Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Safety and Efficacy of Ziv-Aflibercept in the Treatment of Refractory Diabetic Macular Edema

Mohammed Ashraf, MS, FRCOphth; Hassan El Kayal, MS; Ahmed A. R. Souka, MD

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate the safety and efficacy of ziv-aflibercept (Zaltrap; Sanofi-Aventis, Bridgewater, NJ/Regeneron Pharmaceuticals, Tarrytown, NY) in the treatment of refractory diabetic macular edema (DME).

PATIENTS AND METHODS:

Retrospective case series looking at the safety of ziv-aflibercept in patients with DME refractory to previous anti-vascular endothelial growth factor (VEGF) therapy. Detailed ophthalmologic examination, best-corrected visual acuity, and optical coherence tomography measurements were performed pre-switch, as well as at each monthly follow-up visit.

RESULTS:

The study included 34 eyes of 26 patients. The mean number of ziv-aflibercept injections post-switch was 2.03 injections. Visual acuity improved from a mean of 0.63 logMAR pre-switch to 0.51 logMAR after the first visit and 0.46 logMAR after the second visit post-switch (P < .084). Macular thickness improved from a mean of 513.79 μm to 411.79 μm (P = .006) on the first visit and 426.76 μm (P = .029) after the second visit post-switch. No adverse ocular or systemic side effects were reported on any of the follow visits.

CONCLUSION:

Ziv-aflibercept appears to be safe and effective in patients with refractory DME previously treated with other anti-VEGF agents in the short term.

[Ophthalmic Surg Lasers Imaging Retina. 2017;48:399–405.]

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate the safety and efficacy of ziv-aflibercept (Zaltrap; Sanofi-Aventis, Bridgewater, NJ/Regeneron Pharmaceuticals, Tarrytown, NY) in the treatment of refractory diabetic macular edema (DME).

PATIENTS AND METHODS:

Retrospective case series looking at the safety of ziv-aflibercept in patients with DME refractory to previous anti-vascular endothelial growth factor (VEGF) therapy. Detailed ophthalmologic examination, best-corrected visual acuity, and optical coherence tomography measurements were performed pre-switch, as well as at each monthly follow-up visit.

RESULTS:

The study included 34 eyes of 26 patients. The mean number of ziv-aflibercept injections post-switch was 2.03 injections. Visual acuity improved from a mean of 0.63 logMAR pre-switch to 0.51 logMAR after the first visit and 0.46 logMAR after the second visit post-switch (P < .084). Macular thickness improved from a mean of 513.79 μm to 411.79 μm (P = .006) on the first visit and 426.76 μm (P = .029) after the second visit post-switch. No adverse ocular or systemic side effects were reported on any of the follow visits.

CONCLUSION:

Ziv-aflibercept appears to be safe and effective in patients with refractory DME previously treated with other anti-VEGF agents in the short term.

[Ophthalmic Surg Lasers Imaging Retina. 2017;48:399–405.]

Introduction

Diabetic retinopathy (DR), and in particular diabetic macular edema (DME), is a leading cause of visual impairment in the working-age population around the world.1 Anti-vascular endothelial growth factors (VEGFs) have become the standard of care in the treatment of DME after several randomized clinical trials established their efficacy compared to other treatment modalities such as laser therapy and steroids.2–4

In most developing countries, the primary treatment of choice is bevacizumab (Avastin; Genentech, South San Francisco, CA). Based on the results of Protocol T, 50% of patients treated with bevacizumab will have residual edema by the end of the first year of treatment.5 This would mean that a large percentage of patients might need to be switched to an alternative anti-VEGF if they are not responding to therapy. A few studies have looked into the effect of switching from bevacizumab to ranibizumab (Lucentis; Genentech, South San Francisco, CA) or aflibercept (Eylea; Regeneron, Tarrytown, NY).6,7,9,10 Both ranibizumab and aflibercept would both represent a major price difference compared to the previously administered bevacizumab and might indirectly lead to treatment failure or non-compliance.

