key: cord-1032243-1nkbpj2v authors: Okada, Mali; Mitchell, Paul; Finger, Robert P.; Eldem, Bora; Talks, S. James; Hirst, Ceri; Paladini, Luciano; Barratt, Jane; Wong, Tien Yin; Loewenstein, Anat title: Non-adherence or non-persistence to intravitreal injection therapy for neovascular age-related macular degeneration: a mixed-methods systematic review date: 2020-08-05 journal: Ophthalmology DOI: 10.1016/j.ophtha.2020.07.060 sha: a7441cdb4ff5ec32b6498c32c6fa7bf3069e4479 doc_id: 1032243 cord_uid: 1nkbpj2v TOPIC: Systematic review of risk factors for non-adherence and non-persistence to intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection therapy for neovascular age-related macular degeneration (nAMD). CLINICAL RELEVANCE: Lack of adherence (non-adherence) or under-treatment (non-persistence) with respect to evidence from clinical trials remains a significant barrier to optimizing real-world outcomes for patients with nAMD. Contributing factors and strategies to address this are poorly understood. METHODS: Studies that reported factors for non-adherence and/or non-persistence to anti-VEGF therapy as well as studies examining strategies to improve this were included. Trial eligibility and data extraction were conducted according to Cochrane review methods. Risk of bias was assessed using the Mixed Method Assessment Tool and certainty of evidence evaluated according to the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative Research) tool. Data were collated descriptively. RESULTS: Of the 1284 abstract results screened, 124 articles were assessed in full and 37 studies met the inclusion criteria. Definitions of non-adherence and non-persistence varied or were not reported. Non-persistence occurred early with up to 50% of patients stopping treatment by 24 months. High rates of non-adherence were similarly reported, occurring in 32 – 95% of patients. Certainty of this finding was downgraded to moderate level due to heterogeneity in definitions used across studies. Multiple factors determine non-adherence and non-persistence, including at condition, therapy, patient, social/economic and health systems/health-care team level. Moderate quality evidence points to lower baseline vision and poorer response to treatment as condition-related variables. The effects of other factors were of lower certainty, predominantly due to small numbers and potential biases in retrospective assessment. Although many factors are non-modifiable (e.g., patient co-morbidity), other factors are potentially correctable (e.g., lack of transport or mismatched patient expectations). Evidence on strategies to improve adherence and persistence is limited, but where available, these have proven effective. CONCLUSIONS: Awareness of factors related to poor patient adherence and persistence in nAMD could help identify at-risk populations and improve real world outcomes. Further work is required to develop uniform definitions as well as establishing high quality evidence on interventions that can be easily implemented. Of the 1284 abstract results screened, 124 articles were assessed in full and 37 studies 23 met the inclusion criteria. Definitions of non-adherence and non-persistence varied or 24 were not reported. Non-persistence occurred early with up to 50% of patients stopping 25 treatment by 24 months. High rates of non-adherence were similarly reported, 26 occurring in 32 -95% of patients. Certainty of this finding was downgraded to 27 moderate level due to heterogeneity in definitions used across studies. Multiple 28 factors determine non-adherence and non-persistence, including at condition, therapy, 29 patient, social/economic and health systems/health-care team level. Moderate quality 30 evidence points to lower baseline vision and poorer response to treatment as 31 condition-related variables. The effects of other factors were of lower certainty, 32 predominantly due to small numbers and potential biases in retrospective assessment. 33 Although many factors are non-modifiable (e.g., patient co-morbidity), other factors 34 J o u r n a l P r e -p r o o f Intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections have 3 revolutionized the treatment of neovascular age-related macular degeneration 4 (nAMD). 1, 2 Landmark clinical trials have demonstrated that, not only can anti-VEGF 5 injections stabilize disease, but that initial and prolonged visual gains are also 6 common. 3 Real-world evidence however suggests that even with these "less taxing" alternate 15 dosing regimens, outcomes seen in practice mostly do not reach the levels achieved in 16 trial settings, with the discrepancy possibly due to lack of adherence to clinical trial 17 regimens (defined in this paper as non-adherence) or lack of persistence with 18 following recommended clinical trial regimens over time (defined as non-persistence). 19 For example, a recent meta-analysis of real-world observational data based on 20 approximately 26,000 patients reported a mean visual gain of only +5.0 Early 21 Treatment of Diabetic Retinopathy Study (EDTRS) letters after 12 months of 22 treatment, with a mean number of 5.4 injections over 8.3 visits. 