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mHealth for Treatment Adherence (397) mHealth for Treatment Adherence (397) Chronic Disease Self-Management in Childhood and Adolescence (139)

Published on in Vol 7, No 8 (2019): August

Preprints (earlier versions) of this paper are available at https://preprints.jmir.org/preprint/13452, first published .
A Multidimensional Electronic Hydroxyurea Adherence Intervention for Children With Sickle Cell Disease: Single-Arm Before-After Study

A Multidimensional Electronic Hydroxyurea Adherence Intervention for Children With Sickle Cell Disease: Single-Arm Before-After Study

A Multidimensional Electronic Hydroxyurea Adherence Intervention for Children With Sickle Cell Disease: Single-Arm Before-After Study

Authors of this article:

Susan Creary1 Author Orcid Image ;   Deena Chisolm1 Author Orcid Image ;   Joseph Stanek1 Author Orcid Image ;   Jane Hankins2 Author Orcid Image ;   Sarah H O'Brien1 Author Orcid Image
Article Authors Cited by (17) Tweetations (3) Metrics

    Original Paper

    1Nationwide Children's Hospital, The Ohio State University, Columbus, OH, United States

    2St Jude Children's Research Hospital, Memphis, TN, United States

    Corresponding Author:

    Susan Creary, MD, MSc

    Nationwide Children's Hospital

    The Ohio State University

    FOB 3rd Floor

    Columbus, OH, 43205

    United States

    Phone: 1 614 722 3563

    Fax:1 614 722 3559

    Email: susan.creary@nationwidechildrens.org


    Background: Hydroxyurea is a disease-modifying medication for patients with sickle cell disease (SCD). Despite demonstrated efficacy, hydroxyurea nonadherence in clinical practice is common and results in worse health outcomes for nonadherent patients. Mobile Directly Observed Therapy (Mobile DOT) is a pilot-tested, electronic, multidimensional hydroxyurea adherence intervention for children with SCD. Mobile DOT includes sending daily text message reminders to patients to take hydroxyurea, patients recording and sending daily videos that capture their hydroxyurea administrations for the research team to review and track adherence, providing personalized feedback to patients about their adherence, and providing small monetary incentives to patients if they achieve high hydroxyurea adherence.

    Objective: This study aimed to determine if Mobile DOT increases hydroxyurea adherence in children with SCD and to explore its impact on hematologic and clinical outcomes.

    Methods: This was a single-arm, 6-month intervention study of patients with SCD on hydroxyurea who were aged ≤19 years and reported having access to an electronic device. Participants’ hydroxyurea adherence when they received Mobile DOT was compared with their adherence 6 months before and after receiving Mobile DOT. Participants’ medication possession ratio (MPR) was calculated from their pharmacy dispensing records and was used to measure adherence. Laboratory and clinical outcomes were abstracted from participants’ electronic medical records. Infrequently hospitalized patients who received at least 160 days of the intervention were considered to be engaged participants.

    Results: Of 91 patients who were approached, 55 enrolled and 34 engaged with Mobile DOT. The median age of the engaged participants was 10 years (range 2-18.8 years), and 21 (62%, 21/34) participants were male, 28 (82%, 21/34) had hemoglobin SS SCD, and 19 (56%, 19/34) were prescribed hydroxyurea for at least a year before enrollment. With Mobile DOT, engaged participants’ median MPR increased from 61.7% to 84.4% (P<.001) and significantly more (67% vs 30%; P=.002) achieved ≥80% hydroxyurea adherence compared with baseline values. Engaged participants’ mean fetal hemoglobin (HgbF) levels and mean corpuscular volumes (MCV) improved significantly after 6 months of Mobile DOT (P=.04 and P=.001, respectively), but their adherence, HgbF levels, and MCV returned to baseline values during the 6 months after the intervention. Hospitalizations and the clinical outcomes that were measured occurred infrequently during the study. Nonengagement was associated with being female and having a recent SCD complication. In addition, having insufficient electronic data, being unable to quickly complete Mobile DOT each day, and not perceiving that Mobile DOT was beneficial may have further decreased engagement.

    Conclusions: Mobile DOT shows promise as an effective intervention for some children with SCD. Modifications that may improve recruitment, reduce attrition, and increase engagement were identified and could increase the impact that Mobile DOT has on children with SCD.

    Trial Registration: ClinicalTrials.gov NCT02578017; https://clinicaltrials.gov/ct2/show/NCT02578017

    JMIR Mhealth Uhealth 2019;7(8):e13452

    doi:10.2196/13452

    Keywords

    hydroxyurea; children; sickle cell disease; mobile health; mhealth; adherence; textmessaging 


    Sickle cell disease (SCD) is the most common, severe inherited blood disorder. Children with SCD experience substantial morbidity, including frequent vaso-occlusive crisis (VOC) pain and acute chest syndrome (ACS) episodes, stroke, and decreased quality of life [1,2]. Hydroxyurea is a once-daily, Food and Drug Administration–approved, preventative, and disease-modifying medication for children with SCD. Multiple large studies show that hydroxyurea improves quality of life while reducing the frequency of VOC and ACS episodes, hospitalizations, hospital readmissions, and transfusions in children with SCD [3-5]. Despite demonstrated efficacy and safety, hydroxyurea nonadherence is common in clinical practice. Health insurance claims data suggest that only 30% to 50% of children with SCD on hydroxyurea in the United States take it on at least 80% of the days it is prescribed, and this nonadherence is associated with worse clinical outcomes, lower quality of life, and higher costs of care for nonadherent patients [2,6,7].

