Clinical Commentary Review

The Special Challenge of Nonadherence With Sublingual Immunotherapy Bruce G. Bender, PhDa, and John Oppenheimer, MDb

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 hyperlipidemia2 and 25% of children with asthma7 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

a

Department of Pediatrics, National Jewish Health, Denver, Colo 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: [email protected]. 2213-2198/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2014.01.003 b

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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 asthma8 and 39% of 52,039 patients with hypertension10 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 exacerbations 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 patients15 and 82% of Dutch patients16 abandoned immunotherapy before reaching the targeted 3-year mark. In the United States, SLIT treatment abandonment 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 treatments. 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 alone19 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, longterm 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 However, fewer than half of patients on SLIT persist to that point,

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Abbreviations used COPD- chronic obstructive pulmonary disease SLIT- Sublingual immunotherapy

and, the earlier that the discontinuation occurs, the more rapidly any gains are lost. Demonstrated in Figure 1, increasing lengths of SLIT resulted in increasing durations of allergic symptom control, with least sustained benefit seen after only 3 years of treatment. Initially buoyed by patient-reported SLIT adherence of 80% to 90% in clinical trials,22,23 neither researchers nor clinicians have been prepared to guide care when patients are partially adherent or drop out in the first or second year of treatment. Key evidence that might allow for management of incomplete adherence is unavailable. Given the availability of SLIT in Europe for more than 2 decades, a remarkable dearth of data exists, and many questions have yet to be clearly answered. What do patients tell us about their reasons for discontinuation? Is any sustained clinical benefit achieved with prematurely terminated treatment? To what degree and after what minimum treatment interval is a sustained effect seen? Is a need for other medications reduced with partial adherence? What is the impact of intermittent adherence? Does incomplete adherence result in an increase or decrease in adverse effects? What is the impact of incomplete adherence on the cost-benefit profile of SLIT?

Improving SLIT adherence The SLIT evidence base provides little information about how to address poor adherence to SLIT. A single report included an examination of efforts to improve SLIT adherence.24 In this study, 239 patients who were receiving SLIT self-selected to receive an education plan with follow-up telephone calls from a nurse (n ¼ 149) or no intervention (n ¼ 90). Although discontinuation rates were lower in the intervention group (5%) compared with the no intervention group (18%), these results require confirmation in a randomized, controlled study. Clearly, recognition of the need to address SLIT nonadherence opens the way to further investigation of adherence-enhancing strategies. Even without a body of SLIT-specific adherence intervention research, health care providers can adopt strategies generated from research in other chronic health conditions and apply them to improve SLIT adherence. Evidence-based strategies to improve SLIT adherence may include the following strategies. Communicate effectively. Effective communication strategies rest on the importance of listening to and addressing patient concerns, discussing treatment options, allowing the patient a voice in choosing the treatment he or she prefers, and prescribing only when the patient clearly indicates his or her commitment to sustained adherence. When the physician’s goal for immunotherapy does not match the patient’s goal, then adherence is likely to be poor.25 Differences in goals and patient expectations must be discussed and resolved before the treatment plan is finalized.26 Shared decision making is a communication strategy that includes attempts to increase concordance about treatment choices and goals, leads to higher adherence of patients with asthma,27 and is well suited to provider-patient discussions regarding SLIT.

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Provide adequate information. Although results are mixed as to whether basic patient education programs can change behavior in most patients, at a minimum, patient education changes behavior in at least some patients, and other adherence interventions will likely be more effective when patient education is included. Children28 and adults29,30 who received education about their illness and treatment demonstrated modest increases in medication adherence. To help assure improved adherence, patients who begin SLIT must have a thorough understanding of this treatment, including clear and realistic expectations regarding the need for commitment to treatment to achieve potential benefits. Develop a standard follow-up protocol. Some practices adopt a standardized follow-up protocol to help encourage greater adherence to treatment. The adherence protocol can include scheduling regular follow-up appointments both to evaluate symptom control and to reinforce education and review of the patient’s understanding of previously discussed information. Telephone follow-up between clinic appointments is one of the least costly means of maintaining contact with patients, monitoring progress, and reinforcing medication adherence. These telephone calls can be scheduled at standard intervals, particularly in the period immediately after the introduction of SLIT medications. Patients who received telephone calls every two months were more adherent to antihypertensive treatment than a no-call control group.31 Combining telephone calls with letters about their medication further improved adherence in adults with breast cancer.32 A study of patients with various medical and psychiatric conditions revealed that patients attended more clinic visits with telephone prompting and patient reminder letters that provided information about the reason for the appointment.33 Even a relatively simple intervention that consisted of 2 mailings to patients about the importance of bblocker therapy after a heart attack improved adherence by a small but statistically significant amount.30 To prevent discontinuation, follow-up for patients newly on SLIT should be immediate and occur on multiple occasions. Telephone follow-up for patients started on SLIT can be made by any member of the clinic staff, be brief, query medication filling and use, and invite patient questions after a clinic visit. Consider adopting telecommunication technology to reach out to patients. The rapid uptake of information technology across all demographics of the US population has been leveraged to improve treatment adherence and reduce cost. Interactive behavioral change technology includes the use of mobile communication technology and the Worldwide Web to support self-management of chronic health conditions.34 Numerous studies have examined the potential for interactive behavioral change technology, including contacting patients via e-mail,35,36 text messaging,37 interactive voice recognition,38,39 or speech-recognition technology,40,41 to engage and activate patients toward better management of their disease. A review of electronic-reminder randomized trials identified 8 studies that demonstrated that text messages and other forms of electronic reminders significantly increased medication adherence.42 As these technologies evolve and likely become less costly, programs to systemize their use in clinical practice, including their automatic deployment from electronic health records, will become more widely available.43

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FIGURE 1. Mean monthly symptom control scores in patients on (A) 3-year, (B) 4-year, or (C) 5-year treatment protocols. The mean duration of SLIT treatment is indicated by arrows at the bottom. Loss of symptom control was followed by reintroduction of treatment. The asterisks indicate a significant difference versus the control group.

