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polypoidal choroidal vasculopathy ( pcv ) , which was first described by yannuzzi et al , is characterized by numerous recurrent , bilateral , asymmetric , serosanguinous detachments in the retinal pigment epithelium.1 several treatment strategies have been reported for pcv.2 among them , photodynamic therapy3 and intravitreal injection of anti - vascular endothelial growth factor ( vegf ) including ranibizumab4 ( lucentis ; genentech , san francisco , ca , usa ) have shown favorable results .
serious complications after photodynamic therapy for pcv were reported , such as massive subretinal hemorrhage and retinal atrophy.5 with anti - vegf therapy , polypoidal lesions regressed in only 40% of the cases.4 hence , prolonged treatment might be required for pcv . with prolonged use of ranibizumab , diminution of biological effects adversely affect long - term efficacy .
one possible mechanism of diminution is tachyphylaxis , which is defined as phenomena causing reduced drug efficacy by repeated administration.6 the chance of developing tachyphylaxis was 2% after intravitreal ranibizumab ( ivr ) for age - related macular degeneration ( amd),7 and prevention of tachyphylaxis was important for long - term therapeutic effects against pcv .
one possible countermeasure for tachyphylaxis is cessation of drug treatment;6 however , discontinuation of the treatment might result in irreversible retinal damage by deterioration from pcv .
another possible countermeasure for tachyphylaxis is introduction of a drug with a different mechanism of action .
aflibercept ( eylea ; regeneron , tarrytown , pa , usa and bayer healthcare , berlin , germany ) is a recombinant soluble decoy receptor fusion protein.8 in contrast to the antibody - based vegf binding strategy used by ranibizumab , aflibercept incorporates the second binding domain of the vegf receptor-1 and the third domain of the vegf receptor-2.9 the binding affinity of intravitreal aflibercept ( iva ) to vegf is higher than that of ranibizumab.9 a rapid improvement after conversion to aflibercept from ranibizumab was reported for eyes with chronic refractory amd.10 conversion to aflibercept might be a prospective countermeasure for ranibizumab tachyphylaxis in pcv . in this study
, we evaluated the visual and anatomical response of iva in eyes with pcv after development of ranibizumab tachyphylaxis , and evaluated therapeutic effects 3 months after conversion from ranibizumab to aflibercept .
this retrospective study was performed according to the tenets of the declaration of helsinki and was approved by the institutional review boards of tokyo medical university and ibaraki medical center .
informed consent for the examination was obtained from all patients . at each visit , all patients received a comprehensive ophthalmologic examination , including best - corrected visual acuity ( bcva ) , indirect ophthalmoscopy , slit - lamp biomicroscopy with a contact lens , fundus photography , and optical coherence tomography ( oct : 3d oct-2000 ; topcon , tokyo , japan ) .
central retinal thickness ( crt ) was measured using an oct b - scan image .
the clinical diagnosis of pcv was made by identification of polypoidal lesions with indocyanine green angiography .
all eyes were initially treated with three consecutive intravitreal injections of 0.5 mg ranibizumab every 4 weeks .
an additional ivr was given if any of the following changes were observed : ( 1 ) any serous retinal detachment , ( 2 ) increasing intraretinal fluid , ( 3 ) enlargement of a pigment epithelial detachment , and ( 4 ) new macular hemorrhages .
all eyes were converted to intravitreal injection of 2 mg aflibercept after diagnosis of ranibizumab tachyphylaxis .
tachyphylaxis was defined as the phenomenon in which the repeated intravitreal ranibizumab resulted in a complete lack of response after initial treatment response.7 initial treatment response was defined as complete resolution of intra / subretinal fluid and pigment epithelial detachment after the initial treatment regimen .
lack of response was considered as an increase in intra / subretinal fluid or pigment epithelial detachment despite two or more intravitreal injections of ranibizumab .
after an initial single injection of aflibercept , all eyes were examined every 4 weeks .
retreatment was applied according to the same protocol for intravitreal ranibizumab , at every 4 weeks , and retreatment was applied at least every 8 weeks , regardless of the findings . for statistical analysis ,
bcva , as measured with a landolt chart , was converted to a logarithm of the minimal angle of resolution .
the bcva and crt were compared at baseline , at complete resolution after ivr , at reactivation after ivr , at initial iva , and at 4 and 12 weeks after initial iva .
statistical significance was calculated using a wilcoxon signed - rank test and defined as p < 0.05 .
statistical software ( statview 5.0 ; sas institute , cary , nc , usa ) was used for statistical analyses .
this study included ten eyes of ten japanese patients ( seven males , three females ) with pcv , ranging from 61 years to 85 years of age ( mean : 73.3 years ) .
the mean greatest linear dimension at baseline was 3925 m ( range 8507600 m ) based on fluorescein angiography , and 2830 m ( range 8004600 m ) based on indocyanine green angiography . the mean bcva at baseline was significantly improved at the initial treatment response by ivr ( p = 0.025 , table 1 ) .
the mean crt at baseline was significantly reduced at the initial treatment response period ( p = 0.008 , table 1 ) .
the mean number of ivr at reactivation was 7.9 ( range 414 ) , and the mean duration from initial ivr was 308 days ( range 105518 days ) .
the mean crt at reactivation was increased from the initial treatment response ( p = 0.09 , table 1 ) .
after reactivation , the mean crt was increased ( p = 0.11 , table 1 ) despite monthly ivr ( mean 4.4 injections , range 28 injections ) .