    Strategies to improve adherence to medications for other chronic diseases include interventions such as directly observed therapy for tuberculosis [8], reminder alerts for hyperlipidemia and hypertension [9], counseling or motivational interviewing for human immunodeficiency virus [10], and incentives or contingency management for diabetes [11]. In children and adolescents with chronic diseases, including those with SCD, electronic devices show promise as useful tools to provide these interventions to improve adherence and disease self-management [12-15]. Single-dimension adherence interventions, however, have inherent limitations. They also show varying levels of success at increasing adherence likely because they are not able to address multiple components of the Health Behavior Model (HBM), the health promotion theory frequently used to explain medication adherence behavior [16]. The HBM proposes that perceived disease severity, susceptibility to disease complications, self-efficacy, costs and benefits of being adherent, and receiving reminder cues are factors that influence adherence. For example, in the context of the HBM, hydroxyurea nonadherence could occur if patients and/or their families do not perceive the long-term health benefits of taking hydroxyurea outweigh the potential risk of experiencing side effects or the length of time that they must take hydroxyurea before its benefits begin to manifest. In addition, for young children with SCD who rely on caregivers to be adherent, nonadherence could result if caregivers do not have the self-efficacy skills to (1) remember to administer the hydroxyurea when it is due, (2) accurately measure the correct dose of hydroxyurea, and/or (3) deliver hydroxyurea to their children if they are uncooperative with administration. Finally, for adolescents with SCD, perceived invulnerability or insusceptibility, which are common during this stage of development, could contribute to hydroxyurea nonadherence and negative health outcomes.

    Therefore, to address multiple HBM constructs that can influence hydroxyurea adherence behavior using devices that most children with SCD report having access to [17], we pilot tested an electronic, multidimensional adherence strategy called Mobile Directly Observed Therapy (Mobile DOT) and published these results in 2014 [18]. Mobile DOT is a hydroxyurea adherence strategy that includes sending daily text message (short message service [SMS]) to patients to remind them to take hydroxyurea, patients recording and sending daily videos that capture their hydroxyurea administrations to the research team to review and track adherence, electronically providing personalized feedback to patients about their adherence, and providing small monetary incentives to patients if they achieve high hydroxyurea adherence. In our pilot work, we found that Mobile DOT was a feasible and acceptable adherence intervention and could achieve ≥90% hydroxyurea adherence in a small cohort of children with SCD. The objectives of this study were to determine if Mobile DOT increases hydroxyurea adherence and to explore its potential impact on hematologic and clinical outcomes in a larger population of children with SCD.


    Study Design, Recruitment, and Participants

    These data were collected as part of an institutional review board–approved study. The details of the Mobile DOT intervention and the protocol for this study were previously published [19]. Briefly, this was a single-arm, cross-over study performed at Nationwide Children’s Hospital (NCH), a large, comprehensive pediatric hospital in Ohio. English-speaking patients with SCD (any genotype) who were aged ≤19 years, prescribed hydroxyurea for at least the previous 180 days, not receiving chronic transfusion therapy, planned to receive care at NCH for the following year, and had (or their legal guardian had) personal daily access to an electronic device (eg, smartphone or tablet) that could receive SMS text message alerts and record and send daily videos were eligible. Electronic device access was confirmed, before enrollment, when the patient successfully submitted a video to the secure Mobile DOT website.

    Patients were sequentially approached to participate when they presented for clinical care, and follow-up study visits were completed during participants’ standard of care hematology visits. Participants’ electronic medical records (EMRs) were used to collect demographic information, laboratory and clinical data, hydroxyurea dispensing pharmacies, and duration of hydroxyurea treatment. Hydroxyurea dosing and monitoring were left to clinicians’ discretion and tracked using the EMR, but institutional standards, derived from published hydroxyurea protocols [20], were available to guide this management.

    There were 3 sequential study periods: baseline, Mobile DOT, and postintervention that were each approximately 180 days. The baseline period was defined as the 180 days before enrollment, the Mobile DOT period started the day following enrollment, and the postintervention period started immediately after the Mobile DOT period. The Mobile DOT and postintervention periods were designed to be 180 days but could vary slightly in length to coordinate participants’ study visits with their standard of care hematology visits. In addition, because hydroxyurea administration that occurs in the hospital setting is highly monitored and includes interventions that are separate from Mobile DOT (eg, all hydroxyurea dose administrations are observed and tracked by a nurse), only participants who completed at least 160 days of the Mobile DOT period and who were hospitalized for fewer than 20 days during this time were considered to be engaged participants. Participants who completed at least 160 days of the postintervention period before their final study visit and were hospitalized for fewer than 20 days during this period were considered to have completed the study.

    Mobile Directly Observed Therapy

    A custom and secure Mobile DOT website to send the alerts and store participants’ videos was built by the research technology team at NCH and run under an Apache Web server (version 2.2.15; Apache Software Foundation), was written in the Perl and JavaScript languages, and was run on a 64-bit CentOS 6.5 Linux operating system. Participants were informed before consenting of the potential risk that videos could potentially be intercepted during transmission to the secure website, but their videos were secure once they were received by the website.

    Alerts

    Participants identified their preferred hydroxyurea administration time and developed their own personalized SMS text message alerts at enrollment. Using a secure Microsoft Exchange mail server, participants and/or their consenting caregivers (if aged <14 years) were sent up to 4 SMS text message alerts to remind them to take hydroxyurea every day.

