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QUESTION

HOW LONG ARE WE GOING TO HAVE TO KEEP DOING FREQUENT INTRAVITREAL INJECTIONS—ANY OTHER OPTIONS ANYTIME SOON? WHAT ARE WE WAITING FOR?

Margaret A. Greven, MD
Diana V. Do, MD

Intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) medications are the current standard of care for the treatment of neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusion with macular edema. The 3 currently available drugs in this class are ranibizumab and aflibercept, which are US Food and Drug Administration–approved for the treatment of these conditions, and bevacizumab, which is frequently used off-label. Studies have demonstrated the half-life of these drugs are 7 days for ranibizumab and 9 days for both bevacizumab and aflibercept.^1–3 Ranibizumab and bevacizumab are thought to have a duration of action of approximately 1 month, while aflibercept has been approved for every 1- or 2-month administration.

The goal of treating with these medications is to preserve and improve vision by halting disease activity. The activity of disease is usually determined by the presence of intra- or subretinal fluid, and retinal pigment epithelial detachment associated with choroidal neovascularization in neovascular AMD on optical coherence tomography (OCT) imaging. The 3 common treatment regimens are monthly injections; treat and extend, wherein the interval between injections is gradually increased if the condition remains inactive and shortened to the previous duration at which the patient was inactive, if activity recurs; and as needed, or pro re nata (PRN) injections.

The necessary frequency and duration of intravitreal injections depends on which condition is being treated. In AMD, evidence shows us that there is a continued need for frequent intravitreal injections. The 2-year results of the Comparison of AMD Treatment Trial (CATT), comparing ranibizumab to bevacizumab and monthly injections to PRN injections in neovascular AMD, showed that visual acuity improved over the first 6 months of treatment with monthly or PRN treatment. Improvements were maintained in patients who were continued on a monthly treatment schedule but declined slightly with PRN treatment between year 1 and 2, suggesting more frequent treatment is associated with better visual acuity outcomes.4 The 5-year results of the CATT follow-up study, an open label follow-up of patients who had been enrolled in the CATT study and received treatment with ranibizumab or bevacizumab at the treating doctor’s discretion for an additional 3 years after the first 2 years of the study, showed similar results. Patients received a mean of 4 to 5 injections per year after the first 2 years. However, the mean visual acuity declined an average of 11 letters from year 2 to year 5.⁵ It is unclear why these patients lost vision over time as the etiology may be multifactorial. This worsening of vision with reduced treatment frequency could suggest that undertreatment leads to worse vision outcomes and highlights the suggestion that patients continue to require injections even at 5 years after the initiation of treatment. In addition, the development of macular atrophy over time in some of these eyes can also lead to vision loss.

The need for continued frequent injections in neovascular AMD was also supported by the 7-year results of the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD), MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD), and HORIZON (An Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to AMD) studies, which showed that patients who continued to receive the most injections (> 11 injections over a 3-year period) had better visual acuity outcomes.⁶ Based on this evidence, in our neovascular AMD patients, we treat aggressively if there is evidence of disease activity on OCT. If all disease activity has resolved, we transition to a treat-and-extend protocol. Once the required interval between injections is established, we continue to treat indefinitely at this interval to prevent recurrent choroidal neovascularization.

The need for continued frequent treatment in neovascular AMD contrasts to the treatment requirement in DME. The 5-year results of the DRCRnet (Diabetic Retinopathy Clinical Research Network) Protocol I showed that patients with DME who received frequent ranibizumab injections, with prompt or deferred laser, during the first year required significantly less injections in subsequent years. These eyes were able to maintain visual acuity improvement despite requiring fewer injections in years 3 through 5.⁷ Patients received a mean of 8 or 9 injections in the first year, 2 or 3 injections in the second year, 1 or 2 injections in the third year, and 0 or 1 injection in the fourth year, depending on whether the patient received ranibizumab with prompt or deferred laser. Similarly, the 2-year results of Diabetic Retinopathy Clinical Research Network Protocol T, where patients were randomized to treatment with aflibercept, ranibizumab, or bevacizumab, demonstrated that in the first year patients required an average of 10, 10, or 9 injections respectively, but in the second year, the requirement decreased to 5, 6, or 6, while maintaining sustained visual acuity improvement.⁸ Our protocol for treating DME is to treat aggressively initially with monthly injections until the edema resolves and then convert to a PRN treatment approach.