5 This is well below 23 the +11.3 letters seen in the ANCHOR trial with monthly intravitreal ranibizumab, 6 24 +8.9 letters in VIEW1/VIEW 2 studies 7 with every 8 weeks intravitreal aflibercept. 25 Long term results from both clinical trials and registry data also confirm this finding, 26 with more frequent injections consistently showing better visual outcomes. 8,9 27 28 Given the importance of encouraging ongoing and frequent injections, there is a 29 relative lack of awareness amongst physicians and the health community of the 30 barriers that lead to the inter-related phenomenon of non-adherence and non-31 persistence of anti-VEGF treatment in nAMD in the real-world. Terminology and 32 agreed definitions may not exist. There is even less discussion on strategies to correct 33 or counteract these barriers. Previous studies have attempted to look at this from a 34 J o u r n a l P r e -p r o o f local practice level or focused only on the patient experience. 10,11 However a 1 comprehensive analysis has not been performed to date. To our knowledge this is the 2 first systematic review of the factors affecting treatment non-adherence and non-3 persistence to intravitreal anti-VEGF injections in nAMD. 4 5 6 This systematic review was conducted in accordance with the principles set out in the 9 Cochrane Handbook for Systematic Reviews of Interventions. 12 The protocol for this 10 systematic review was registered with the international PROSPERO database (ID: 11 172653) prior to data extraction. Our results and methods are presented in reference to 12 the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 13 Studies were eligible to be included in this systematic review based on the following 18 criteria as set out in the PICO paradigm (Patient, Intervention, Comparator and 19 Outcome), Table 1 . No eligibility restrictions were placed based on the type of anti-20 VEGF used or the treatment regimen employed. The minimum definitions of non-21 adherence and non-persistence were not set in advance, in order to allow for maximal 22 inclusion of studies examining this topic. However, it was accepted that terms such as 23 'non-adherence' were synonymous with 'non-compliance'. Similarly, the term 'non-24 persistence' was interchangeable with 'discontinuation', 'cessation', 'lost to follow-25 up' or 'drop out'. Both quantitative and qualitative studies were eligible for inclusion 26 in order to comprehensively address all aspects of the research question. Conference abstracts were also excluded due to the inability to critically assess 31 findings. 32 33 J o u r n a l P r e -p r o o f The primary outcome measure for this review was reasons or risk factors for 1 treatment non-adherence and non-persistence following at least one intravitreal anti-2 VEGF injection. Secondary outcome measures included efficacy of strategies to 3 improve treatment adherence and/or persistence as well as the rates of non-4 adherence/non-persistence itself. Further assessments were also made for factors that 5 may be identified as general barriers to treatment. 6 7 Search methods for identifying studies 8 9 The following databases were searched: MEDLINE, EMBASE, Cochrane Central 10 Register of Controlled Trials (CENTRAL), clinicaltrials.gov online database and 11 Google Scholar. Databases were last searched and results updated on 19 March 2020. 12 In addition, the reference lists from eligible studies were also reviewed to identify any 13 additional suitable reports. No language restrictions were imposed but if the report 14 was not in English, the text was translated to allow for data extraction and full 15 analysis of the risk of bias. There were no limits placed on publication date, but all 16 studies had to be original and available in full. J o u r n a l P r e -p r o o f Study origins and treatment setting (eg. country, hospital clinic), patient 1 demographics (eg. age and baseline visual acuity), as well as treatment details 2 including type of anti-VEGF and regimen employed were recorded. Factors or 3 correlates reported in the study relating to treatment non-adherence or non-persistence 4 were evaluated. Additionally, any strategies evaluated to improve the adherence or 5 persistence were also extracted. The methodological quality of each study was can be used across qualitative, quantitative and mixed-methods studies. 13 The overall 8 quality and certainty of the evidence in the systematic review was evaluated using a 9 modified GRADE approach to include qualitative evidence synthesis -the GRADE-10 CERQual (Confidence in the Evidence from Reviews of Qualitative Research) tool. criteria with patient death, patient transfer for some studies but not others) and 20 differences in time period (total non-persistence over several years versus yearly 21 rates) and lack of raw data for some studies to enable re-analysis. As an alternative, 22 rates were tabulated according to each study and the data range provided. Factors for 23 non-adherence and non-persistence were also extracted from each study. These were social/economic factors. 