    Video Directly Observed Therapy

    Participants were instructed to self-record (or have their consenting caregiver record if aged<11 years) their daily hydroxyurea administrations with their electronic device and email these videos as an attachment every day to the secure website for the research team to review. Participants were trained to record continuous videos that allowed for easy participant recognition, a view of their hydroxyurea before and during administration, and a view of their empty mouth after ingestion. Participants who were instructed to temporarily discontinue hydroxyurea by their clinical provider (eg, for myelosuppression) were instructed to continue to submit daily videos, stating this information to be considered adherent during this time. VDOT was not required during hospitalizations. Temporary electronic device access lapses (for up to 5 days for each 60-day segment of the intervention period) were allowed, but to be considered adherent during these lapses, participants had to notify the research team (by email, SMS text message, or voicemail) on each of these days to confirm that they had taken their hydroxyurea.

    A background script on the secure server retrieved the participants’ emails with video attachments. Videos were stored locally on the operating system in a participant directory with restricted access to the research team. Information about the participants, the emails, and videos were stored in a local SQLite database. To ensure that the videos were unique, the research team reviewed all videos to ensure that they represented valid hydroxyurea administration and checked the megabyte size of the videos to ensure variability if there was concern that participants were submitting videos that were not unique. Only 2 research team members who were familiar with the participants were responsible for reviewing and tracking adherence.

    Feedback

    The research team attempted to contact participants (or their consenting caregiver) through SMS text message, email, or telephone when a video was not received to encourage daily hydroxyurea adherence and provide positive feedback when participants achieved the adherence incentive goal.

    Incentives

    Participants were mailed a US $30 gift card if their videos confirmed at least 90% adherence over the past 30 days. A research team member spent approximately 1 min per participant per day to track adherence and send messages when needed.

    Outcome Measures

    Medication Possession Ratio

    MPR is the percentage of days during a given period of time that patients have access to a medication. MPR was the primary adherence measure used because the pharmacy dispensing data needed for this calculation could be retrospectively collected. Previous studies suggest if multiple months of pharmacy dispensing records are used, MPR provides an accurate quantitative estimate of patients’ maximum possible adherence during that time [21-23]. Hydroxyurea dispensing records were requested after the participant completed their participation in the study and from all pharmacies that participants’ self-reported they used and/or were identified in their EMR. Participants’ hydroxyurea MPR was calculated for each study period using the following formula: the number of days that dispensing records confirmed access to hydroxyurea in a study period divided by the total number of days in a study period, multiplied by 100. MPR calculations accounted for hydroxyurea doses that were held or received during any hospitalization and for any prescribed dose adjustments documented in the EMR during the study. Participants’ with a hydroxyurea MPR of ≥80% during a study period were defined as adherent for that period because improved clinical outcomes were seen at this adherence threshold in a randomized pediatric SCD hydroxyurea clinical trial [3,24].

    Video Directly Observed Therapy Adherence

    Observed adherence, either in-person or by video, is a reliable and valid measure of patients’ medication adherence [21]. Engaged participants’ VDOT adherence was calculated using the following formula: the number of days VDOT was completed divided by the total number of days in the Mobile DOT period multiplied by 100. VDOT adherence calculations accounted for days that the research team was notified of device access lapse and for doses received during hospitalizations.

    Laboratory Data

    Large pediatric clinical trials show that hydroxyurea exposure significantly increases fetal hemoglobin (HgbF) production, total hemoglobin (Hgb), and mean corpuscular volume (MCV) and reduces absolute neutrophil counts (ANC) [3,25-27]. In this study, laboratory studies that were obtained during standard of care hematology visits within 40 days of the end of a study period were analyzed. NCH uses Sebia Zone Electrophoresis to reliably quantify HgbF levels [28] and the Sysmex XN-1000, a standard hematology analyzer, to reliably measure Hgb, MCV, and ANC [29].

    Clinical Outcomes

    Multiple pediatric clinical trials confirm that hydroxyurea reduces hospitalizations, erythrocyte transfusions, ACS episodes, and VOC episodes requiring hospitalization [3,30]. These outcomes were abstracted from participants’ EMR during the study.

    Satisfaction Survey

    To measure the amount of time that it took participants to complete Mobile DOT each day, their willingness to continue the intervention without payment, and their satisfaction and perceived effectiveness of the intervention, participants (or the consenting caregivers of participants aged<14 years) completed the 5-point Likert scale Mobile DOT satisfaction survey [18] at the end of their Mobile DOT period or at their withdrawal visit. Participants who withdrew were also asked to provide a reason for withdrawal.

    Study Withdrawal

    Participants who discontinued hydroxyurea moved out of the area or informed the research team that they did not want to continue to participate were immediately withdrawn from the study. The research team also stopped sending SMS text message alerts and attempting to contact participants who did not submit a video or respond to research staff communications for more than 30 consecutive days during the Mobile DOT period. These participants were withdrawn from the study at their next clinic visit.

    Statistical Analysis

    Descriptive statistics were used to describe sample characteristics and report the clinical outcomes, frequency and percentages for qualitative variables, and median and range or mean and standard error for quantitative variables. Nonparametric tests were used to compare baseline characteristics between engaged and nonengaged participants. McNemar test was used to compare proportion of patients who were adherent at baseline and with Mobile DOT. To compare adherence and hematologic measures across the 3 study periods, linear mixed models with Tukey-adjusted pairwise comparisons were used. All P values were 2-sided, and P<.05 was considered statistically significant. Statistical analyses were performed using SAS software, version 9.4 (SAS Institute).


    Study Participants

    Between July 2014 and January 2017, 91 unique prospective participants were approached, 55 enrolled (76% of the planned sample size), 34 engaged with the Mobile DOT intervention, and 29 completed the study (Figure 1). All the participants planned to use a smartphone as their electronic device. None of the patients who declined participation reported privacy concerns as a reason for study refusal. Recruitment ended before enrolling the planned sample size when 97% of the prospective patients had been approached because recruitment would have needed to be extended for multiple months to approach the remaining patients at their standard hematology visits.

