Bringing Mohammad to the mountain: New strategies for intravitreal therapy service delivery

Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is a well-established therapeutic option for neovascular age-related macular degeneration (nAMD),¹ diabetic macular oedema (DMO)² and retinal vein occlusion (RVO).³ The number of Medicare claims for intravitreal injections (item#42738) has increased from 181 140 to 621 001 per annum from 2012 to 2022; the equivalent of 8–24 injections per 1000 population-year.⁴ This is increase is due to, in part, the expanding indications and improved patient access. With the rapidly growing demand, advances in treatments and models of care are essential to provide sufficient service delivery to patients requiring intravitreal therapy (IVT). Broadly, the considerations of an IVT service can be divided into pharmacologic agents, treatment regimens, drug delivery, staffing, treatment setup and complications management.

Newer pharmacological agents show promise for increased durability. Faricimab (Vabysmo) allows treatment intervals of up to 16 weeks in around 60% of patients after 2 years of treatment for nAMD⁵ and DMO.⁶ Aflibercept 8 mg (Eylea HD) allows for maintenance of 16 week treatment intervals in 70% of nAMD patients and 84% of DMO patients after 2 years of treatment, with 28% of nAMD patients even meeting criteria for 24 week intervals. A direct comparison between these two agents cannot be made, as true head-to-head studies are yet to be conducted and the treatment and extension criteria for their pivotal phase III studies differed.

Monthly administration is not feasible nor necessary in all patients. Compared with fixed dosing, a treat-and-extend (T&E) regimen has been shown to reduce the treatment burden without compromising efficacy in patients requiring anti-VEGF agents for nAMD.⁷ There is less consensus for treatment regimens in treating DMO, although a recent systematic review supports the use of T&E in this disease too.⁸

The port delivery system (PDS) allows at least a six monthly refill-exchange,⁹ but has a higher rate of endophthalmitis than intravitreal injections at around 2%,¹⁰ and does not necessarily reduce visit burden as the device itself requires surveillance for local complications. Intraocular gene therapy (intravitreal, subretinal or suprachoroidal) holds the promise of lifelong treatment,¹¹ but this has been associated with up to a 21%–45% rate of vector-related uveitis.¹²

Worldwide, the vast majority of intravitreal injections are still performed by ophthalmologists. Variances in this model are seen in some centres in the UK and Singapore, where nurses can administer intravitreal injections under ophthalmology supervision. Virtual AMD clinics have been employed in over 60% of United Kingdom (UK) eye departments.¹³ Home monitoring paired with artificial intelligence has the potential to reduce the clinic visit burden by shifting treatment delivery towards a PRN regimen. In May 2024, the Notal Vision Home OCT SCANLY® received US Food and Drug Administration (FDA) for this purpose.

In this issue, Lee et al.¹⁴ reports a novel oursourcing of intravitreal injections to junior medical officers in rural Western Australia. The rate of IVT delivery was equivalent to 6 injections per 1000 population-year; a significantly lower rate than the National and State average of 24 and 19 per 1000 population-year in 2022, respectively. To address the lack of ophthalmologists available to deliver IVT in remote WA, Lions Outback Vision (LOV)-trained junior medical officers, who were not in an ophthalmology specialist training program, performed the intravitreal injections. This cohort comprised doctors in their second to sixth year after completing medical school.

The injection procedure performed by LOV junior medical officers was similar to that described by Lee et al. in a survey of Australian and New Zealand practitioners.¹⁵ IVT was carried out in the outpatient clinic setting or in a mobile clinic van (similar to 96% of the respondents of the Lee et al. survey).¹⁵ Subconjunctival lignocaine was used in all patients (used by 64% of Lee et al. survey respondents).¹⁵ Either chlorhexidine or povidone-iodine were used (100% of Lee et al. survey respondents).¹⁵ Speculum, calliper and antibiotics were not used, thus reducing the carbon footprint and wastage from the IVT setup,^{16, 17} although there is some evidence that speculum use can reduce endophthalmitis rates.¹⁸

The treatment indications reported in this series were presented as a proportion per total number of injections rather than per number of eyes or patients. Therefore, it is difficult to ascertain if the predominance of DMO (46%) is a reflection of a higher number of diabetic patients seen in the LOV catchment area or more treatment episodes required in each diabetic patient due to the monthly IVT regime and frequent bilateral disease.