all eyes were judged with ranibizumab tachyphylaxis based on complete lack of response , and were converted to iva .
indocyanine green angiography images at conversion to iva showed polypoidal lesions in nine of ten eyes ( figure 1 ) , and polypoidal lesion could not be detected in one eye . at 4 weeks after a single injection by iva
, oct findings were improved in all eyes ( figure 1 ) , and mean crt was significantly reduced from time of first iva ( p = 0.005 , table 1 ) . in the 12 weeks after conversion to iva , three injections by iva were applied to one eye , and two injections by iva were applied to nine eyes .
the mean crt at 12 weeks after conversion was significantly reduced from the time of first iva ( p = 0.005 , table 1 ) . in one eye with three injections ,
intra / subretinal fluid was gradually decreased throughout the observation period , and intra / subretinal fluid disappeared at 12 weeks after the first iva . among the eyes with two injections , five eyes showed increased intra / subretinal fluid at 8 weeks after iva , and intra / subretinal fluid disappeared again at 4 weeks after retreatment . in the other four eyes with two injections ,
no significant changes in the mean bcva were observed throughout the follow - up after initial treatment response .
ranibizumab was approved by the united states food and drug administration in december 2005 , and ranibizumab became a mainstay for the treatment of amd.11 in contrast , aflibercept was approved in november 2011 , and accordingly , clinicians have only limited clinical experience with aflibercept compared to ranibizumab .
the predicted biological activity of aflibercept is higher than ranibizumab,9,12 hence , aflibercept is used as a rescue drug for refractory amd with ranibizumab . in this study , switching to aflibercept resulted in significant improvement in anatomical outcome in eyes with pcv with ranibizumab tachyphylaxis .
after approval of ranibizumab , monotherapy with ranibizumab became a leading therapeutic modality for amd.11 eyes with amd might receive repeated ivr for a long time , and thereby the risk of tachyphylaxis or tolerance may potentially increase . in our study ,
all cases showed increases in intra / subretinal fluid or pigment epithelial detachment despite repeated intravitreal ranibizumab , which could be considered as tachyphylaxis rather than tolerance.7 one possible mechanism of ranibizumab tachyphylaxis is the development of emerging anti - ranibizumab antibodies.13 to prevent antibody development , use of drugs with different molecular structure could be an effective alternative .
switching the treatment to bevacizumab achieved 81% success rate after development of ranibizumab tachyphylaxis for amd.14 in our study , conversion to aflibercept showed better success rates than bevacizumab .
bevacizumab and ranibizumab have similar protein structures.15 in contrast , aflibercept has a different molecular structure than ranibizumab,15 and this dissimilarity might produce a better success rate than bevacizumab .
another possible mechanism of ranibizumab tachyphylaxis is the presence of another pathway other than the vegf - a family .
vegf - a is the target of ranibizumab,16 and is considered important in the development of choroidal neovascularization through its potent angiogenic and vasopermeable abilities.17,18 however , for pcv vascular lesions , ranibizumab could regress the polypoidal lesions in pcv only in 40% of the cases , and ranibizumab had no effect on the regression of branching vascular networks.4,19 in addition to vegf - a , other members of the vegf family , including placental growth factor20 and vegf - b21 have critical roles for angiogenesis and hyperpermeability , and these substances might be related to the activities of pcv vascular lesions .
afibercept could suppress these vegf effects , and might have greater effectiveness for suppression of pcv vascular lesions.9 another potential mechanism is upregulation of the receptors on the vascular lesions , thus the amount of given ranibizumab might be insufficient to suppress the pcv vascular lesions .
the binding affinity of aflibercept to vegf is higher than that of ranibizumab;9 hence aflibercept could have greater ability to treat this upregulation . in the view ( vegf trap - eye : investigation of efficacy and safety in wet amd ) study , treatment
every 2 months after three initial monthly shots with aflibercept was effective for treatment - nave amd.8 for eyes treated after development of ranibizumab tachyphylaxis , there is no established protocol for aflibercept treatment . in this study ,
this high recurrence rate suggests the necessity of more frequent injections , including three initial monthly injections .
the limitations of our study include the small number of cases , and short follow - up periods after conversion to aflibercept . a long - term follow - up after conversion to aflibercept
this limits the study regarding the development of ranibizumab tachyphylaxis and efficacy of aflibercept for pcv .
in conclusion , conversion to aflibercept is effective for pcv after development of ranibizumab tachyphylaxis .
purposeto evaluate the effect of aflibercept treatment after developing ranibizumab tachyphylaxis for the treatment of polypoidal choroidal vasculopathy ( pcv).patients and methodsten eyes from ten patients with pcv who developed ranibizumab tachyphylaxis were reviewed . 
 tachyphylaxis was defined as when repeated intravitreal ranibizumab ( ivr ) resulted in a complete lack of response after initial treatment response . 
 all treatments were converted to intravitreal aflibercept ( iva ) after development of ranibizumab tachyphylaxis . 
 central retinal thickness ( crt ) was compared at baseline , at complete resolution after ivr , at reactivation after ivr , at initial iva , and at 4 and 12 weeks after initial iva.resultsmean number of ivr treatments before conversion to iva was 11.3 ( range 516 ) . 
 all eyes had positive therapeutic responses after conversion to iva . 
 mean crt at 4 and 12 weeks after initial iva was significantly decreased from baseline initial iva ( p = 0.005).conclusionswitching therapy to aflibercept is effective for patients with pcv who develop tachyphylaxis to ranibizumab .