    Dispensing records were received for 54 (33 engaged) participants, and these participants were included in the MPR analyses. At baseline, 14 (25%, 14/54) enrolled participants were adherent (MPR ≥80%) to hydroxyurea, and 17 (31%, 17/54) had a hydroxyurea MPR <50%.

    Table 1 shows a comparison of the baseline characteristics between engaged and nonengaged participants. Of the 17 engaged participants who were aged<10 years, 8 (47%) were adherent to hydroxyurea at baseline and 3 (27%) of the 11 nonengaged participants who were aged<10 years were adherent at baseline. In addition, 2 (13%) of the 17 engaged participants who were aged ≥10 years were adherent to hydroxyurea at baseline, and one (10%) of the 10 nonengaged participants who were aged ≥10 years was adherent to hydroxyurea at baseline. Engaged participants received Mobile DOT for a median of 191 days, and those who completed the study were followed for a median of 181 days during the postintervention period. Engaged participants’ median prescribed hydroxyurea dose did not significantly change from baseline to the end of the Mobile DOT period (25.9 mg/kg/day vs 25.8 mg/kg/day; P>.99). Of those who completed the study, 21 (72%) were prescribed a dose that was within 5 mg/kg/day of their baseline dose, but their median prescribed hydroxyurea dose was significantly lower at the end of the postintervention period compared with baseline (23.5 mg/kg/day; P=.004).

    ‎
    Figure 1. Participant flow diagram (Mobile DOT: Mobile Directly Observed Therapy).
    View this figure
    Table 1. Participants’ baseline characteristics.
    CharacteristicsAll (n=55)Nonengaged (n=21)Engaged (n=34)P value
    Median age (years; range)10.0 (2.0-19.0)9.4 (2.7-19.0)10.0 (2.0-18.8).95
    Age (years), n (%).99

    		<1028 (51)11 (52)17 (50)

    		Oct-1722 (40)8 (38)14 (41)

    		≥18523
    Male, n (%)26 (47)5 (234)21 (62).01
    Race, n (%).52

    		Black or African American53 (96)21 (100)32 (94)

    		Biracial202
    Genotype, n (%).93

    		SS47 (856)19 (91)28 (82)

    		SC3 (6)1 (5)2 (6)

    		SB02 (4)1 (5)1 (3)

    		SB+2 (4)0 (0)2 (6)

    		Other (SE)1 (2)0 (0)1 (3)
    Duration of hydroxyurea use, n (%).8

    		6-12 months25 (456)10 (48)15 (44)

    		>12 months30 (55)11 (52)19 (56)
    Indication for hydroxyurea, n (%)

    		Clinical complication53 (96)21 (100)32 (94).52

    		Severe genotype or family requesta4 (7)1 (5)3 (9).99
    Median hydroxyurea dose (mg/kg/d)25.925.925.9.41
    Hydroxyurea MPRb

    		Median, %61.766.761.1.86

    		0%-19%, n312—c

    		20%-39%, n963—

    		40%-59%, n11110—

    		60%-79%, n1798—

    		≥80%, n14410—
    Median hematologic studies

    		Hemoglobin, g/dL9.38.69.4.14

    		MCVd, fl/L90.991.888.2.68

    		Hemoglobin F, %21.117.824.8.07

    		Absolute neutrophil count per µL369047703415.003

    aInitiated hydroxyurea therapy before experiencing a sickle cell disease complication.

    bMedication possession ratio (MPR) could not be calculated for 1 participant because dispensing records were not received.

    cDescriptive data only.

    dMCV: mean corpuscular volume.

    Hydroxyurea Adherence

    Participants’ median hydroxyurea MPR was significantly higher with Mobile DOT compared with baseline, but median postintervention MPR was not significantly different compared with baseline (Figure 2). The proportion of engaged participants that were adherent (MPR ≥80%) to hydroxyurea significantly increased from 30% at baseline to 67% with Mobile DOT (P=.002). In addition, 20 (61%) of the engaged participants increased their MPR by >15% with Mobile DOT compared with their baseline. Median VDOT adherence (88.1%) and MPR adherence (87.8%) for the engaged participants during the Mobile DOT period were not significantly different (P=.99).

    ‎
    Figure 2. Participants’ hydroxyurea MPR adherence during each study period (Mobile DOT: Mobile Directly Observed Therapy; MPR: medication possession ratio).
    View this figure

    Hematologic and Clinical Outcomes

    Engaged participants’ mean MCV and HgbF levels at the end of Mobile DOT were significantly higher than baseline but were not significantly different at the end of postintervention period compared with baseline. Engaged participants’ mean Hgb and ANC did not significantly change throughout the study (Figure 3).

    During the baseline period, 8 participants received at least one erythrocyte transfusion (6 nonengaged vs 2 engaged, P=.04), 11 had at least one ACS episode (8 nonengaged vs 3 engaged, P=.01), and 12 had at least one VOC hospitalization (7 nonengaged vs 5 engaged, P=.18). The cohort experienced a total of 13 ACS episodes and 26 VOC hospitalizations during the baseline period, but 1 participant accounted for 9 of these VOC hospitalizations and was nonengaged during the Mobile DOT period because of continued recurrent VOC hospitalizations. During the Mobile DOT period, 3 engaged participants received at least one erythrocyte transfusion, 2 had at least one ACS episode, and 6 had at least one VOC hospitalization. During the postintervention period, 1 participant required at least one transfusion, 3 had at least one ACS episode, and 3 had at least one VOC hospitalization.