A cheaper alternative to aflibercept is the identical fusion protein ziv-aflibercept (Zaltrap; Sanofi-Aventis, Bridgewater, NJ/Regeneron Pharmaceuticals, Tarrytown, NY) that was approved by the U.S. Food and Drug Administration in August 2012 for the treatment of metastatic colorectal carcinoma. Both aflibercept and ziv-aflibercept are structurally identical; however, ziv-aflibercept has been formulated with buffers that result in a much higher osmolarity. Recent case series have shown that ziv-aflibercept can be safely used as an intravitreal drug, complementing previous animal and in vitro studies.8–12

In this retrospective study, we will report on several cases with refractory DME that were switched to ziv-aflibercept after failing to show response to previous anti-VEGF therapy. These patients were switched because of their nonresponse and inability to afford being switched to or be maintained on the more expensive anti-VEGFs (ranibizumab/aflibercept). We will look at the safety outcomes as well as visual and anatomic outcomes after switching to ziv-aflibercept.

Patients and Methods

We retrospectively reviewed the files of 26 patients who had been switched to ziv-aflibercept for refractory DME. The patients had been treated as a part of routine clinical practice and not as a part of a formal clinical study. Prior to obtaining informed written consent, the patients were made aware that the intraocular use of ziv-aflibercept was off-label with a clear explanation of the recent safety data. The study adhered to the tenets of the Declaration of Helsinki. All patients were injected at ICare Eye Hospital, Alexandria, Egypt.

Eligible patients had DME diagnosed by optical coherence tomography (OCT) that had been previously treated with at least three injections of anti-VEGF therapy (ranibizumab, bevacizumab, or aflibercept) during the past 4 months. These patients demonstrated a less-than-10% decrease in central subfield thickness (CST) during the last two injections of anti-VEGF and had residual macular edema (intraretinal cysts or subretinal fluid) immediately prior to switching. Patients with prior treatment of bevacizumab were switched to ziv-aflibercept because of their inability to afford more expensive drugs such as ranibizumab or aflibercept. Patients with prior treatment of ranibizumab and aflibercept were switched to ziv-aflibercept because of the presumed reduced efficacy of bevacizumab and their financial inability to maintain or be switched to another expensive anti-VEGF. Patients were only injected after a wash-out period of 4 weeks to 6 weeks. Cases were injected using a pro re nata strategy where injections were guided based mainly on OCT fluid findings. Patients were retreated if they had residual fluid with an OCT CST greater than 300 μm.

Comprehensive ocular examinations were performed and included measurement of best-corrected visual acuity using standardized Snellen visual acuity charts or decimal visual acuity charts, applanation tonometry, and slit lamp biomicroscopy of the anterior and posterior segments. Comprehensive ocular examinations were performed at each visit. All patients underwent spectral-domain OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany) at baseline and at each subsequent visit prior to re-injection of ziv-aflibercept. Patients were followed up for 10 days and 1 month after every injection.

Intravitreal Injection

Ziv-aflibercept is packaged in vials of 100 mg per 4 mL (concentration of 1.25 mg/0.05 mL). Aliquots of 0.05 mL were prepared at ICare Eye Hospital in the operating room under complete sterile conditions by a trained scrubbed physician using 1 mL Tuberculin BD syringes (Becton, Dickinson and Company, Franklin Lakes, NJ). Sterile vials were punctured only once, and the aliquoted drug was stored at 4°C and used within 1 month. The efficacy of ziv-aflibercept 1 month after preparation has been demonstrated previously by Mansour et al. by VEGF assays showing no loss of VEGF blockade at 1 month storage.12

Intravitreal injections were performed according to a standard protocol using a strict aseptic technique under topical anesthesia in an operating room. After instillation of topical anesthesia and povidone iodine solution, draping and a sterile eyelid retractor were placed. Intravitreal injections were performed with 29-gauge needles inserted through the pars plana, 4 mm posterior to the limbus in phakic eyes and 3.5 mm in pseudophakic eyes.

