How is choroidal neovascularization (CNV) treated?

Updated: Jan 07, 2019
  • Author: Lihteh Wu, MD; Chief Editor: Andrew A Dahl, MD, FACS  more...
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Current knowledge of molecular events in the pathogenesis of choroidal neovascularization (CNV) has allowed CNV to be targeted with very specific antiangiogenic factors. Targeting VEGF allows a two-hit strategy: antiangiogenesis and antipermeability. VEGF is 50,000 times more potent than histamine in inducing vascular permeability. An important component of decreased vision is the accumulation of subretinal fluid secondary to increased vascular permeability. [2]

The major limitation of anti-VEGF treatment is the injection burden. Most patients require multiple injections. Therefore, a number of different protocols are looking at combining photodynamic therapy, corticosteroids, and anti-VEGF drugs. [3, 4, 5, 6, 7]

Currently, the treatment of choice for CNV secondary to exudative ARMD is intravitreal anti-VEGF therapy. A reduced biological response to both intravitreal ranibizumab and bevacizumab has been reported by several authors. [26, 27, 28, 29, 30, 31] A distinction between tachyphylaxis and drug tolerance should be made. [32] Tachyphylaxis refers to the loss of drug effectiveness following repetitive use during a short period of time. In general, drug effectiveness is restored after a short drug holiday. In contrast, drug tolerance develops slowly over time. Increasing the drug dosage or shortening the dosing interval improves its effectiveness. A drug holiday does not restore its effectiveness. [32]

Several mechanisms have been proposed to explain these phenomena. VEGF blockade may lead to an increase in other angiogenic signaling pathways as a compensatory mechanism. [33] Up-regulation of VEGF production by macrophages within CNV has also been proposed. [28] Anti-bevacizumab and anti-ranibizumab auto-antibodies have been documented in the systemic circulation of patients undergoing chronic anti-VEGF therapy for exudative AMD. These auto-antibodies may neutralize the effect of anti-VEGF agents. [28] } CNV lesion composition might change with time with more mature and therefore less VEGF sensitive vessels. [28, 33]

A retrospective case series reported that tachyphylaxis occurred in 5 of the 59 patients treated with intravitreal bevacizumab. [28] In this study, the median time to develop tachyphylaxis with intravitreal bevacizumab was 100 weeks, with a median number of 8 intravitreal injections. Another retrospective case series identified tachyphylaxis in 2% of patients being treated with ranibizumab. [26]

Several strategies, including drug holidays, increasing the drug dosage, combination therapy, and switching from one anti-VEGF drug to another anti-VEGF agent, have been advocated to counteract these phenomena. [28, 29, 31, 32] Gasperini and colleagues showed that in 81% of cases, the switch from ranibizumab to bevacizumab and vice versa was at least somewhat effective in further reducing subretinal fluid. [29]

Several other antiangiogenic compounds are currently in different stages of development. [34] These agents include genetic therapy with vectors carrying anti-angiogenics, [35] si (small interference) RNA-VEGF, various PDGF inhibitors, angiopoietin inhibitors, and combretastatin A4.

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