The over-representation of bevacizumab usage (45%) was similar to previous reports from two tertiary hospitals in South Australia¹⁷ (50%) and a tertiary hospital in the Northern Territory¹⁹ (48%). Importantly, this is the first report of MVASI being used off-label in Australia. None of the endophthalmitis cases arose from the use of MVASI. Although Lee et al.¹⁴ did not address the visual outcomes of patients receiving bevacizumab off-label, this should be an important future consideration when implementing a remote IVT service, given that the retreatment interval may need to be longer in the remote setting due to access logistics and clinic scheduling. Previous reports have shown similar visual acuity gains when starting treatment with bevacizumab compared to ranibizumab or aflibercept 2 mg but at the cost of more frequent injections or switching to a second agent.^{20, 21} In central retinal vein occlusion, the outcome may be worse when bevacizumab is used initially.²⁰ Lee et al.¹⁴ acknowledged a significant barrier to using PBS-listed anti-VEGF agents was the lack of stock in remote community pharmacies. Interestingly, only 2.9% of the injections were for the dexamethasone implant (Ozurdex), which may reflect the longer injection intervals or underutilisation due to the challenge of monitoring for an intraocular pressure rise in the remote setting.²² The small fraction of faricimab usage (0.8%) likely represents the fact that it was only PBS listed in January 2023, 5 months before Lee et al.'s audit ended. Its usage will likely have increased, given a recent report of improved durability to enable retreatment interval extension.²³ Aflibercept 8 mg has recently been PBS approved in Australia, but was not available at the time of the audit.

Endophthalmitis can be endogenous²⁴ or exogenous after intraocular procedures such as cataract and glaucoma surgery,^{25, 26} or penetrating eye injury. Given the large number of IVT performed, this has become the most common cause of exogenous endophthalmitis with rates around 0.06%.^{27, 28} Lee et al.¹⁴ described three cases of endophthalmitis related to IVT with one patient presenting 4 weeks after treatment. Given all three cases were treated for DMO and all received bevacizumab (Avastin), the endophthalmitis rate may be as high as 0.06% in those receiving Avastin for DMO, to as low as 0.02% in those receiving any type of injection for any indication. These rates are within the range of reported large case series. The presenting vision was hand movement in all three cases, and all received a tap and inject as well as vitrectomy in tertiary centres. Two of the three had a good visual outcome. The authors acknowledged the significant challenge in managing rural patients with endophthalmitis given the distance they need to travel and the paramount importance of providing an early tap and inject (preferably <2 h)²⁸ and vitrectomy (preferably <24 h)²⁹ in reducing the risk of poor visual outcomes.

Like Mohammad who had to adapt and meet the mountain when it didn't come to him, we must also evolve our strategies for medical service delivery. Procedures need to be customised to the local environment and resources, but be supported by audit data to ensure adequate efficacy and safety. Expanding the scope of practice of junior medical officers may reduce the tyranny of distance and assist with service delivery in rural locations, so long as adequate consultant supervision is provided.

None.

Fred K. Chen: Received research grant from Bayer, speaker and consulting fees from Novartis, Roche, Apellis and PYC Therapeutics. Adrian T. Fung: Alcon (lecture honoraria, advisory board, travel fees, research), Roche (consultant, lecture honoraria, advisory board, travel fees, research), Bayer (consultant, lecture honoraria, advisory board, travel fees, research), Novartis (lecture honoraria, travel), Apellis (advisory board), Astellas (advisory board), Abbvie (lecture honoraria, travel fees, research), Ionis Pharmaceuticals (research), Opthea (equity). Rachael C. Heath Jeffery: None.