Statistics

Statistical analysis of the data was fed to the computer and analyzed using IBM SPSS software package version 20.0 (IBM Corp, Armonk, NY). The Kolmogorov-Smirnov test was used to verify the normality of distribution of the variables. Wilcoxon signed rank test was used to compare two related groups for abnormally distributed quantitative variables. Mixed linear model with post hoc test (LSD) was assessed for comparison between different periods. The reference category was the pre-switch level. Significance of the obtained results was judged at the 5% level.

Results

Thirty-four eyes of 26 patients with refractory DME were included in this retrospective study. All patients had previously received several intravitreal injections of anti-VEGF therapy, the details of which are illustrated in Table 1. The mean number of injections before switching to ziv-aflibercept was 5.93 injections, and the mean patient age was 55.74 years. Patients received a mean of 2.03 injections of ziv-aflibercept after switching.


Demographic Data of Patients Included in the Study

Table 1:

Demographic Data of Patients Included in the Study

With regard to visual acuity (Table 2; Figure 1), after using a mixed model analysis to account for the multiple comparisons that were done for the visual acuity data, there was no significant difference between the visual acuity (VA) pre-switch and 1 month after the first injection (P ≥ .18). However, there was a significant improvement in VA at the second and third post-switch visits (P = .084 and P = .023) compared to the pre-switch VA. A final VA of 20/40 or better was achieved in 40% of eyes after the first injection of ziv-aflibercept (14 of 34 eyes) and in 32% of eyes (eight of 25) after the second injection.


Changes in Visual Acuity (logMAR) After Switching to Ziv-Aflibercept in Cases With Refractory Diabetic Macular Edema

Table 2:

Changes in Visual Acuity (logMAR) After Switching to Ziv-Aflibercept in Cases With Refractory Diabetic Macular Edema


Change in best-corrected visual acuity after switching to ziv-aflibercept.

Figure 1.

Change in best-corrected visual acuity after switching to ziv-aflibercept.

With regard to anatomic outcomes, after mixed model analysis, there remained a statistically significant decrease in CST at each time point compared to pre-switch values (Table 3; Figures 2 and 3). In addition, after the first injection of ziv-aflibercept, 20% of eyes (seven of 34) achieved a CST of less than 300 μm.


Anatomical Outcomes After Switching to Ziv-Aflibercept in Cases With Refractory Diabetic Macular Edema

Table 3:

Anatomical Outcomes After Switching to Ziv-Aflibercept in Cases With Refractory Diabetic Macular Edema


Change in central subfield thickness after switching to ziv-aflibercept in refractory diabetic macular edema.

Figure 2.

Change in central subfield thickness after switching to ziv-aflibercept in refractory diabetic macular edema.


Figure illustrating three cases with refractory diabetic macular edema who were switched to ziv-aflibercept.

Figure 3.

Figure illustrating three cases with refractory diabetic macular edema who were switched to ziv-aflibercept.

In terms of safety outcomes, there were no observable signs of intraocular inflammation, endophthalmitis, or increase in lens opacity at any of the follow-up visits. Three eyes showed subconjunctival hemorrhage that disappeared 30 days post-injection. Subjectively, patients did not complain of any significant post-injection pain or decrease in vision.

Discussion

The present study has demonstrated the efficacy of ziv-aflibercept in the treatment of refractory DME. VA improved from a mean of 0.63 logMAR (approximate Snellen equivalent: 20/80) at the pre-switch visit to 0.51 logMAR after 1 month (20/60) and 0.32 logMAR (20/40) at the final visit. There was also a statistically significant improvement in CST from 514 μm at the pre-switch visit to 412 μm after 1 month and 369 μm at the final follow-up visit. In addition, 20% of eyes had a CST of less than 300 μm after the first injection. There were no significant side effects to report, demonstrating the presumed safety of the drug.

The safety and efficacy of aflibercept has previously been demonstrated in several large trials.13,14 A comparative study found equal local and systemic safety profiles between the three major anti-VEGF agents: aflibercept, ranibizumab, and bevacizumab.5 With the economic impact of repeated anti-VEGF injections, many patients and doctors prefer to start with bevacizumab as a first-line drug. Unfortunately, not all patients are responsive, and many require a shift in therapy. For many of these patients, switching to a more expensive drug is usually difficult. Ziv-aflibercept was estimated by Mansour et al.12 to cost, per injection, approximately as much as bevacizumab.12 This would make ziv-aflibercept the more economically preferable drug for countries where insurance coverage is lacking.