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CONCLUSIONS Studies of SLIT adherence have revealed that a majority of patients will abandon treatment long before full effectiveness is reached. Perhaps because the challenges of SLIT adherence were not anticipated, the available evidence base does not provide direct guidance toward increasing SLIT adherence. Still, lessons from adherence intervention studies in other chronic health conditions can give providers tools and strategies to help improve SLIT adherence. Educating patients and engaging them at regular intervals with standardized follow-up protocols will help. Importantly, thoughtful communication that includes sensitivity to patient concerns and preferences, and a willingness to negotiate treatment goals and plans, is a powerful strategy that can lead to greater adherence and treatment success. Certainly, studies directed specifically at SLIT adherence and potential interventions to improve it are greatly needed. REFERENCES 1. Eaton DK, Kann L, Kinchen S, Shanklin S, Flint KH, Hawkins J, et al. Youth risk behavior surveillance-United States, 2011. MMWR Surveill Summ 2012;61:1-162. 2. Wiegand P, McCombs J, Wang J. Factors of hyperlipidemia medication adherence in a nationwide health plan. Am J Manag Care 2012;18:193-9. 3. Shaw R, Bosworth H. Baseline medication adherence and blood pressure in a 24-month longitudinal hypertension study. J Clin Nurs 2012;21:1401-6. 4. Egede L, Gebregziabher M, Dismuke C, Lynch CP, Axon RN, Zhao Y, et al. Medication nonadherence in diabetes: longitudinal effects on costs and potential cost savings from improvement. Diabetes Care 2012;35:2533-9. 5. Vestbo J, Anderson J, Calverley P, Celli B, Ferguson GT, Jenkins C, et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax 2009;64:939-43. 6. Williams L, Peterson E, Wells K, Ahmedani BK, Kumar R, Burchard EG, et al. Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. J Allergy Clin Immunol 2011;128:1185-91. 7. Krishnan J, Bender B, Wamboldt F, Szefler SJ, Adkinson NF Jr, Zeiger RS, et al. Adherence to inhaled corticosteroids: an ancillary study of the Childhood Asthma Management Program clinical trial. J Allergy Clin Immunol 2011;129:112-8. 8. Bender B, Pedan A, Varasteh L. Adherence and persistence with fluticasone propionate/salmeterol combination therapy. J Allergy Clin Immunol 2006;118: 899-904. 9. Huetsch J, Uman J, Udris E, Au D. Predictors of adherence to inhaled medications among veterans with COPD. J Gen Intern Med 2012;27:1506-12. 10. Evans C, Eurich D, Remillard A, Shevchuk Y, Blackburn D. First-fill medication discontinuations and nonadherence to antihypertensive therapy: an observational study. Am J Hypertens 2012;25:195-203. 11. Penning-van B, Van Herk-Sukel M, Gale R, Lammers J, Herings R. Three-year dispensing patterns with long-acting inhaled drugs, in COPD: a database analysis. Respir Med 2011;105:259-65. 12. Osterberg L, Blaschke T. Adherence to medication. N Eng J Med 2005;353: 487-97. 13. Bosworth H, Granter B, Mendy P, Brindis R, Burkholder R, Czajkowski SM, et al. Medication adherence: a call for action. Am Heart J 2011;162:412-24. 14. National Council on Patient Information and Education. Enhancing prescription medication adherence: a national action plan. 2007. Available from: http:// www.talkabouttrx.org/documents/enhancing.prescription_medicine_adherence .pdf. Accessed December 8, 2013. 15. Claes C, Mittendorf T, Grav von der Schulenburg J. Persistence and frequency of prescriptions of subcutaneous allergen-specific immunotherapy (SCIT) prescribed with the German statutory health insurance. Med Klin (Munich) 2009; 104:536-42. 16. Kiel M, Roder E, Gerth van Wijk R, Al M, Hop W, Rutten-van Molken M. Reallife compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy. J Allergy Clin Immunol 2013;132:353-60. 17. Hsu N, Reisacher W. A comparison of attrition rates in patients undergoing sublingual immunotherapy vs subcutaneous immunotherapy. Int Forum Allergy Rhinol 2012;2:280-4. 18. Stokes S, Quinn J, Sacha J, White K. Adherence to imported fire ant subcutaneous immunotherapy. Ann Allergy Asthma Immunol 2013;110:165-7. 19. Stempel D, Stoloff S, Carranza Rosenzweig J, Stanford R, Ryskina K, Legorreta A. Adherence to asthma controller medication regimens. Respir Med 2005;99:1263-7.

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