- Top of page
- MATERIALS AND METHODS
Background: The objective was to examine the prevalence and frequency of oral medication nonadherence using a multimethod assessment approach consisting of objective, subjective, and biological data in adolescents with inflammatory bowel disease (IBD).
Methods: Medication adherence was assessed via pill counts, patient/parent interview, and 6-thioguanine nucleotide (6-TGN)/6-methylmercaptopurine nucleotide (6-MMPN) metabolite bioassay in 42 adolescents with IBD. Pediatric gastroenterologists provided disease severity assessments.
Results: The objective nonadherence prevalence was 64% for 6-MP/azathioprine (AZA) and 88% for 5-aminosalicylate (5-ASA) medications, whereas subjective nonadherence prevalence was 10% for 6-MP/AZA and 2% for 5-ASA. The objective nonadherence frequency was 38% for 6-MP/AZA and 49% for 5-ASA medications, and subjective nonadherence frequency was 6% for 6-MP/AZA and 3% for 5-ASA. The bioassay data revealed that only 14% of patients had therapeutic 6-TGN levels.
Conclusions: The results indicate that objectively measured medication nonadherence prevalence is consistent with that observed in other pediatric chronic illness populations, and that objective nonadherence frequency is considerable, with 40%–50% of doses missed by patients. Subjective assessments appeared to overestimate adherence. Bioassay adherence data, while compromised by pharmacokinetic variation, might be useful as a cursory screener for nonadherence with follow-up objective assessment. Nonadherence in 1 medication might also indicate nonadherence in other medications. Clinical implications and future research directions are provided.
Inflammatory bowel disease (IBD) affects ≈71 in 100,000 children and adolescents (43 per 100,000 with Crohn's disease [CD] and 28 per 100,000 with ulcerative colitis [UC]) in the US,1 with roughly one-fourth of all patients diagnosed as children or adolescents (i.e., under 18 years of age). Treatment of IBD can involve several medications with varying regimens, dietary modification, and potentially surgery depending on symptoms, severity of illness, and response to treatment. Patients' adherence to prescribed treatments has significant ramifications for each of these clinical decisions as well as patient morbidity and mortality and cost-effectiveness of care.2–6 The undesirable side effects of some medications (e.g., weight gain, cushingoid appearance, immune suppression) and the complex treatment regimens for IBD patients (e.g., varying dosing schedules and pill quantities for each medication) are likely to disrupt adherence and effective management of this condition.
Research on adherence in IBD is scant and primarily restricted to the adult population. Adult studies have revealed medication nonadherence prevalence rates ranging from 35%–45%.7–9 However, these data are of limited utility when considering nonadherence in children and adolescents, given the complex developmental challenges unique to childhood and adolescence, the maturation of cognitive and behavioral patterns (e.g., health beliefs) that affect self-management, and the sharing of treatment adherence responsibility between children/adolescents and their caregivers.10 Across pediatric chronic illness populations the prevalence of nonadherence is ≈50% in children5 and 65%–75% in adolescents.11 However, only a few studies have examined adherence rates in pediatric IBD, with results indicating nonadherence prevalence estimates ranging from 50%–66%.12–14 Unfortunately, each of these studies utilized different unimodal assessment methods including an unstandardized self-report questionnaire, unstandardized patient/parent interview, and pharmacy record data. Thus, assessment methodology to date has varied with respect to objective versus subjective measurement, target behavior assessed (e.g., consumption of medication, refill of prescription), medication assessed, and method of assessment, resulting in differing nonadherence prevalence estimates and diminished generalizability and validity of data. Moreover, no study in pediatric IBD has examined nonadherence prevalence rates across various measures, and none have reported frequency of nonadherence (i.e., percent of prescribed doses not taken).
Several measures of adherence can potentially be used in pediatric IBD. Behavioral assessments provide a plethora of retrospective and prospective data regarding timing, frequency, and patterns of nonadherence. However, they are limited by potential response bias in self-report measures, mechanical malfunction in electronic monitors, and behavioral manipulation such as discarding pills to influence pill count data.5 Bioassays such as 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine nucleotide (6-MMPN) levels have been suggested as potentially useful adherence markers for 6-mercaptopurine (6-MP)/azathioprine (AZA).15–17 However, their utility is qualified by the fact that they have not been validated against traditional measures of adherence. Moreover, like other bioassays, they are subject to pharmacokinetic variation in absorption, metabolism, and excretion, as well as behavioral manipulation such as “white coat” adherence.5 Despite their limitations in quantifying adherence, bioassays provide key adherence data in that they can confirm ingestion. Although detectable yet nontherapeutic metabolite levels can suggest either nonadherence or pharmacokinetic influence, or both, cases in which both 6-TGN and 6-MMPN levels are subtherapeutic/unquantifiable likely indicate nonadherence; however, this has yet to be demonstrated empirically. Thus, although there is no “gold standard” of adherence assessment, and limitations exist with any measure of adherence, both behavioral and biological measures offer unique data that could be used to better understand nonadherence. Determining the most advantageous approach to adherence assessment is critical to the clinical care of these patients, particularly in light of the relationship between nonadherence and increased disease severity that has been observed in adult IBD.18
Given the paucity of adherence data in pediatric IBD and lack of understanding of how different types of adherence assessments function in this population, the primary aim of this study was to examine objective versus subjective oral medication nonadherence prevalence and frequency in adolescents with IBD. This was conducted using a multimethod assessment battery consisting of objective (i.e., pill counts), subjective (i.e., semistructured clinical interview), and biological (i.e., 6-TGN/6-MMPN assays) measures. Because immunomodulators and antiinflammatory agents are commonly prescribed medications in pediatric IBD, 6-MP/AZA and 5-aminosalicylic acid (5-ASA) were targeted for adherence assessment. These medications are ideal for assessment given the considerably different dosing schedules and quantities of pills per dose. It was hypothesized that nonadherence prevalence in IBD would be comparable to other adolescent chronic illness populations (i.e., 65%–75%),11 and that subjective assessment of nonadherence would yield lower nonadherence (i.e., higher adherence) prevalence and frequency estimates than objective assessment. Due to the lack of extant data regarding the utility of 6-TGN/6-MMPN assays for adherence assessment, we also conducted exploratory analyses to examine prevalence and frequency of nonadherence in the subsample of patients who demonstrated subtherapeutic/unquantifiable 6-TGN/6-MMPN levels.