14 Factors were analyzed qualitatively according to theme, but 28 also quantitatively with an odds ratio or percentage, where reported. Non-persistence 29 or non-adherence due to patient death or transfer of care was excluded from analysis. 30 If possible, intentional discontinuation by treating physician from disease stability or 31 remission was separated from unintentional non-persistence in the analysis. Of the 37 eligible studies, the majority (n = 33) assessed the factors for treatment non-21 adherence and/or non-persistence, and a further four studies reported barriers to 22 treatment without additional assessment of adherence/persistence. 15, 16 Only two of the 23 final studies explored strategies to improve treatment non-adherence/non-persistence. 24 Study characteristics are summarized in Table 2 . 25 The studies were mainly European and US-based, with a predominantly Caucasian 27 population; only three reports involved patients from Asian countries. [17] [18] [19] The 28 majority of studies assessed patients treated with intravitreal ranibizumab on a PRN 29 dosing regimen, with a few more recent studies including intravitreal aflibercept or 30 ranibizumab on a T&E regimen, Table 2 . This reflects the timing of treatment 31 initiation of these patients, with most receiving their first anti-VEGF injection prior to 32 tertiary hospital (university affiliated hospitals or dedicated retinal clinic) as opposed 1 to a local clinic (general comprehensive clinic), Table 2 . There was significant variation in the terminology and the definitions of non-6 adherence and/or non-persistence used across all studies. Definitions were not 7 reported in some studies. 16,20,21 Synonyms used for non-adherence included 'non-8 compliance', 22,23 'absenteeism' 24 or 'non-attendance'. 25 Synonyms for non-persistence 9 included 'treatment discontinuation/cessation' 18, 26, 27 or 'lost to follow up' 10 Non-adherence was variably defined as: 11 • No treatment or consultation with a measure of visual acuity and OCT at least 12 every 6 weeks 28 13 • Extreme violation of prescribed treatment 22 14 • Non-attendance of every clinic appointment 19 15 • Receiving less than the recommended 8 injections over 12 months 25 16 • Deviation from treatment recommendations (by patient or physician) with gap 17 in treatment and/or consultation by > 8 weeks 29 18 • Visit outside of the prescribed 28 days ± 7 days window 19 20 Non-persistence was variably defined as: 21 • Treatment discontinuation before 12 months, 30 study period 26, 27 or 22 permanently 31 23 • No treatment or visit at clinic for more than 4 months 32 , 6 months 15,33,34 or 12 24 months 35,36 25 • No follow up by any ophthalmologist for 3 months 28 26 • No follow up within a 12 months period after receiving at least 1 anti-VEGF 27 injection 37 28 • Loss of follow up of at least 24 months 18 29 30 In some cases, intentional non-persistence, either due to assessed treatment futility or 31 treatment success with inactive disease, as agreed to by patient and treating physician, 32 was not explicitly differentiated from patients who were lost to follow up. Non-adherence to treatment or to monitoring appointments was high with variable 4 rates depending on how strictly it was defined (32 -95%). 25,28,29 In one study, which 5 assessed non-adherence as no treatment or consultation at least every 6 weeks when 6 using a PRN protocol, almost all patients (n = 346, 95.6%) fulfilled this criteria over a 7 12 month period, with a mean of 2.1 ± 1.1 gaps. 28 When determined by self-report 8 however, rates of perceived non-adherence were much lower, with patients in a 9 another study estimating their rates of non-adherence at 15.7% (n = 143) and 10 caretakers estimating this at a higher 25.8% (n = 230). 19 Unsurprisingly, the observed 11 rates of non-adherence were lower in a clinical trial setting, with a secondary analysis 12 of the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT) 13 reporting only 10.0% of 1060 patients not attending a study visit on time when 14 defined as an average visit interval of 4 weeks ± 7 days over a 24 month period. 38 15 However, when the longest interval between two visits were calculated, 83.3% of 16 patients still had at least one visit interval that was not on time. 17 Patients who discontinued treatment due to either disease remission or treatment 19 futility as judged by their physician accounted for 3 -30% of all nAMD patients who 20 commenced treatment. After excluding these patients, remaining rates of reported 21 non-intentional treatment non-persistence varied between 3 -57% at 12 months, with 22 lower rates when non-persistence was defined as lack of follow up visits rather than 23 lack of anti-VEGF treatment. 35 Studies of non-persistence to treatment beyond 24 24 months were limited, but where available, recorded very high rates of non-persistence, 25 Condition-related factors such as worse visual acuity at baseline was associated with 2 an increase (OR: 2.37, p = 0.05) in non-adherence, 29 though this was not statistically 3 significant in another study by the same authors. 