The treatment requirement for retinal vein occlusion with macular edema can vary. The RETAIN study examined outcomes of patients treated for macular edema secondary to branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) with ranibizumab with a mean follow-up of just over 4 years. Patients with BRVO required an average of about 7 injections the first year, 2.6 injections for the second year, and an average of about 2 injections during both the third and fourth years. About half of BRVO patients still required infrequent injections after 4 years. Patients with CRVO required about 7 injections the first year, 4 injections the second year, 4 injections the third year, and about 3 injections the fourth year. In patients with CRVO, 54% of patients still required frequent injections after 4 years.9 In our retinal vein occlusion patients, we initially begin with monthly injections until the macular edema has resolved on OCT imaging. Subsequently, we convert to a treat-and-extend protocol to prevent recurrent macular edema or treat on a PRN basis.

Intravitreal steroids are an option to decrease the number of anti-VEGF injections for some eyes with DME and retinal vein occlusion with cystoid macular edema; however, intravitreal steroids may lead to steroid-induced glaucoma and cataract progression in some eyes. Steroid options include preservative-free Triesence (triamcinolone acetonide), Ozurdex (dexamethasone), and Iluvien (fluocinolone acetonide).

Challenges

The evidence tells us that neovascular AMD is a chronic condition that likely requires careful monitoring and frequent treatment. For DME, scientific studies suggest the treatment burden decreases significantly over time. In retinal vein occlusion, eyes with macular edema can require chronic treatment and careful monitoring is necessary. This need for frequent evaluation and possible treatment for these conditions places an enormous burden on our patients. With an aging population and rising prevalence of diabetes, it also places a strain on the health care system. The development of extended-release anti-VEGF treatments holds promise to address these issues in the future.

Future Directions

Several approaches to long-term or extended-release anti-VEGF agents are currently in development. One such approach is implantable reservoir technology that involves surgically attaching a refillable drug reservoir to the sclera to deliver a sustained dose of drug over time. Another approach is encapsulated cell technology which could allow the continuous production of anti-VEGF by immortalized cells within a capsule injected into the vitreous cavity. Still another possible future treatment is gene therapy which could be used to allow the eye to produce its own anti-VEGF. Finally, long-acting anti-VEGF molecules could allow an intravitreal injection to maintain effect for longer than the current duration. Although these approaches to an extended anti-VEGF effect are still under investigation, we believe that within the next 10 years, we will have long-acting anti-VEGF treatments available for our patients. Until then, we will continue with frequent intravitreal injections to give our patients the best visual acuity outcomes.

References

1.     Krohne TU, Eter N, Holz FG, Meyer CH. Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Am J Ophthalmol. 2008;146(4):508-512.

2.     Krohne TU, Liu Z, Holz FG, Meyer CH. Intraocular pharmacokinetics of ranibizumab following a single intravitreal injection in humans. Am J Ophthalmol. 2012; 154(4):682-686.

3.     Do DV. Update on aflibercept pharmacokinetics and treatment of diabetic macular edema. Presented at: Angiogenesis, Exudation, and Degeneration; February 11, 2017. Miami, FL.

4.     Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398.

5.     Maguire MG, Martin DF, Ying GS, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2016;123(8):1751-1761.

6.     Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120(11):2292-2299.

7.     Elman MJ, Ayalla 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.

8.     Wells, JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351-1359.

9.     Campochiaro PA, Sophie R, Pearlman J, et al. Longterm outcomes in patients with retinal vein occlusion treated with ranibizumab: the RETAIN study. Ophthalmology. 2014;121(1):209-219.

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