Clinical Commentary Review The Special Challenge of Nonadherence With Sublingual Immunotherapy Bruce G. Bender, PhD a , and John Oppenheimer, MD b Denver, Colo; and Rutgers, NJ Patient nonadherence is a problem that impacts all chronic illness treatments. To determine the degree of nonadherence and its impact on treatment effect in sublingual immunotherapy (SLIT), we conducted a systematic review of published research that assessed adherence or tested interventions to improve SLIT adherence. Adherence to SLIT is similar to other long-term therapies. Across studies, 55% to 82% of patients abandoned SLIT before completing the recommended course of therapy. Only 1 study attempted to test an educational intervention to improve SLIT adherence. Composite evidence indicates that 3 to 5 years of sustained SLIT is required for full long-term benefits, but fewer than half of the patients on SLIT persist to that point. Surprisingly little research has addressed the consequence of partial adherence, including implication to its cost-benefit profile or strategies to improve adherence. Lessons from research into treatments of other chronic health conditions suggest several adherence interventions that may be applied to SLIT, including strategic use of communication and education tools, incorporation of standardized follow-up visits, and employment of telecommunication technologies. Ó 2014 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2014;2:152-5) Key words: Sublingual immunotherapy; Adherence Nonadherence is a problem that plagues all chronic illness therapies. Studies have demonstrated that most patients with cardiovascular disease, respiratory disorders, diabetes, and cancer are, to varying degrees, nonadherent with their medication. 1-8 For example, only 35% of adults with hyperlipidemia 2 and 25% of children with asthma 7 demonstrated full adherence to their prescribed medication. Among patients with chronic obstructive pulmonary disease (COPD), long-term adherence with inhaled corticosteroid or long-acting b-agonist medications averaged 19.8% and 25.6%, respectively. 9 Remarkably, many patients simply abandon their treatments altogether. Large administrative and pharmacy database studies have revealed that 59% of 5504 patients with asthma 8 and 39% of 52,039 patients with hyper- tension 10 did not return within a year to refill their medication after an initial dispensing of their prescribed daily medication. Among patients with chronic obstructive pulmonary disease, discontinuation of refills was 86% and 90% in year 2, continuing to 92% and 94% by year 3 for patients on long-acting b-agonist with and without inhaled corticosteroid, respectively. 11 A dose-response relationship can be identified wherein the relative benefit of most chronic illness medications increases as adherence rises. In turn, illness control declines with dwindling adherence. For example, systolic blood pressure increased with decreasing antihypertensive medication, 3 hospitalizations and death increased with decreased COPD medication, 5 and exacer- bations increased with decreased asthma medication use. 6 Further, because declining adherence undermines disease control, it also contributes to increased cost. Although diabetes-related pharmacy costs decreased by 37% with decreasing adherence, these savings were subsequently offset by a 41% higher inpatient cost with an estimated overall cost increase that approached $1 billion. 4 The annual national impact of nonadherence across conditions has been estimated to be a staggering $100 billion to $300 billion dollars in direct and indirect cost. 12-14 IS SUBLINGUAL IMMUNOTHERAPY ADHERENCE ANY DIFFERENT? Not surprisingly, adherence to sublingual immunotherapy (SLIT) is similar to other long-term therapies. Studies have reported that 76% of German patients 15 and 82% of Dutch patients 16 abandoned immunotherapy before reaching the tar- geted 3-year mark. In the United States, SLIT treatment aban- donment rates have ranged from 55% 17 to 65%. 18 Should we be surprised by these dropout rates? If the implicit assumption has been that adherence to SLIT will be optimal because it is a convenient, at-home treatment delivered orally, we have failed to pay attention to the overwhelming evidence from other treat- ments. In the case of asthma, the availability of more convenient medication delivery systems, including oral (eg, montelukast) and combination inhaled medications (eg, fluticasone-samerol) resulted in adherence superior to inhaled corticosteroid alone 19 but still less than 50% for both medication classes. 8,20 Unlike many therapies for chronic conditions in which full benefit is achieved as long as the patient is taking the medication, long- term moderation of the immune system and symptom reduction through SLIT is achieved only by sustained adherence over several years. Composite evidence indicates that 3 to 5 years of sustained SLIT is required for full long-term benefits. 21 How- ever, fewer than half of patients on SLIT persist to that point, a Department of Pediatrics, National Jewish Health, Denver, Colo b Department of Medicine, New Jersey Medical School, Rutgers, NJ No funding was received for this work. Conflicts of interest: B. G. Bender is on the Merck Board; has received research support from GlaxoSmithKline; and has received lecture fees from Merck. J. Oppenheimer is on the ABAI and ACAAI boards; has received consultancy fees from GlaxoSmithKline, Mylan, AstraZeneca, Teva, and Meda; has provided expert witness testimony on the topic of Medicare malpractice; has received research support from AstraZeneca, GlaxoSmithKline, Novartis, and Medimmune. Received for publication January 3, 2014; revised January 16, 2014; accepted for publication January 20, 2014. Corresponding author: Bruce G. Bender, PhD, National Jewish Health, 1400 Jackson St, Denver, CO 80206. E-mail: benderb@njhealth.org. 2213-2198/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.01.003 152