Although both aflibercept and ziv-aflibercept contain the same fusion protein, initial fears regarding ziv-aflibercept's safety were raised because of differences in the preparation of both drugs. One of the major differences between them is the difference in osmolarity, with aflibercept being an isosmotic solution (300 mOsm/kg), whereas the buffers in ziv-aflibercept make it far more concentrated (1,000 mOsm/kg). Initial data from Marmor et al.15 showed that in rabbits and primates, solutions less than 500 mOsm caused no retinal pigment epithelium (RPE) damage, whereas tonicity between 500 mOsm and 1,000 mOsm produced partial damage, and those above 2,000 mOsm produced severe damage. This initially led to some reservations about using the more hypertonic concentration of ziv-aflibercept. Another cause for concern was a study by Malik et al.,11 which showed that at clinical doses, ziv-aflibercept showed mild mitochondrial toxicity, whereas ranibizumab and aflibercept did not. However, the study also showed that bevacizumab, a drug that is widely used intravitreally, showed similar mitochondrial toxicity, bringing into question its in vivo applicability. The same study looked at the safety profile of various anti-VEGF drugs: ranibizumab, bevacizumab, aflibercept, and ziv-aflibercept on RPE cells in culture. The cells were exposed to various concentrations of each drug for duration of 24 hrs. It was found that at 10 times the concentration, cell viability decreased in cells treated with bevacizumab, aflibercept, and ziv-aflibercept. Cells treated with 10 times the concentration of ranibizumab did not show a decrease in viability. However, at other concentrations, which included two times the concentration, there were no pathological changes. Taken together, the data seem to indicate that at therapeutic doses, there appears to be no negative effects on RPE cells and only when concentrations far exceeded normal injected doses do those side effects appear. Furthermore, a study looking into the injection of ziv-aflibercept in rabbit eyes has shown that it was equally as safe as aflibercept, with no signs of anatomic toxicity after 7 days.10 In addition, there were no statistically significant differences between both drugs recorded on electroretinogram (ERG) 24 hours or 1 week after the procedure. Even more interesting, there were no statistically differences in aqueous pH and osmolality at baseline or during follow-up, indicating that ziv-aflibercept had no major impact on eye osmolality. Mansour et al.12 proposed that this might be due to the diluting effect of injecting an 0.05 mL dose into 4 mL of vitreous, which might decrease the osmolality of ziv-aflibercept.

There have been individual case reports where patients have been injected with ziv-aflibercept. Recently, several prospective studies have been published highlighting the safety of intravitreal ziv-aflibercept in different macular diseases.8,9,12,16,17 There are three studies that have looked at ziv-aflibercept in DME: two that looked at treatment-naïve cases (17 eyes), and one that had a combined cohort of treatment-naïve and chronic cases.18–20 The first study was by Andrade et al. and looked at the safety and efficacy of ziv-aflibercept in cases of treatment-naïve DME.18 The study looked at seven patients with a follow-up duration of 24 weeks. Patients received six monthly injections of ziv-aflibercept. The study showed a statistically significant improvement in both VA and central retinal thickness from 392 μm to 266 μm (P = .002). The study also looked at safety outcomes with emphasis on full-field electroretinogram (ERG). The primary outcome was the mean change of dark adapted combined standard B-wave amplitude from baseline, which showed no significant change (P = .691). Furthermore, for the remaining ERG parameters, no significant change was reported from baseline at final follow-up. No other complications were reported. Recent data published from our group showed similar efficacy and safety in the treatment of naïve DME in 10 patients after 3 months of follow up.19 The efficacy of ziv-aflibercept in chronic cases was suggested by Mansour et al., who conducted a prospective study that included a total of 17 eyes, of which 12 were not treatment-naïve, but it was not apparent if they were refractory to previous treatment.20 These previous studies are in line with the results of the present study, which shows the safety and efficacy of the ziv-aflibercept in the treatment of DME.