- Top of page
- MATERIALS AND METHODS
This study is the first to examine both prevalence and frequency of medication nonadherence in pediatric IBD using a multimethod objective and subjective adherence assessment approach with behavioral and biological measures. Consistent with the primary hypothesis, results indicated that nonadherence prevalence was comparable to other adolescent chronic illness populations. In fact, prevalence of nonadherence was slightly higher for 5-ASA medications (i.e., 88%) using pill count data than has been observed in other adolescent populations. This suggests that this group of medications might be particularly difficult for adolescent patients to take regularly as prescribed. Factors that may make adherence to 5-ASA medications challenging include frequent dosing each day and quantity of pills per dose. Nonadherence frequency pill count data indicated that a considerable percentage of both 6-MP/AZA and 5-ASA doses are missed (38% and 49%, respectively). Thus, not only are a majority of IBD patients nonadherent (using <80% as the cutpoint), but ≈40%–50% of medication doses are missed by patients.
Also consistent with our hypotheses, self-report adherence assessment data yielded considerably lower nonadherence (i.e., high adherence) estimates in this sample. While these data likely represent an overestimation of adherence, which is a common problem in adolescents, the comparison of objective and subjective data in this study highlights an important point: although adolescents demonstrate significant nonadherence to medication, they may not accurately perceive the extent of the problem. This discrepancy between subjective and objective adherence represents a salient opportunity and avenue for intervention by health care providers, and underscores the importance of multimethod adherence assessment.
Examination of bioassay data revealed a low percentage of patients with therapeutic 6-TGN levels, which was possibly a function of pharmacokinetic influence. Moreover, these assays did not accurately reflect objectively measured nonadherence. The exception to this was that patients with subtherapeutic/unquantifiable 6-TGN/6-MMPN levels exhibited extreme nonadherence prevalence and frequency. However, this finding is quite preliminary given the small subsample used. Importantly, perhaps the most significant finding of this study was that nonadherence to 1 medication was generalizable to the other medication. This was true for both objective and bioassay assessments in which patients that were nonadherent to 6-MP/AZA were also nonadherent to 5-ASA medications.
These findings have several clinical implications. Adherence should be monitored by patients, families, and practitioners and assessments should be incorporated into routine visits. Unfortunately, patients do not always bring medication to clinic visits for pill counts, leaving clinicians with restricted and less reliable options, such as self-reports or bioassays. The preliminary data from this study suggest that low metabolite values might indicate nonadherence to oral medication, and could potentially be used as a cursory screener for nonadherence. However, suspected nonadherence should always be verified by validated measures of adherence, and patient nonadherence should be normalized and discussed openly and nonjudgmentally with patients and their families. Ideally, an assessment of treatment adherence should include multiple measures to capitalize on the strengths of each and account for their inherent weaknesses. Although self-reported adherence is likely to be overestimated, it may serve as a catalyst to desensitize patients to discussing adherence issues during clinic appointments, and thus might improve the validity of future self-reporting. Finally, these data indicate that adherence to 5-ASA medications might be particularly challenging and should be considered as a target for intervention (e.g., modification of dosing schedule). Nevertheless, a thorough assessment of which treatments pose adherence difficulties and the specific barriers to completing those treatments is necessary for each patient, as specific problem behaviors will vary considerably across patients.
The findings of this study should be considered within the context of several limitations. First, the modest sample size suggests that generalization of these findings should be made with caution. Second, the mean family income in this sample was higher than expected; however, the socioeconomic status of the IBD population is likely negatively skewed compared to other disease populations based on the overrepresentation of Caucasians diagnosed with IBD. Nevertheless, because nonadherence in this sample was similar to that found in other populations, it is unlikely that socioeconomic factors influenced the primary outcome variable in this study. Third, the adherence measures utilized in this study represent assessment tools that can readily be used in clinic or via follow-up telephone contact. Yet more detailed information regarding patterns of nonadherence would likely have been available with the use of electronic monitoring of medication adherence. Finally, the extent to which metabolism of 6-MP/AZA was affected by liver functioning is not known, as these tests were not conducted simultaneously with 6-TGN/6-MMPN assays.
Future research efforts focusing on large-scale examination of nonadherence in this population is needed to establish generalizability and improve assessment methods; this is currently under way. Second, research should examine the value-added contribution of adherence assessment via electronic monitors. The additional data from such an approach would inevitably result in further empirical questions regarding timing and patterns of dosing, and would be useful in developing treatment protocols and calculating optimal timing of such interventions. Additionally, longitudinal approaches to data analyses are needed to examine the predictive utility of various assessments for future adherence behavior. Moreover, statistical and pharmacokinetic modeling of adherence is warranted based on the novelty of this area of research. Finally, studies examining trajectories of adherence during patients' transition from pediatric to adult health care are critical to understanding the changes in disease management behavior and potential points of intervention during this poorly understood developmental period for patients with IBD.