28 Patients whose vision improved 4 with treatment of > 3 lines also were more likely to be adherent (19.9% vs 12.0%, p = 5 0.04), though the converse (ie. loss of vision) did not appear to influence adherence 6 pattern, in at least one study. 29 7 8 Of all patient-related variables, patient illness (21.0 -42.8%) accounted for a 9 significant cause of non-adherence. 19, 25 Many patients however also reported fear of 10 injections as a major barrier to treatment (n = 30, 21%), with a small number also 11 reporting discomfort after injections as a reason for avoidance. 19 12 13 A substantial cause for non-adherence overall related to health system factors. 14 Patients stated sometimes forgetting their appointment (15%), the appointments were 15 too frequent or inconvenient (10%) or there was insufficient clinic capacity with no 16 available appointments in the time frame the patient required (47%). 19 ,25 17 18 Social factors however play a significant role for most patients with many citing a 19 lack of caretakers to take them to appointments (25.9%). Only one study examined 20 cost factors, with less than 10% reporting financial burden as the primary issue for 21 non-adherence. 19 Seasonal factors may also play a role, with one study recording In general, the reasons for non-persistence reflected those seen for non-adherence, 29 Table 4 . 30 Baseline visual acuity was a strong condition-specific factor, with worse baseline 32 vision in the affected eye conferring higher risk of non-persistence of between 1.4 to 33 8.1 times. However, there was no consistent threshold level of visual acuity where this 34 risk increased. Poor response to treatment and worse final visual acuity was also 1 associated with higher rates of non-persistence. There was conflicting evidence as to 2 whether bilateral disease was a risk factor, with some studies suggesting a 3.7 fold 3 increased risk of discontinuation if bilateral injections were required, 28,30 whilst other 4 studies suggested that bilaterality was a protective factor. 37 The therapy regimen may also contribute to risk of non-persistence. In a Japanese 7 study using PRN treatment, patients who were only given a single injection, instead of 8 three loading dose at initiation, had a higher risk of non-persistence. 17 Patients also reported fear of injections as a barrier to treatment, though the extent to 19 which this was responsible varied between 3 and 30% overall. However, patient 20 perception that the treatment was not helpful or not required was a strong risk factor, 21 accounting for up to 42% in some series. 39 However, the studies did not clarify if this 22 was related to an expectation of improvement with treatment and subsequent 23 disappointment when only stability of vision was achieved. This is in keeping with the 24 finding that patients who ceased treatment often reported that lack of information 25 about the treatment plan or the expected outcomes of treatment versus natural 26 history. 39,40 27 Health system and socio-economic-related factors however represented a significant 29 cause for treatment non-persistence as reported by patients. Lack of transport or 30 distance to the treatment centre was a key factor in most studies, accounting for 5 to 31 46% of responses. In contrast, in Denmark, where the government funds transport to 32 the hospital, only one of the four Danish studies included in the review reported 33 transport as an issue. Follow up burden was also reported as a significant factor, 34 though the specifics of whether this was regimen related was not explored. The 1 impact of cost or the financial burden on treatment persistence was quite variable, 2 accounting for as low as 2% in one large multi-country study 26 and as high as 30% in 3 others. 41 Interestingly in Sweden, where treatment for nAMD is covered by the 4 Swedish National Insurance, 50.6% of patients reportedly still discontinued treatment 5 during the first year of diagnosis. In some surveys, patients reported that indirect 6 costs, related to transport for example, was more significant than the cost of the 7 treatment itself. 42 Government and insurance regulations may also play a factor. In a 8 2013 study from Germany, the authors examined the role of reimbursement and the 9 approval pathway on adherence to treatment. 41 At the time, patients in Germany were 10 required to obtain approval from their insurance company prior to treatment. The cost 11 of the injection was covered by insurance but required upfront payment before 12 obtaining a refund. Patients were only approved for three injections at a time, before 13 their case was reviewed. Consequently, up to a third of patients reported some 14 difficulties with the upfront payment and a small proportion had difficulties obtaining 15 approval or refunds. Similarly, in the real-world multi-national AURA study, 16 researchers found there were significant differences between countries in the number 17 of injections given, ranging from a mean of 3.2 injections over 2 years in Venezuela 18 to 11.0 injections in Ireland. 