 We present the 2-year safety and efficacy outcomes of IVZ (1.25 mg) in a multicenter setting.

    Materials and methods

    This is a prospective non-randomised three-centre study examining sustained clinical efficacy by standard ophthalmic examinations and clinical history. This study was adhered to the tenets of the Declaration of Helsinki. The study duration was from March 2015 to September 2017. All patients signed a formal consent for this off-label protocol. Inclusion criteria included a minimum of 1-year follow-up and a minimum of six injections of IVZ for naive or previously treated conditions such as nAMD, DME and RVO-CME. Exclusion criteria included use of other antivascular endothelial growth factor (VEGF) therapy or intravitreal corticosteroid during the study period, central corneal scar, dense cataract, infectious conjunctivitis, vitreous haemorrhage, asteroid hyalosis, macular ischaemia, hole, schisis or scar and prior vitreoretinal surgery. Eyes with non-measurable CMT due to media opacities or subretinal blood were also excluded. A washout period of 2 months was adopted for previously treated with other anti-VEGF, the shift being either from inadequate response or for financial reason.

    Consecutive patients with macular diseases were followed monthly. Ziv-aflibercept 0.05 mL (1.25 mg aflibercept) was prepared and injected according to standard protocols (compounding under sterile conditions with storage at 4°C for 4 weeks). Best-corrected visual acuity (BCVA) was assessed by 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 optical coherence tomography (OCT) were done monthly using 3D-2000 Topcon FA plus (Topcon, Tokyo, Japan) in Lebanon, Cirrus (Carl Zeiss Meditec, Dublin, California, USA) in India and Spectralis (Heidelberg Engineering GmbH, Heidelberg, Germany) in Egypt. Central macular thickness (CMT) measurements (mean thickness in the central 1000 µm diameter area) were corrected for machine use.9 12 The injection regimen followed the protocol for DME or RVO-CME set by initial 5 monthly injections then treat and extend (TAE) (Lebanon and Egypt) or pro-re-nata (PRN) (India and Egypt). For eyes with nAMD, three initial monthly injections were done followed by PRN therapy (India and Egypt) or three initial monthly, then monthly till the absence of activity by OCT, then TAE (Lebanon and Egypt).

    Statistical analyses were carried out using SPSS V.22. Paired comparison was done using Wilcoxon signed-rank test calculator to assess the change in both vision and macular thickness. Significance was set at P value of 0.05.

    Results

    A total of 107 eyes of 91 subjects (56 right eyes and 51 left eyes, 17 bilateral) were treated for nAMD (42 eyes), DME (32 eyes) and RVO-CME (11 eyes) (eight eyes central RVO, one eye with hemicentral RVO and two eyes with branch RVO), polypoidal vascular choroidopathy (three eyes), retinal angiomatous proliferation (three eyes) and one eye with peripapillary haemangioma (table 1). Racial distribution included 78 Caucasians and 13 Indians. The mean age was 68.6 (range 27–92) years. The total number of injections was 1121. There were 50 treatment naive eyes (all Caucasians) and 58 treatment non-naive eyes. Prior intravitreal injections included a total of 43 eyes receiving bevacizumab (total 239 injections), 20 eyes received ranibizumab (total 46 injections), seven eyes received aflibercept (Eylea) (total nine injections) and two eyes received triamcinolone (total two injections). Some eyes had prior focal laser (four eyes), panretinal photocoagulation (nine eyes) or photodynamic therapy (five eyes). There were 72 phakic eyes and 36 pseudophakic eyes. Systemic diseases among study subjects included systemic hypertension (43 patients), diabetes mellitus (50 patients), coronary artery disease (12 patients), cerebrovascular accident (four patients) and morbid obesity (four patients) (table 2). Treatment protocol was TAE in Lebanese series (59 eyes), PRN in the Indian series (13 eyes) and mixed (nine eyes TAE and 25 eyes PRN) in the Egyptian series (table 2).

    Table 1

    Clinical characteristics of collaborative series of patients treated with intravitreal ziv-aflibercept

    Table 2

    Vision and macular thickness characteristics of collaborative series of patients treated with intravitreal ziv-aflibercept

    Combining all disease categories, CMT decreased significantly by 137.5±145.5 µm at the 12-month follow-up (P<0.001), by 124.4±153.7 µm at the 18-month follow-up (P<0.001) and by 133.0±153.0 µm at the 24-month follow-up (P<0.001) (table 2). BCVA gain was 0.33±0.4 at the 12-month follow-up (P<0.001), 0.22±0.52 at the 18-month follow-up (P=0.002) and 0.35±0.37 at the 24-month follow-up (P<0.001) (table 3). Naive cases, eyes with nAMD or DME or RVO-CME separately had significant visual gains and macular flattening at 2-year follow-up (table 3). Representative case of naive AMD is shown in figure 1.

    Figure 1

    Optical coherence tomography composite at (A) baseline, (B) 1 month, (C) 1 year and (D) 2 years after intravitreal injections of ziv-aflibercept. This 77-year-old healthy Caucasian male presented with sudden visual drop of few hours duration in the left eye. He had an acute submacular haemorrhage secondary to neovascular age-related macular degeneration. Best -corrected visual acuity improved from finger counting 4 m to 6/15 at 1 year (total 12 injections) and to 6/12 at 2 years (total 11 injections).