    ‎
    Figure 3. Engaged participants’ (n=34) laboratory studies at the end of each study period (ANC: absolute neutrophil count; Hgb: hemoglobin; MCV: mean corpuscular volume; Mobile DOT: Mobile Directly Observed Therapy).
    View this figure

    Satisfaction Survey

    All the engaged participants and 16 (76%) of the nonengaged participants completed the satisfaction survey. Of the engaged participants, 31 (92%) agreed that they took hydroxyurea more often with Mobile DOT, 34 (100%) agreed that Mobile DOT was easy to use, 30 (88%) agreed that they would be willing to continue Mobile DOT, 19 (56%) agreed that they would be willing to continue Mobile DOT without pay, and 30 (88%) reported they could complete Mobile DOT in less than 3 min each day. Of the nonengaged participants, 9 (56%) agreed that they took hydroxyurea more often with Mobile DOT, 8 (50%) agreed that Mobile DOT was easy to use, 7 (44%) agreed they would be willing to continue Mobile DOT, 5 (31%) agreed that they would be willing to continue Mobile DOT without pay, and 8 (50%) reported that they were able to complete Mobile DOT in less than 3 min each day.


    Hydroxyurea Adherence

    Hydroxyurea nonadherence is common among children with SCD [7,24], and an effective hydroxyurea adherence intervention is needed to improve health outcomes. Overall, our results suggest that Mobile DOT improves hydroxyurea adherence, at least temporarily, in children who engage with the intervention. Of the engaged children, two-thirds achieved 80% or higher MPR adherence with Mobile DOT, which is noteworthy considering many of these children had appreciably lower baseline hydroxyurea adherence. Also, median MPR significantly improved with Mobile DOT, despite including some subjects with less potential to improve their MPR because they had 80% or higher adherence at baseline. Finally, although not all the engaged participants achieved 80% or higher adherence with Mobile DOT, many still incrementally increased their adherence (eg, >15% increase or an additional hydroxyurea dose per week), suggesting that Mobile DOT has the potential to improve adherence for some of the most nonadherent children.

    Hematologic Outcomes

    Our results also showed that engaged participants’ mean MCV and HgbF levels increased during the Mobile DOT period. Given that MCV and HgbF level changes from hydroxyurea exposure typically occur before clinical improvements manifest [30], this could be an early indication that with continued use, Mobile DOT may have potential hematologic and clinical benefits. Although significant Hgb changes were not appreciated, this may be related to the relatively short duration of time that Mobile DOT was provided compared with the time required to see improved Hgb with hydroxyurea [3] and our participants’ relatively high baseline Hgb levels. In addition, 15% of our engaged patients had either Hemoglobin SC, Sβ+, or SE, and past studies suggest that other SCD genotypes may not have the same degree of hematologic response with hydroxyurea compared with those with hemoglobin SS [31,32].

    Similar to other medication adherence interventions [33], participants’ adherence and laboratory improvements declined once the intervention was discontinued. Survey results showed that many engaged participants were willing to continue Mobile DOT beyond 6 months, suggesting that for some, Mobile DOT may be able to be used longer term to sustain adherence. However, short booster sessions or additional interventions may be needed for others when their adherence declines. Laboratory improvements likely returned to baseline because adherence declined but also the median prescribed hydroxyurea dose decreased by the end of the study. Mean ANC did not change during the study to suggest that severe myelosuppression frequently occurred that would have necessitated this decrease. Most participants were also prescribed doses at the end of the study that were similar to their baseline doses. We, therefore, suspect this decrease was because many participants were growing children and the hydroxyurea protocol [20] and institutional guidelines do not provide guidance about how frequently to increase hydroxyurea to account for weight gain from growth.

    Clinical Outcomes

    Future studies are needed to definitively determine if Mobile DOT reduces erythrocyte transfusions, hospitalizations, and ACS and VOC episodes because these events occurred infrequently at baseline and participants were followed for a relatively short period of time. To limit underestimating the benefit of effective adherence interventions, future studies should also measure their impact on preventing other patient-reported and costly outcomes, such as VOC episodes, that do not result in hospitalization [34] and stroke [35] that may be ameliorated or prevented with hydroxyurea.

    Limitations

    Several limitations must be considered when interpreting our results. First, despite approaching almost all the eligible patients at NCH, we were unable to enroll our projected sample size [19]. This occurred because we anticipated that more patients at NCH were going to initiate hydroxyurea and become eligible than actually did and because some patients perceived the intervention as too burdensome. These findings underscore the need for interventions, such as shared decision-making tools [36], to increase hydroxyurea acceptance and add to the existing literature that suggests that the time and burden to participate in clinical studies for patients with SCD are prohibitive [37]. In the future, we plan to recruit patients outside of the clinical care setting to avoid approaching patients when they may be overwhelmed by other aspects of their SCD care. This strategy could also increase the number of nonadherent patients that are recruited because clinic nonadherence is associated with hydroxyurea nonadherence [38].

    Second, only two-thirds of the enrolled participants remained engaged with Mobile DOT. As only those who engaged improved their adherence, it is possible that the factors that promoted engagement may have contributed to the observed adherence gains. Therefore, identifying these mediating factors is paramount to increasing the impact that this and other adherence interventions may have on children with SCD. For example, our results suggest that nonengaged participants were more likely to be female and have experienced a recent SCD complication (eg, erythrocyte transfusion and/or ACS episode) compared with engaged participants. The small sample size and small number of clinical complications that occurred during the study limit the ability to definitively determine if these factors influence engagement, if they were related to an unmeasured moderating factor, or if they were merely a random finding observed in this sample. In addition, consistent with the literature that suggests widespread electronic device ownership among African Americans [39], including children with SCD [13], only 3 patients reported that not owning a device prevented them from participating or led to their study withdrawal. However, increasing literature suggests that having an insufficient data plan or inconsistent access to Wi-Fi are common among minority populations [40] and could explain why multiple participants became nonengaged and stopped submitting videos or responding to the research team shortly after they enrolled. Although providing devices and cellular data could potentially increase enrollment and engagement with electronic health interventions and ensure consistent intervention delivery, this could also add significant costs that may limit intervention sustainability and use in clinical practice. Finally, although our study suggests Mobile DOT increases hydroxyurea adherence, it is possible that the Hawthorne effect may have also contributed because participants were aware their adherence was going to be closely monitored.