Drawbacks of our study include its retrospective nature and the nonuniform number of eyes at each time point. There was a high compliance rate at 1 and 2 months; however, at 3 months we had a relatively low compliance rate. The main reason was that this was not a clinical study but routine patient care and, hence, those who achieved a subjectively good visual acuity, achieved dryness at any time point, or showed little response and therefore perceived the treatment ineffective, tended to drop out. Furthermore, the relatively small number of cases means that any interpretation of the data should be done cautiously to prevent overgeneralizations. However, despite the drawbacks, our study is the first study to look at the treatment of resistant DME cases treated with ziv-aflibercept.

In conclusion, ziv-aflibercept does seem to be a promising new option and adds an additional cost effective option to the treatment of refractory DME, especially in developing countries. More long-term studies with larger numbers of patients would help further define the extent of its use in refractory DME.

References

  1. Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: Pathophysiology, screening, and novel therapies. Diabetes Care. 2003;26(9):2653–2664. doi:10.2337/diacare.26.9.2653 [CrossRef]
  2. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615–625. doi:10.1016/j.ophtha.2011.01.031 [CrossRef]
  3. Elman MJ, Ayala A, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122(2):375–381. doi:10.1016/j.ophtha.2014.08.047 [CrossRef]
  4. Domalpally A, Ip MS, Ehrlich JS. Effects of intravitreal ranibizumab on retinal hard exudate in diabetic macular edema: Findings from the RIDE and RISE phase III clinical trials. Ophthalmology. 2015;122(4):779–786. doi:10.1016/j.ophtha.2014.10.028 [CrossRef]
  5. Wells JA, Glassman AR, Diabetic Retinopathy Clinical Research Network et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193–1203. doi:10.1056/NEJMoa1414264 [CrossRef]
  6. Dhoot DS, Pieramici DJ, Nasir M, et al. Residual edema evaluation with ranibizumab 0.5 mg and 2.0 mg formulations for diabetic macular edema (REEF study). Eye (Lond). 2015;29(4):534–541. doi:10.1038/eye.2014.338 [CrossRef]
  7. Hanhart J, Chowers I. Evaluation of the response to ranibizumab therapy following bevacizumab treatment failure in eyes with diabetic macular edema. Case Rep Ophthalmol. 2015;6(1):44–50. doi:10.1159/000375230 [CrossRef]
  8. Chhablani J. Intravitreal ziv-aflibercept for recurrent macular edema secondary to central retinal venous occlusion. Indian J Ophthalmol. 2015;63(5):469–740. doi:10.4103/0301-4738.159909 [CrossRef]
  9. Chhablani J, Narayanan R, Mathai A, Yogi R, Stewart M. Short-term safety profile of intravitreal ziv-aflibercept. Retina. 2016;36(6):1126–1131. doi:10.1097/IAE.0000000000000913 [CrossRef]
  10. Dias JRdO, Badaró E, Novais E, et al. Pre-clinical safety of intravitreal ziv-aflibercept. Investigative Ophthalmology &Visual Science. 2014;55(13):1948–1948.
  11. Malik D, Tarek M, Caceres del Carpio J, et al. Safety profiles of anti-VEGF drugs: Bevacizumab, ranibizumab, aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in culture. Br J Ophthalmol. 2014;98Suppl 1:i11–16. doi:10.1136/bjophthalmol-2014-305302 [CrossRef]
  12. Mansour AM, Al-Ghadban SI, Yunis MH, El-Sabban ME. Ziv-aflibercept in macular disease. Br J Ophthalmol. 2015;99(8):1055–1059. doi:10.1136/bjophthalmol-2014-306319 [CrossRef]
  13. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 2015;122(10):2044–2052. doi:10.1016/j.ophtha.2015.06.017 [CrossRef]
  14. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247–2254. doi:10.1016/j.ophtha.2014.05.006 [CrossRef]
  15. Marmor MF, Martin LJ, Tharpe S. Osmotically induced retinal detachment in the rabbit and primate. Electron miscoscopy of the pigment epithelium. Invest Ophthalmol Vis Sci. 1980;19(9):1016–1029.
  16. de Oliveira Dias JR, Xavier CO, Maia A, et al. Intravitreal injection of ziv-aflibercept in patient with refractory age-related macular degeneration. Ophthalmic Surg Lasers Imaging Retina. 2015;46(1):91–94. doi:10.3928/23258160-20150101-17 [CrossRef]
  17. Videkar C, Kapoor A, Chhablani J, Narayanan R. Ziv-aflibercept: A novel option for the treatment of polypoidal choroidal vasculopathy. BMJ Case Rep. 2015Dec18;2015. pii: bcr2015212988.
  18. Andrade GC, Dias JR, Maia A, Farah ME, Meyer CH, Rodrigues EB. Intravitreal injections of ziv-aflibercept for diabetic macular edema: A pilot study. Retina. 2016;36(9):1640–1645. doi:10.1097/IAE.0000000000001000 [CrossRef]
  19. Ashraf M, Souka AA, El Kayal H, El Manhaly M, Abdallah MH. Three-month outcomes of ziv-aflibercept in the treatment of diabetic macular oedema. Acta Ophthalmol. 2016;94(7):e669. doi:10.1111/aos.13111 [CrossRef]
  20. Mansour AM, Dedhia C, Chhablani J. Three-month outcome of intravitreal ziv-aflibercept in eyes with diabetic macular oedema. Br J Ophthalmol. 2017;101(2):166–169. doi:10.1136/bjophthalmol-2016-308679 [CrossRef]

