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Year : 2014  |  Volume : 4  |  Issue : 1  |  Page : 40-44

Rapid response to intravitreal aflibercept in neovascular age-related macular degeneration after development of tachyphylaxis to bevacizumab and ranibizumab

1 Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital; College of Medicine, Fu Jen Catholic University; College of Medicine, National University, Taipei, Taiwan
2 Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan

Date of Web Publication4-Mar-2014

Correspondence Address:
Cheng-Kuo Cheng
Department of Ophthalmology, Sing-Kong Wu Ho-Su Memorial Hospital, 95, Wen-Chang Road, Shih-Lin District, Taipei
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Source of Support: None, Conflict of Interest: None

DOI: 10.1016/j.tjo.2013.12.005

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This article reports a rapid response of intravitreal aflibercept for the treatment of a case of neovascular age-related macular degeneration that developed tachyphylaxis to bevacizumab and ranibizumab. An 80-year-old man with neovascular age-related macular degeneration became unresponsive to monthly treatment with bevacizumab or ranibizumab after initial responsiveness, to as-needed treatment with these antivascular endothelial growth factor drugs for 49 months. Subretinal fluid and pigment epithelial detachment had sustained in spite of 14 bevacizumab and seven ranibizumab injections prior to intravitreal aflibercept treatment. After only one injection of intravitreal aflibercept, a marked improvement was seen within 1 week. Complete drying of subretinal fluid and marked subsidence of pigment epithelial detachment were noted 4 weeks after the first aflibercept injection and sustained for three consecutive monthly injections. This case reveals that shifting to aflibercept may be an effective alternative treatment for neovascular age-related macular degeneration that becomes tachyphylactic to bevacizumab or ranibizumab.

Keywords: aflibercept, age-related macular degeneration, antivascular endothelial growth factor, bevacizumab, choroidal neovascular membrane, ranibizumab, tachyphylaxis

How to cite this article:
Cheng CK, Chan TY. Rapid response to intravitreal aflibercept in neovascular age-related macular degeneration after development of tachyphylaxis to bevacizumab and ranibizumab. Taiwan J Ophthalmol 2014;4:40-4

How to cite this URL:
Cheng CK, Chan TY. Rapid response to intravitreal aflibercept in neovascular age-related macular degeneration after development of tachyphylaxis to bevacizumab and ranibizumab. Taiwan J Ophthalmol [serial online] 2014 [cited 2022 Jan 26];4:40-4. Available from: https://www.e-tjo.org/text.asp?2014/4/1/40/203924

  1. Introduction Top

Neovascular age-related macular degeneration (nAMD), characterized by the formation of a choroidal neovascular membrane in the macular area, is one of the greatest threats to vision in elderly patients throughout the world, including those in Asia and Taiwan. In recent years, intravitreal injections of antivascular endothelial growth factor (anti-VEGF) agents have been used to treat nAMD. Of these drugs, ranibizumab (Lucentis®, Genentech, Inc., South San Francisco, CA, USA) and bevacizumab (Avastin®, Genentech, Inc.) have been the most widely adopted anti-VEGF agents. Both bevacizumab and ranibizumab are humanized monoclonal antibodies that target all forms of isomers of the VEGF-A family and the drugs have been proved by numerous clinical studies to be highly effective treatment options for nAMD.

Although most patients with typical nAMD respond favorably to these anti-VEGF drugs, as clinical experience has increased over the years it has been discovered that many patients become less responsive to ranibizumab or bevacizumab after prolonged treatment. One long-term unfavorable effect of particular note is tachyphylaxis, which is defined as a progressively decreased therapeutic response to a drug after repeated administration over time.[1] Tachyphylaxis has been demonstrated in both bevacizumab and ranibizumab for the treatment of nAMD.[2],[3],[4],[5] In a retrospective review of 1027 eyes (976 patients) with a mean follow-up time of 24 (range 13–37) months, the percentage of eyes with tachyphylaxis to ranibizumab was approximately 2%.[2] In another, relatively smaller study, tachyphylaxis to bevacizumab was found in six of 58 eyes with nAMD treated with bevacizumab.[3] The median time for developing tachyphylaxis was found to be 100 weeks from the first treatment of bevacizumab.[3]