    Table 3

    Two-year visual and anatomic results from the three collaborating centres following six or more intravitreal injections of ziv-aflibercept stratified by disease categories

    There were no progressions of cataract or lens opacification through the follow-up. Two ocular complications were noted: (1) iritis in one eye after the fourth injection but not afterwards in a patient that received simultaneous bilateral injections and (2) central retinal artery occlusion 2 months after the last injection which was unrelated to injection or procedure. Six eyes developed epiretinal membrane de novo in the macular region. One patient developed extensive subretinal haemorrhage, 1 month after the fourth monthly injection. Two possible related adverse systemic effects were reported throughout the study period: (1) cerebrovascular accident in a 70-year-old healthy woman occurring 70 days following the 16th bilateral injection and no further complications happened after three subsequent bilateral injections and (2) transient repeated ischaemic attack occurring 1 month after the 15th injection with uneventful subsequent four injections in a 71-year-old diabetic smoker.

    Discussion

    This is the longest follow-up study of ziv-aflibercept, attesting to the long-term safety and efficacy of IVZ for intraocular use. Previously raised issue of hyperosmolality-related retinal injury from IVZ have been refuted by various electrophysiological, visual and anatomic (OCT) studies in various series.2 7–9 In addition, ziv-aflibercept appears so far the most cost-effective VEGF antagonist especially in the developing countries with greater efficacy.13 19 Baghi et al 19 compared the visual efficacy of 2 doses of ziv-aflibercept (1.25 mg and 2.5 mg) to bevacizumab (1.25 mg) in 123 eyes with DME at 12 weeks in a randomised double-blind trial. They found no visual acuity differences between the 2 doses of ziv-aflibercept, similar to the VIEW studies22 23 and significant superiority of ziv-aflibercept (1.25 mg) over bevacizumab in eyes with vision less than 6/15.

    Aflibercept (2.0 mg) and ranibizumab (0.3 mg) are not cost-effective relative to bevacizumab for treatment of DME.24 When safety and efficacy results are at odds with cost-effectiveness results,24 then ziv-aflibercept and less so bevacizumab appear to the most affordable VEGF antagonist in DME and wet AMD management.4 25 26 Based on View 1 and 2 findings,22 2 mg and 0.125 mg aflibercept have comparable clinical results. Compounding all available anti-VEGF agents ranibizumab,27 bevacizumab,28 aflibercept27 and ziv-aflibercept4 retains full functional potency of the drugs for at least 1 month. Compounding 4 mL of ziv-aflibercept with a phial cost of US$506 (Lebanese market) into forty 0.1 mL small syringes yields an individual syringe cost of around US$20 compared with aflibercept individual dose of US$1168 (Lebanese market) (58 times less).

    Complications included unilateral transient inflammatory reaction that did not return on further bilateral injection consistent with rare instances of sterile inflammation after aflibercept or other anti-VEGF agents.29 Another instance of central retinal artery occlusion 2 months after injection could be related to the anti-VEGF constrictive effect30 or could be coincidental as the onset was after the VEGF blockade has worn off.

    Limitations of this study include retrospective nature, small sample size, absence of electrophysiological testing, variable treatment protocols and lack of randomised double-blind study. Due to variable treatment protocol across the study sites, this study does not establish safety of a particular treatment protocol. The maximum number of injections included one eye with 21 injections, two eyes with 20 injections and six eyes with 19 injections, some exceeding the 2-year follow-up, yet much longer follow-up is actually needed similar to 4-year follow-up of aflibercept in nAMD.23

    In conclusion, we report prolonged sustained efficacy of IVZ for nAMD, DME and RVO-CME. Compounding ziv-aflibercept under strict standard conditions of preparation, storage and administration does not appear to cause safety concerns like osmolarity and function stability. Off-label IVZ is now added to the list of affordable VEGF antagonists in the third world.

    References

    Footnotes

    • Contributors AMM, MA and JC were responsible for the design of the study and interpretation of the data. AMM, MA, AC, MHY, AAS, AD and JC were responsible for the conduct of the study. AMM, MA, AD and HAM were involved in the management. AMM did the analysis. AMM, AC, AAS and JC were responsible for the preparation. AMM, MA, AC, AAS, AD, HAM and JC reviewed the article. All authors equally contributed to the collection of data and the final approval of the manuscript.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Rafic Hariri University Hospital, Alexandria University and L V Prasad Eye Institute Ethics Committee.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators Rajeev Reddy Pappuru, Taraprasad Das, Padmaja Kumari Rani, Mudit Tyagi, Raja Narayanan, Vivek Dave, Subhadra Jalali, Divya Balakrishnan, Bhushan Uplanchiwar, Kushal Agrawal, Hitesh Agrawal, Remya Paulose, Mahima Jhingan, Vishal Govindhari, Sumit Randhir Singh, Rushil Kumar, Komal Agrawal.

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