26 Although the correlation to reimbursement or approval 19 process was not directly assessed, the authors suggested the difference in injection 20 frequency may be due to these health system related policies. There is limited evidence on the impact of strategies to improve treatment adherence 32 or persistence, with only two studies available in the literature. 15, 44 One report 33 examined whether patients on a PRN regimen who performed their monitoring visit at 34 a local clinic with telemedicine capabilities had better treatment adherence and 1 increased injections compared to patients who had both monitoring and injections at 2 the same tertiary reference centre. The outcomes suggested that the telemedicine 3 group had greater treatment adherence with significantly greater number of 4 monitoring visits (telemedicine group 22.8 visits vs. control group 18.4 visits, p < 5 0.001) and also a greater number of injections (telemedicine group 13.9 injections vs. 6 control group 11.1 injections, p = 0.02) over the total monitoring period. Another 7 study examined whether providing a fast-track approach with same day injection was 8 better than the standard protocol of booking a separate injection visit. 44 In this study, 9 the mean time between date of the monitoring visit to injection was shorter in the fast 10 track group compared to the standard protocol group (4.1 ± 7.5 vs. 5.6 ± 18.7 days 11 respectively). All patients surveyed in the fast track group also reported satisfaction 12 with same day injection. according to the GRADE-CERQual assessment ( Table 5) . persistence and the factors leading to these. There is also lack of awareness of 7 effective methods needed to alter these behaviours which can be inter-related or 8 separate issues for each patient. Organization defines 'adherence' as 'the extent to which a person's behaviour 13 corresponds with agreed recommendations from a health care provider'. 14 Most 14 studies included here followed a PRN treatment protocol, with non-adherence to 15 intravitreal therapy defined as either an all-or-nothing outcome of complete adherence 16 to monthly visits or a more relaxed definition allowing deviation by more than a set 17 number of weeks or months. However, no specific definitions for non-adherence in 18 those using a T&E protocol were provided. Future work to develop a consensus on 19 definitions will need to be able to straddle the differences and incorporate all 20 treatment protocols. Similarly, there was no agreement on definitions for non-21 persistence, with variable timeframes and lack of differentiation as to whether the 22 discontinuation was intentional or unintentional. For many studies, reasons listed for 23 non-persistence included patient death, transfer of care or planned treatment cessation 24 by the physician due to disease remission or treatment futility. Arguably, death or care 25 transfer should be considered under a different context than for traditional causes of 26 non-persistence, and planned treatment cessation should also be categorized 27 separately. 28 The results of the review however indicate that the rate of reported non-adherence and 30 non-persistence in nAMD is high overall at up to 60% non-persistence at 24 months 31 follow-up in some series. The majority of non-persistence occurs within 6 to 12 32 months, suggesting that the decision is often made early on whether to continue with 33 therapy. Interestingly, the rates of non-persistence were higher in one study when it 34 was defined as no further intravitreal injections, as opposed to no monitoring visit, 1 suggesting that some of this early non-persistence is intentional cessation of 2 intravitreal injections, rather than lack of follow up. 35 This may be due to perceived or 3 actual sub-optimal response to treatment or issues with the injection itself, though 4 data separating these outcomes is limited. 5 6 Conversely, once a patient has remained on treatment for several years, they are much 7 less likely to be non-adherent or non-persistent in the future. It may be that once a 8 routine is established and any initial barriers have been overcome, the patient is more 9 invested in continuing their treatment. However, whether these behavioural and 10 environmental influences on patients and their caretakers change over time has not 11 been clearly defined in the literature. 12 The reasons and risk factors for non-adherence and non-persistence are multi-14 dimensional. As expected, strong correlations exist with patient-related factors such as 15 increased systemic comorbidities, longer distance from home to treatment centre, lack 16 of a caretaker to assist with transport and poorer baseline visual acuity. As expected, 17 treatment efficacy was also a protective factor, with patients who experienced greater 18 visual gains more likely to be both adherent and persistent. However, other factors 19 such as bilaterality showed conflicting results with some studies suggesting poorer 20 adherence with unilateral eye involvement 37 whilst others reported worse outcomes 21 with bilaterally treated disease. 