Aflibercept (Eylea®, Regeneron, Tarrytown, PA, USA and Bayer HealthCare, Berlin, Germany) is new member of pharmacotherapy targeting VEGF-A family that was approved for the treatment of nAMD by the Food and Drug Administration in November, 2011. Several large-scale randomized clinical trials have proved that aflibercept is as effective as ranibizumab in the treatment of nAMD.[6] Unlike bevacizumab or ranibizumab, the structure of aflibercept is not an antibody; rather, it is composed of a recombinant soluble decoy receptor fusion protein which incorporates the second binding domain of the VEGF receptor-1 and the third binding domain of the VEGF receptor-2.[7] The binding affinity of intravitreal aflibercept to VEGF was shown to be higher than that of ranibizumab.[7] Studies have suggested that aflibercept may be effective in treating patients with chronic refractory nAMD and persistent fluid despite repeated treatments of intravitreal ranibizumab and/or bevacizumab.[8],[9],[10],[11] Patel et al[12] further reported rapid resolution of pigment epithelial defect (PED) in three patients with neovascular AMD refractory to ranibizumab and bevacizumab.

In this report, we present here the case that developed tachyphylaxis with persistent subretinal fluid (SRF) and PED to monthly injections of bevacizumab or ranibizumab for 14 months. A rapid response with resolution of SRF and a marked decrease in the size of PED was noted 1 week after changing to intravitreal aflibercept injections and was maintained after three consecutive monthly injections. To date, few reports concerning aflibercept treatment of tachyphylaxis in nAMD have been made, which is why we believe that this experience is worth sharing with our colleagues.

  2. Case report Top

An 80-year-old Taiwanese man of Chinese descent complained of bilateral blurred vision and metamorphopsia for 5 months which did not improve, even after an uneventful phacoemulsification and intraocular lens implantation for his cataract. On presentation, his best corrected visual acuity was 6/30 od and 6/15 os. Fundus photography [Figure 1]A and [Figure 1]B and fluorescein angiography showed a classic choroidal neovascularization in both eyes; no polyp was found on indocyanine green angiography [Figure 1]E and [Figure 1]F.
Figure 1: (A) Photographs of color fundus showed drusen and retinal pigment epithelium (RPE) degeneration in the patient's right eye. (B) Retinal hemorrhage and subretinal fluid and pigment epithelial detachment were found in the left eye. (C) Fluorescein accumulation was noted in the early film of fluorescein angiography in the left eye and (D) leakage was found in the late film. There was no polyp found on indocyanine green angiography (ICG) either early (E) or late (F) film.

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Both of the patient’s eyes were treated with intravitreal bevacizumab (2.5 mg in 0.1 mL; Avastin). The right eye responded favorably with subsidence of SRF and intraretinal cysts. Although several recurrences were encountered in his right eye during the follow-up period, the exudative reaction responded favorably each time after intravitreal bevacizumab injection. However, the left eye did not always respond favorably to intravitreal bevacizumab. The patient’s left eye received intravitreal bevacizumab (2.5 mg in 0.1 mL; Avastin) six times from April 6, 2010 to March 11, 2011 as protocol. A good response with nearly total absorption of SRF was noted following the first three injections (monthly injections) [Figure 2]A and [Figure 2]B; however, SRF and PED sustained during the subsequent injections [Figure 2]C. He subsequently received four intravitrealinjections of ranibizumab from April 2, 2011 to October 28, 2011. A good response was noted once again following the first three injections [Figure 2]D; however, the fourth injection was unsuccessful.
Figure 2: Optical coherence tomography of the left eye during treatment. (A) SRF accumulation and PED were found before initiating treatment. (B) SRF subsided, yet persistent PED was noted 1 week after the third intravitreal injection of bevacizumab. (C) SRF increased gradually and PED persisted following six injections of bevacizumab. (D) Remission of SRF was noted after three injections of ranibizumab, but PED was still noted. PED = pigment epithelial detachment; SRF = subretinal fluid.