    Participant Feedback

    Participants’ feedback from this study provides insights into modifications that may make this and other adherence interventions more engaging, reduce attrition, and increase adherence in future studies. First, changing the frequency that medication reminders alerts are provided could reduce alert fatigue. In addition, providing feedback that notifies participants how their adherence compares with their previous adherence and with others’ could influence participants’ perception of the intervention. Incentives may be needed to reward both high adherence and incremental adherence improvements to encourage the most nonadherent participants to continue to engage with the intervention. Finally, for multidimensional interventions, quantifying each component’s impact on adherence could identify if components need to be eliminated or optimized or if additional components, such as gamification, may be needed because they might promote engagement with the entire intervention [41].

    MPR was used to measure hydroxyurea adherence in this study. Although the medication event monitor system caps are considered the gold standard adherence measure [42], these devices were not used in this study because they are not compatible with liquid hydroxyurea formulations, which are commonly used in young children. It is important to note, however, that MPR only measures access to medication and not actual medication administration and can also be unreliable if dispensing reports are inaccurate or incomplete [21]. Engaged participants’ hydroxyurea adherence by MPR and VDOT were similar in this study, but for patients who may have accumulated a supply of hydroxyurea from past prescriptions, MPR may underestimate adherence. Ultimately, studies that validate hydroxyurea adherence measures are needed to accurately identify nonadherent children who could benefit from an adherence intervention. Furthermore, other hydroxyurea adherence interventions are under study, including an electronic alert intervention [43] and a community health care worker intervention [44], and show feasibility, and valid measures will be needed to determine which intervention is most effective.

    Finally, systematic reviews suggest there are insufficient data to determine if mobile health interventions, such as Mobile DOT, are cost-effective [45,46]. Although an increasing number of insurers are already providing financial incentives to their members to encourage healthy behaviors [47], to employ insurers to provide this health behavior intervention in clinical practice, future studies will need to evaluate if it is economically feasible and sustainable. We acknowledge that the cost to improve hydroxyurea adherence may be significant, considering poor adherence is difficult to improve and sustain. However, the cost to provide this intervention could be reduced if technology improvements reduce the time and resources required for implementation and if it is reserved for patients with adherence challenges. Ultimately, we suspect that because SCD is a chronic disease that results in costly complications that are reduced with effective hydroxyurea use [48], even relatively costly adherence interventions may still be implementable, and perhaps cost-effective, in clinical practice.

    Conclusions

    In conclusion, we demonstrate improved 6-month hydroxyurea adherence, MCV, and HgbF level among children with SCD who engaged with an electronic, multidimensional hydroxyurea adherence intervention. Future studies that determine how to increase patient engagement with hydroxyurea adherence interventions, how to sustain improved adherence, and how these interventions impact the outcomes of children with SCD are warranted. If successful, they may be generalizable to improve medication adherence and outcomes of other chronically ill populations.

    Acknowledgments

    SC was supported by the National Heart Lung and Blood Institute 5K23HL127303. The content is the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    Conflicts of Interest

    None declared.