28 22 23 Surprisingly cost was not as consistent a risk factor as expected, with financial 24 barriers only accounting for 2 -30% of causes of non-persistence and less than 10% 25 for non-adherence. This may be due to the variety of countries included in this review. 26 For example, access to intravitreal injections is relatively easy and mostly funded by 27 the government in places like the United Kingdom and Sweden. In contrast lower 28 socioeconomic status was significantly associated with higher non-persistence in a 29 study based out of the United States where insurance status significantly impacted 30 ability to access healthcare. 37 National health policy also plays a role, as different 31 countries may have different rules on the total number of injections that can be 32 subsidized per patient. For example, in Taiwan, patients can be reimbursed for 3 to 7 33 doses in each eye of either ranibizumab or aflibercept over a two-year period by an 34 approved ophthalmologist. Switching between intravitreal agents is also restricted, so 1 the decision on anti-VEGF type needs to be made at the initial application, regardless 2 of treatment outcomes. The unique reimbursement rules and need for approval can 3 therefore influence access and persistence in each country. However, even in 4 countries where the cost of the drug itself may be funded, patients reported some 5 financial stress related to indirect costs for treatment, such as the cost of parking 10 as 6 well productivity losses, with the caregiver needing to take time off work to 7 accompany patients for treatment. 46 Physicians' decision-making, including tolerance to fluid on OCT imaging, may also 10 be influenced by a patient's request to defer treatment, or to influence it. In a recent 11 study comparing real-world clinician versus reading-centre assessment of CNV 12 disease activity, 20% of scans were judged active by the reading centre, but no 13 injections were given. 49 Of these cases, some were assessed by the clinician as 14 chronic degenerative cysts only whilst others were monitored in a 'watch and wait' 15 fashion, reportedly due to patient preference. 16 17 Another unexpected finding from the review was that treatment burden did not rank 18 as highly as expected as a cited cause for treatment non-persistence or non-adherence, 19 accounting for only 7 to 18.9% of all cases. It may be that this terminology, when 20 used in questionnaires, is considered too general or vague for some patients, who 21 prefer to ascribe the difficulties to more specific barriers as 'lack of transport' or 'ill 22 health'. This is reflected in the studies examining perceived barriers to treatment, with 23 patients identifying visit frequency as a significant burden and preferencing regimens 24 with less visits such as the T&E regimen. 45 Patients also reported greater satisfaction 25 with same-day injection protocols when using a PRN regimen, suggesting that 26 treatment burden due to visit frequency was an issue. 44 Phase III trials are currently 27 underway investigating the use of ranibizumab sustained delivery devices. 50,51 Future 28 studies looking at the adherence patterns for these longer-acting devices will be 29 helpful in confirming if perception of treatment burden is similarly reduced. 30 The importance of various risk factors for non-adherence and non-persistence 32 identified in this systematic review however may not necessarily remain static over 33 time. The majority of studies included here assessed patients who were treated prior to 34 1 ranibizumab on a PRN regimen (eTable 3, Supplementary materials) and treatment 2 and/or monitoring was often discontinued by the physician due to perceived lack of 3 disease activity. Although we were not able to study the effects of different injection 4 regimens on rates of adherence and persistence, there is increasing adoption of T&E 5 as the preferred protocol in many countries. Changes to reimbursement criteria and 6 updated regulatory requirements may also influence accessibility of treatment in some 7 countries. In addition, it is likely that capacity constraints will also exert more intentions or willingness to stop treatment may help to identify at risk patients and 34 help to trigger interventions before the event. Further evaluation is required to assess 1 whether providing education for patients and their caretakers at varying time points, 2 for example at baseline prior to commencing treatment, after 3 months and at one year 3 may help to clarify the goals of treatment and encourage persistence into the long 4 term. In addition, text message reminders have been shown to be a simple cost-5 effective tool in the primary care setting to notify patients of upcoming healthcare 6 appointments. This intervention can be easily applied to remind nAMD patients of 7 their next clinic or injection visit and may be an effective solution for those 15% of 8 respondents who reported missed appointments due to forgetfulness. 