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As the SRF and PED persisted and his visual acuity decreased, we shifted back to bevacizumab on December 30, 2011 and again on March 2, 2012. However, the patient did not respond to the treatment and SRF increased prominently after the second injection. We subsequently arranged another course of three monthly injections of ranibizumab from May 11, 2012 to September 8, 2012, but the patient showed no signs of response whatsoever.

Due to sustained SRF and PED, we once again attempted an intravitreal injection of bevacizumab from October 26, 2012 to May 8, 2013 (a total of six injections). The patient responded poorly to bevacizumab and was found to have increased SRF and PED despite monthly treatments [Figure 3]C. His visual acuity gradually deteriorated.
Figure 3: (A) Fundus picture after 14 injections of bevacizumab and seven injections of ranibizumab. (B) Stippled hyperfluorescence with leakage was still noted on late fluorescein angiography in the left eye. (C) Prominent SRF and persistent PED were noted on optical coherence tomography. (D) Both SRF and PED decreased dramatically 1 week after the first injection of aflibercept. (E) SRF regressed completely and PED became almost completely flat 3 months after the initial injection. PED = pigment epithelial detachment; SRF = subretinal fluid.

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At this time, aflibercept became available for a premarketing trial in Taiwan and we filed a clinical trial application for this patient. After obtaining informed consent from the patient and a permit from the institutional review board of Shin Kong Wu Ho-Su Memorial Hospital and the Taiwanese government’s Ministry of Health and Welfare, we began injections of 2 mg of aflibercept intravitreally to the left eye of the patient. The SRF and PED dramatically decreased 1 week after the first intravitreal injectionof EYLEA® [Figure 3]D. The patient then received a monthly injection three times. The SRF became completely dry and the PED became almost completely flat 1 month after the third injection [Figure 3]E. The best-corrected visual acuity also improved from 6/36 to 6/18 after 3 months of treatment with aflibercept.

  3. Discussion Top

Our report clearly shows the immediate efficacy of changing to intravitreal aflibercept for the treatment of a Taiwanese patient with nAMD who had developed tachyphylaxis to bevacizumab and ranibizumab. The left eye of our patient initially showed subsidence of SRF and improvement in macular edema after three monthly injections of bevacizumab. However, the subsequent recurrence of SRF and macular edema became refractory to a subsequent 11 injections of intravitreal bevacizumab. Again, the patient initially responded after being transferred to intravitreal ranibizumab for three injections, but again became refractory to another subsequent four injections. However, after changing to treatment with aflibercept, the SRF that had persisted for over 14 months rapidly regressed within 1 week and became completely dry in 4 weeks. In addition, the prominent PED that persisted from the beginning of treatment with bevacizumab or ranibizumab also became markedly decreased within 1–4 weeks after intravitreal aflibercept injection.

Several other studies have shown the ability of aflibercept to decrease SRF or intraretinal fluid in eyes with nAMD which were refractory to intravitreal ranibizumab or bevacizumab. Cho et al[9] reported that, in 28 eyes with persistent SRF after repeated and regular intravitreal ranibizumab or bevacizumab, or both, injections (mean 20 injections, range 7–37), 89% (25 eyes) showed anatomical improvement and 18% (5 eyes) were dry at 1 month after a single aflibercept injection. The central subfoveal thickness significantly improved (p < 0.001) from 295 to 272 microns after one aflibercept injection and remained improved (274 microns, p = 0.008) after an average of 4.4 aflibercept injections (range 3–6) over 6 months. At the end of 6 months, 64% (18 eyes) showed anatomical improvement and 25% (seven eyes) were dry.