    1. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994 Jun 9;330(23):1639-1644. [CrossRef] [Medline]
    2. Badawy SM, Thompson AA, Lai J, Penedo FJ, Rychlik K, Liem RI. Health-related quality of life and adherence to hydroxyurea in adolescents and young adults with sickle cell disease. Pediatr Blood Cancer 2017 Dec;64(6). [CrossRef] [Medline]
    3. Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, BABY HUG Investigators. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011 May 14;377(9778):1663-1672 [FREE Full text] [CrossRef] [Medline]
    4. Thornburg CD, Calatroni A, Panepinto JA. Differences in health-related quality of life in children with sickle cell disease receiving hydroxyurea. J Pediatr Hematol Oncol 2011 May;33(4):251-254 [FREE Full text] [CrossRef] [Medline]
    5. Zhou J, Han J, Nutescu EA, Gordeuk VR, Saraf SL, Calip GS. Hydroxycarbamide adherence and cumulative dose associated with hospital readmission in sickle cell disease: a 6-year population-based cohort study. Br J Haematol 2018 Dec;182(2):259-270 [FREE Full text] [CrossRef] [Medline]
    6. Thornburg CD, Calatroni A, Telen M, Kemper AR. Adherence to hydroxyurea therapy in children with sickle cell anemia. J Pediatr 2010 Mar;156(3):415-419 [FREE Full text] [CrossRef] [Medline]
    7. Candrilli SD, O'Brien SH, Ware RE, Nahata MC, Seiber EE, Balkrishnan R. Hydroxyurea adherence and associated outcomes among Medicaid enrollees with sickle cell disease. Am J Hematol 2011 Mar;86(3):273-277 [FREE Full text] [CrossRef] [Medline]
    8. Iseman MD, Cohn DL, Sbarbaro JA. Directly observed treatment of tuberculosis. We can't afford not to try it. N Engl J Med 1993 Feb 25;328(8):576-578. [CrossRef] [Medline]
    9. Chapman RH, Ferrufino CP, Kowal SL, Classi P, Roberts CS. The cost and effectiveness of adherence-improving interventions for antihypertensive and lipid-lowering drugs*. Int J Clin Pract 2010 Jan;64(2):169-181. [CrossRef] [Medline]
    10. Binford MC, Kahana SY, Altice FL. A systematic review of antiretroviral adherence interventions for HIV-infected people who use drugs. Curr HIV/AIDS Rep 2012 Dec;9(4):287-312 [FREE Full text] [CrossRef] [Medline]
    11. Stanger C, Ryan SR, Delhey LM, Thrailkill K, Li Z, Li Z, et al. A multicomponent motivational intervention to improve adherence among adolescents with poorly controlled type 1 diabetes: a pilot study. J Pediatr Psychol 2013 Jul;38(6):629-637 [FREE Full text] [CrossRef] [Medline]
    12. Majeed-Ariss R, Baildam E, Campbell M, Chieng A, Fallon D, Hall A, et al. Apps and adolescents: a systematic review of adolescents' use of mobile phone and tablet apps that support personal management of their chronic or long-term physical conditions. J Med Internet Res 2015 Dec 23;17(12):e287 [FREE Full text] [CrossRef] [Medline]
    13. Badawy SM, Cronin RM, Hankins J, Crosby L, DeBaun M, Thompson AA, et al. Patient-centered ehealth interventions for children, adolescents, and adults with sickle cell disease: systematic review. J Med Internet Res 2018 Dec 19;20(7):e10940 [FREE Full text] [CrossRef] [Medline]
    14. Thakkar J, Kurup R, Laba TL, Santo K, Thiagalingam A, Rodgers A, et al. Mobile telephone text messaging for medication adherence in chronic disease: a meta-analysis. JAMA Intern Med 2016 Mar;176(3):340-349. [CrossRef] [Medline]
    15. Badawy SM, Barrera L, Sinno MG, Kaviany S, O'Dwyer LC, Kuhns LM. Text messaging and mobile phone apps as interventions to improve adherence in adolescents with chronic health conditions: a systematic review. JMIR Mhealth Uhealth 2017 May 15;5(5):e66 [FREE Full text] [CrossRef] [Medline]
    16. Clark NM, Houle CR. Theoretical models and strategies for improving adherence and disease management. In: Shumaker SA, Schron EB, Ockene JK, McBee WL, editors. The Handbook of Health Behavior Change. New York: Springer Publishing; 1998:5-32.
    17. Badawy SM, Thompson AA, Liem RI. Technology access and smartphone app preferences for medication adherence in adolescents and young adults with sickle cell disease. Pediatr Blood Cancer 2016 May;63(5):848-852. [CrossRef] [Medline]
    18. Creary SE, Gladwin MT, Byrne M, Hildesheim M, Krishnamurti L. A pilot study of electronic directly observed therapy to improve hydroxyurea adherence in pediatric patients with sickle-cell disease. Pediatr Blood Cancer 2014 Jun;61(6):1068-1073. [CrossRef] [Medline]
    19. Creary S, Chisolm DJ, O'Brien SH. ENHANCE-(Electronic Hydroxyurea Adherence): a protocol to increase hydroxyurea adherence in patients with sickle cell disease. JMIR Res Protoc 2016 Oct 3;5(4):e193 [FREE Full text] [CrossRef] [Medline]
    20. Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. J Am Med Assoc 2014 Sep 10;312(10):1033-1048. [CrossRef] [Medline]
    21. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005 Aug 4;353(5):487-497. [CrossRef] [Medline]
    22. Johnston JM, Pennypacker HS. Strategies and Tactics of Behavioral Research. New York: Routledge; 2009.
    23. Andrade SE, Kahler KH, Frech F, Chan KA. Methods for evaluation of medication adherence and persistence using automated databases. Pharmacoepidemiol Drug Saf 2006 Aug;15(8):565-74; discussion 575. [CrossRef] [Medline]
    24. Thornburg CD, Rogers ZR, Jeng MR, Rana SR, Iyer RV, Faughnan L, BABY HUG Investigators. Adherence to study medication and visits: data from the BABY HUG trial. Pediatr Blood Cancer 2010 Feb;54(2):260-264 [FREE Full text] [CrossRef] [Medline]
    25. Ware RE, Eggleston B, Redding-Lallinger R, Wang WC, Smith-Whitley K, Daeschner C, et al. Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy. Blood 2002 Jan 1;99(1):10-14 [FREE Full text] [CrossRef] [Medline]
    26. Cokic VP, Smith RD, Beleslin-Cokic BB, Njoroge JM, Miller JL, Gladwin MT, et al. Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J Clin Invest 2003 Jan;111(2):231-239 [FREE Full text] [CrossRef] [Medline]
    27. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N Engl J Med 1995 May 18;332(20):1317-1322. [CrossRef] [Medline]