Demographic Data of Patients Included in the Study

Mean Age (SD)55.74 years (8.35)

Eyes/Patients34/26

Sex
  Female19
  Male7

Mean Number of Injections Prior to Switching (SD)5.93 (2.54)

Anti-VEGF Regimen Pre-Switch
  BVZ only12
  BVZ and AFLB2
  Both RBZ and BVZ16
  Anti-VEGF and TA4

Mean Number of Ziv-Aflibercept Injections Post-Switch (SD)2.03 (0.75)

Changes in Visual Acuity (logMAR) After Switching to Ziv-Aflibercept in Cases With Refractory Diabetic Macular Edema

Pre-Switch VisitFirst Visit Post-SwitchSecond Visit Post SwitchThird Visit Post Switch
Eyes With Data34332510
Mean (SD) logMAR Visual Acuity0.63 (0.41)0.51 (0.34)0.46 (0.35)0.32 (0.28)
Median (Q1, Q3) logMAR Visual Acuity0.52(0.30–0.84)0.39 (0.30–0.79)0.39 (0.18–0.74)0.30 (0.04–0.49)
Visual Acuity Change From Pre-Switch Visit Mean (SD)0.122 (0.15)0.145 (0.15)0.112 (0.14)
P Value LSDReference.18.084*.023*

Anatomical Outcomes After Switching to Ziv-Aflibercept in Cases With Refractory Diabetic Macular Edema

Pre-Switch VisitFirst Visit Post-SwitchSecond Visit Post-SwitchThird Visit Post-Switch
Eyes With Data34342510
Mean (SD) Central Subfield Thickness (µm)513.79 (196.2)411.79 (128.7)426.76 (113.6)368.70 (83.0)
Median (Q1, Q3) Central Subfield Thickness (µm)490.0 (391.0–597.5)403.0 (307.5–500.0)405.0 (359.0–458.0)351.0 (306.0–395.0)
Central Subfield Thickness (µm) Change From Pre-Switch Visit Mean (SD)102.0 (215.4)70.7 (79.5)132.2 (110.6)
P Value LSDReference.006*.029*.008*
Authors

From the Ophthalmology Department, Faculty of Medicine, Alexandria University, Kafr Abdou, Roshdi, Alexandria, Egypt.

The authors report no relevant financial disclosures.

Address correspondence to Mohammed Ashraf, MS, FRCOphth, Ophthalmology Department, Faculty of Medicine, Alexandria University, 27 Maarouf Rasafi St., Kafr Abdou, Roshdi, Alexandria, Egypt; email: Moah384@gmail.com.

Received: October 21, 2016
Accepted: February 22, 2017

10.3928/23258160-20170428-06

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