In another study of 68 eyes with nAMD that were refractory to ranibizumab or bevacizumab, or both, Yonekawa et al[11] also reported a significant decrease in central macular thickness, SRF, and intraretinal fluid after conversion to aflibercept for both the first and final injections (mean 3.8 injections, mean follow-up time 18 weeks). These workers suggested that the enhanced anatomical response seen with aflibercept in their previously treated patients may represent a stronger clinical activity of aflibercept or tachyphylaxis to the earlier long-term treatments.

PED, an anatomical feature that was regarded to be less responsive than SRF or intraretinal fluid to ranibizumab and bevacizumab,[13],[14] has also been reported to respond favorably to aflibercept.[10],[12] In a retrospective study of 34 eyes with nAMD (33 patients) with persistent subfoveal fluid despite previous treatment with ranibizumab, Kumar et al[10] found that, after changing to treatment with aflibercept, not only the SRF and intraretinal fluid significantly subsided, but also the height and diameter of the PED significantly decreased at the 6-month follow-up. In their report, the mean visual acuity was also significantly improved at the 6month follow-up. The case reported here also showed a marked subsidence of previously prominent PED beginning 1 week after the first treatment with aflibercept, which remained nearly flat over the course of three subsequent monthly injections. The bestcorrected visual acuity of our patient gradually improved from 6/ 36 to 6/18 after three consecutive monthly injections.

Aflibercept has been suggested to have higher biological activity to neutralize the effect of VEGF than ranibizumab and bevacizumab.[7],[15] An in vitro study conducted by Papadopoulos et al[7] showed that aflibercept had 94 and 119 times the binding affinity to VEGF-A165 of ranibizumab and bevacizumab, respectively. Aflibercept has also been shown to possess not only an anti-VEGF effect, but also an antiplacental growth factor effect; the latter is known to be an important factor in facilitating angiogenesis.[16] These characteristics could be a contributing factor which enables aflibercept to treat eyes with nAMD which were either refractory or becoming tachyphylactic to ranibizumab or bevacizumab.

The mechanism of tachyphylaxis to bevacizumab or ranibizumab as it relates to the treatment of nAMD remains unclear. Proposed mechanisms[2] include the formation of neutralizing antibodies to the anti-VEGF drugs,[17] the desensitization of the target tissue to the drug (possibly caused by the upregulation of the production of VEGF by macrophages in the tissue of choroidal neovascularization),[18],[19] or the possibility that choroidal neovascularization is reactivated by other growth factors and pathways.[20],[21] Sometimes simply switching to a similar drug with different properties may be sufficient to overcome tachyphylaxis.[1] For example, several retrospective studies have suggested that shifting from bevacizumab to ranibizumab or vice versa may be enough to resume the efficacy of treatment for nAMD after a patient develops tachyphylaxis.[22],[23] Therefore it remains uncertain whether aflibercept is superior to the other antiVEGF drugs in the treatment of nAMD and further investigations should be conducted.

In summary, our case shows a rapid response of aflibercept treatment for nAMD with tachyphylaxis to both ranibizumab and bevacizumab in a Taiwanese patient of Chinese descent. This report is probably the first clinical experience of such a condition in a patient of Chinese descent in Taiwan and suggests that use of aflibercept to treat nAMD which has become unresponsive to other anti-VEGFs could be a promising treatment strategy.

Conflicts of interest: All contributing authors declare no conflicts of interest.