    28. Greene DN, Pyle AL, Chang JS, Hoke C, Lorey T. Comparison of Sebia capillarys flex capillary electrophoresis with the BioRad variant II high pressure liquid chromatography in the evaluation of hemoglobinopathies. Clin Chim Acta 2012 Aug 16;413(15-16):1232-1238. [CrossRef] [Medline]
    29. Becker P, Fenneteau O, da Costa L. Performance evaluation of the Sysmex XN-1000 hematology analyzer in assessment of the white blood cell count differential in pediatric specimens. Int J Lab Hematol 2016 Feb;38(1):54-63. [CrossRef] [Medline]
    30. Estepp JH, Smeltzer MP, Kang G, Li C, Wang WC, Abrams C, et al. A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy. Am J Hematol 2017 Dec;92(12):1333-1339 [FREE Full text] [CrossRef] [Medline]
    31. Zimmerman SA, Schultz WH, Davis JS, Pickens CV, Mortier NA, Howard TA, et al. Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 2004 Mar 15;103(6):2039-2045 [FREE Full text] [CrossRef] [Medline]
    32. Luchtman-Jones L, Pressel S, Hilliard L, Brown RC, Smith MG, Thompson AA, et al. Effects of hydroxyurea treatment for patients with hemoglobin SC disease. Am J Hematol 2016 Feb;91(2):238-242 [FREE Full text] [CrossRef] [Medline]
    33. Berg KM, Litwin AH, Li X, Heo M, Arnsten JH. Lack of sustained improvement in adherence or viral load following a directly observed antiretroviral therapy intervention. Clin Infect Dis 2011 Nov;53(9):936-943 [FREE Full text] [CrossRef] [Medline]
    34. Smith WR, Ballas SK, McCarthy WF, Bauserman RL, Swerdlow PS, Steinberg MH, Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. The association between hydroxyurea treatment and pain intensity, analgesic use, and utilization in ambulatory sickle cell anemia patients. Pain Med 2011 May;12(5):697-705. [CrossRef] [Medline]
    35. Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD with transfusions changing to hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet 2016 Feb 13;387(10019):661-670 [FREE Full text] [CrossRef] [Medline]
    36. Crosby LE, Shook LM, Ware RE, Brinkman WB. Shared decision making for hydroxyurea treatment initiation in children with sickle cell anemia. Pediatr Blood Cancer 2015 Dec;62(2):184-185 [FREE Full text] [CrossRef] [Medline]
    37. Lebensburger JD, Sidonio RF, Debaun MR, Safford MM, Howard TH, Scarinci IC. Exploring barriers and facilitators to clinical trial enrollment in the context of sickle cell anemia and hydroxyurea. Pediatr Blood Cancer 2013 Aug;60(8):1333-1337 [FREE Full text] [CrossRef] [Medline]
    38. Creary SE, O'Brien SH, Stanek J, Hankins JS, Garee A, Ball KR, et al. A retrospective review to determine if children with sickle cell disease receive hydroxyurea monitoring. Pediatr Qual Saf 2017;2(3):e024 [FREE Full text] [Medline]
    39. Horrigan J. Pew Research Center. 2009. Wireless Internet Use   URL: http://pewinternet.org/Reports/2009/12-Wireless-Internet-Use.aspx
    40. Smith A. Pew Research Center. 2014. African Americans and Technology Use: A Demographic Portrait   URL: http:/​/www.​pewresearch.org/​wp-content/​uploads/​sites/​9/​2014/​01/​African-Americans-and-Technology-Use.​pdf
    41. Johnson D, Deterding S, Kuhn K, Staneva A, Stoyanov S, Hides L. Gamification for health and wellbeing: a systematic review of the literature. Internet Interv 2016 Nov;6:89-106 [FREE Full text] [CrossRef] [Medline]
    42. Ingerski LM, Hente EA, Modi AC, Hommel KA. Electronic measurement of medication adherence in pediatric chronic illness: a review of measures. J Pediatr 2011 Oct;159(4):528-534 [FREE Full text] [CrossRef] [Medline]
    43. Estepp JH, Winter B, Johnson M, Smeltzer MP, Howard SC, Hankins JS. Improved hydroxyurea effect with the use of text messaging in children with sickle cell anemia. Pediatr Blood Cancer 2014 Nov;61(11):2031-2036. [CrossRef] [Medline]
    44. Green NS, Manwani D, Matos S, Hicks A, Soto L, Castillo Y, et al. Randomized feasibility trial to improve hydroxyurea adherence in youth ages 10-18 years through community health workers: the HABIT study. Pediatr Blood Cancer 2017 Dec;64(12) [FREE Full text] [CrossRef] [Medline]
    45. Iribarren SJ, Cato K, Falzon L, Stone PW. What is the economic evidence for mhealth? A systematic review of economic evaluations of mhealth solutions. PLoS One 2017;12(2):e0170581 [FREE Full text] [CrossRef] [Medline]
    46. Badawy SM, Kuhns LM. Economic evaluation of text-messaging and smartphone-based interventions to improve medication adherence in adolescents with chronic health conditions: a systematic review. JMIR Mhealth Uhealth 2016 Oct 25;4(4):e121 [FREE Full text] [CrossRef] [Medline]
    47. Loewenstein G, Asch DA, Volpp KG. Behavioral economics holds potential to deliver better results for patients, insurers, and employers. Health Aff (Millwood) 2013 Jul;32(7):1244-1250. [CrossRef] [Medline]
    48. Wang WC, Oyeku SO, Luo Z, Boulet SL, Miller ST, Casella JF, BABY HUG Investigators. Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia. Pediatrics 2013 Oct;132(4):677-683 [FREE Full text] [CrossRef] [Medline]

    ‎
    ACS: acute chest syndrome
    ANC: absolute neutrophil count
    EMR: electronic medical record
    HgbF: fetal hemoglobin
    Hgb: total hemoglobin
    HBM: Health Behavior Model
    MCV: mean corpuscular volume
    MPR: medication possession ratio
    Mobile DOT: Mobile Directly Observed Therapy
    NCH: Nationwide Children’s Hospital
    SCD: sickle cell disease
    SMS: short message service
    VOC: vaso-occlusive crisis

    Edited by G Eysenbach; submitted 21.01.19; peer-reviewed by N Shah, NA Duncan, S Badawy; comments to author 14.03.19; revised version received 19.04.19; accepted 23.04.19; published 08.08.19

    Copyright

    ©Susan Creary, Deena Chisolm, Joseph Stanek, Jane Hankins, Sarah H O'Brien. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 08.08.2019.

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