19 9 10 However, some interventions to improve adherence, whilst seemingly obvious, may 11 prove more challenging to implement. For example, transportation was identified as a 12 key barrier in this review. Though ideally all patients would be provided 13 transportation to clinic appointments, the attitudes and regulations governing this may 14 differ between health care systems. In the US, offering free transport to Medicare 15 patients may be considered an inappropriate inducement to treatment, and therefore, 16 legal review should be considered to understand if it is appropriate. Usually, it is not 17 permitted. In Australia, community volunteer driver programs and Red Cross 18 transport services are currently available initiatives. However, the vast distance 19 between home and treatment location for many rural and regional patients makes this 20 a deterrent. Finally, even in geographically smaller countries such as Sweden, where 21 there is universal free transport to hospitals, some patients still struggle to engage with 22 their treatment, 20 which highlights the multifactorial nature of this problem. 23 The challenges of non-adherence or non-persistence to intravitreal therapy is 25 important and not only isolated to patients with nAMD. It represents a significant 26 problem in patients receiving anti-VEGF injections for other indications such as 27 diabetic macular edema or retinal vein occlusion. 56 However, given the relatively 28 rapid deterioration that can happen in nAMD as compared to macular oedema from 29 other retinovascular conditions, the effect of non-adherence on visual acuity is 30 potentially more damaging and permanent. 29 31 32 Studies have consistently shown that results from clinical trials are not necessarily 33 translatable to the real world, with discrepancies likely due to differences in patient 34 population and underutilization of treatment. This systematic review reveals moderate 1 level evidence to support the finding that high levels of non-adherence and non-2 persistence is observed, particularly in the first 12 months. Indeed, the current novel 3 coronavirus (SARS-CoV-2) pandemic is a concern, as many patients are likely to 4 have been or continue to be non-adherent during this period. The long-term impact on 5 this population is yet to be known. 6 7 In addition, reasons for patient non-adherence and non-persistence to intravitreal 8 injections are complex and multifactorial, though the evidence for specific factors are 9 of low to medium level in quality. Further work is currently underway to standardize 10 and better define these terms. We need effective tools to identify and triage the 11 patients at risk, in order to develop meaningful interventions best suited to the 12 individual patient at the appropriate moment in their treatment course. Current efforts 13 to improve drug duration and efficacy may help to reduce treatment burden, but it is 14 likely coordinated solutions that target other domains, such as transport and access to 15 care, will be required to optimize the long-term visual outcomes for all patients. Table 3 . Reported rates of non-persistence to either treatment or monitoring visits over time (excluding patient death or transfer of care) Age-related macular degeneration. 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ClinicalTrials.gov. Available at: 3 Available from Extension Study for the Port Delivery System With Ranibizumab (Portal) Adherence to therapies in patients 9 with type 2 diabetes Lack of Treatment Persistence and 12 Treatment Nonadherence as Barriers to Glycaemic Control in Patients with Type 13 2 Diabetes Budenz DL. A clinician's guide to the assessment and management of 16 nonadherence in glaucoma Patient-centered communication to assess and enhance patient 18 adherence to glaucoma medication Treatment Efficacy and 20 Compliance in Patients with Diabetic Macular Edema Treated with Ranibizumab 21 in a Real-Life Setting J o u r n a l P r e -p r o o f Table 5 . Summary of findings and certainty of evidence using GRADE CERQual assessment Contributing studies Confidence in the evidence High rates of non-adherence and non-persistence to anti-VEGF treatment is observed, with the onset highest in the first 12 months Low Serious concerns regarding methodological limitations -in particular with regards to assessment of patient perception of response to treatment. Minor concerns regarding coherence across studies. Social isolation and lack of carer or transport were prominent factors for treatment non-adherence or non-persistence. Indirect costs rather than direct costs of treatment were also barriers. High rates of non-adherence and non-persistence to treatment for neovascular age-related macular degeneration are observed in this systematic review. Multiple factors are implicated, however, reporting of strategies to address this remain limited.