  References Top

Binder S. Loss of reactivity in intravitreal anti-VEGF therapy: tachyphylaxis or tolerance? Br J Ophthalmol. 2012;96:1–2.  Back to cited text no. 1
Eghoj MS, Sorensen TL. Tachyphylaxis during treatment ofexudative age-related macular degeneration with ranibizumab. Br J Ophthalmol. 2012;96:21–23.  Back to cited text no. 2
Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina. 2009;29:723–731.  Back to cited text no. 3
Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal antivascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology. 2008;115:2199–2205.  Back to cited text no. 4
Keane PA, Liakopoulos S, Ongchin SC, et al. Quantitative subanalysis of optical coherence tomography after treatment with ranibizumab for neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2008; 49:3115–3120.  Back to cited text no. 5
Heier JS. Neovascular age-related macular degeneration: individualizing therapy in the era of anti-angiogenic treatments. Ophthalmology. 2013;120(5 Suppl.):S23–S25.  Back to cited text no. 6
Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15:171–185.  Back to cited text no. 7
Bakall B, Folk JC, Boldt HC, et al. Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. Am J Ophthalmol. 2013;156:15–22. e11.  Back to cited text no. 8
Cho H, Shah CP, Weber M, Heier JS. Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab. Br J Ophthalmol. 2013;97: 1032–1035.  Back to cited text no. 9
Kumar N, Marsiglia M, Mrejen S, et al. Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration. Retina. 2013;33:1605–1612.  Back to cited text no. 10
Yonekawa Y, Andreoli C, Miller JB, et al. Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneration. Am J Ophthalmol. 2013;156:29–35. e22.  Back to cited text no. 11
Patel KH, Chow CC, Rathod R, et al. Rapid response of retinal pigment epithelial detachments to intravitreal aflibercept in neovascular age-related macular degeneration refractory to bevacizumab and ranibizumab. Eye. 2013;27:663–667. quiz 668.  Back to cited text no. 12
Punjabi OS, Huang J, Rodriguez L, Lyon AT, Jampol LM, Mirza RG. Imaging characteristics of neovascular pigment epithelial detachments and their response to anti-vascular endothelial growth factor therapy. Br J Ophthalmol. 2013;97:1024–1031.  Back to cited text no. 13
Baba T, Kitahashi M, Kubota-Taniai M, Oshitari T, Yamamoto S. Two-year course of subfoveal pigment epithelial detachment in eyes with age-related macular degeneration and visual acuity better than 20/40. Ophthalmologica. 2012;228:102–109.  Back to cited text no. 14
Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol. 2008;92:667–668.  Back to cited text no. 15
Rakic JM, Lambert V, Devy L, et al. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2003;44:3186–3193.  Back to cited text no. 16
Forooghian F, Chew EY, Meyerle CB, Cukras C, Wong WT. Investigation of the role of neutralizing antibodies against bevacizumab as mediators of tachyphylaxis. Acta Ophthalmol. 2011;89:e206–e207.  Back to cited text no. 17
Grossniklaus HE, Ling JX, Wallace TM, et al. Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis. 2002;8:119–126.  Back to cited text no. 18
Tatar O, Yoeruek E, Szurman P, et al. Effect of bevacizumab on inflammation and proliferation in human choroidal neovascularization. Arch Ophthalmol. 2008;126:782–790.  Back to cited text no. 19
Roh MI, Lim SJ, Ahn JM, Lim JB, Kwon OW. Concentration of cytokines in agerelated macular degeneration after consecutive intravitreal bevacizumab injection. Graefes Arch Clin Exp Ophthalmol. 2010;248:635–640.  Back to cited text no. 20
Funk M, Karl D, Georgopoulos M, et al. Neovascular age-related macular degeneration: intraocular cytokines and growth factors and the influence of therapy with ranibizumab. Ophthalmology. 2009;116:2393–2399.  Back to cited text no. 21
Gasperini JL, Fawzi AA, Khondkaryan A, et al. Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation. Br J Ophthalmol. 2012;96:14–20.   Back to cited text no. 22
de Geus SJ, Jager MJ, Luyten GP, Dijkman G. Shifting exudative age-related macular degeneration patients to ranibizumab after insufficient response to bevacizumab. Acta Ophthalmol. 2013;91:e411–e413.  Back to cited text no. 23


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