Using Electronic Monitoring Devices to Assess Medication Adherence: a Research Methods Framework.

While electronic adherence monitoring devices (EAMDs) are the preferred and most objective medication adherence measurement strategy for many populations and research questions, there is no comprehensive methodological framework for EAMD use. We synthesize recommendations from experts in adherence science and the scientific literature to create a temporal framework of EAMD research methods. The goal of this framework is to provide a step-by-step guide that will enable researchers to design, prepare, implement, and clean data from rigorous, high-quality studies using EAMDs to assess adherence. Resources including a checklist of methodological considerations and example protocols have been created to assist readers in using this framework.

Experience with antiretroviral electronic adherence monitoring among young African American men who have sex with men living with HIV: findings to inform a triaged real-time alert intervention.

We performed a pilot study among young African-American men who have sex with men (AAMSM) of real-time electronic adherence monitoring (EAM) in Chicago to explore acceptability and feasibility of EAM and to inform intervention development. We recruited 40 young AAMSM living with HIV on ART to participate in up to 3 months of monitoring with the Wisepill device. Participants were interviewed at baseline, in response to the first true adjudicated 1-dose, 3-day, and 7-day misses, and at the end of monitoring. Reasons for missing doses and the acceptability and feasibility of electronic monitoring were assessed using mixed methods. The median participant observation time was 90 days (N = 40). For 21 participants with 90 days of follow-up, <90% and <80% adherence occurred in 82% and 79%, respectively in at least one of their monitored months (n = 63 monitored months). The participants generally found the proposed intervention acceptable and useful. Although seven participants said the device attracted attention, none said it led to disclosure of their HIV status. This study found real-time EAM to be generally acceptable and feasible among YAAMSM living with HIV in Chicago. Future work will develop a triaged real-time EAM intervention including text alerts following detection of nonadherence.

Actionable Adherence Monitoring: Technological Methods to Monitor and Support Adherence to Antiretroviral Therapy.

PURPOSE OF REVIEW: Current digital technologies are being used for "actionable adherence monitoring"; that is, technologies that can be used to identify episodes of non-adherence to ART in a timely manner such that tailored interventions based on adherence data can be provided when and where they are needed most. RECENT FINDINGS: Current digital communication technologies used to monitor ART adherence include electronic adherence monitors (EAMs), digital ingestion monitors, cellular phones, and electronic pharmacy refill tracking systems. Currently available real-time adherence monitoring approaches based on cellular technology allow for the delivery of interventions precisely when and where they are needed. Such technology can potentially enable significant efficiency of care delivery and impact on adherence and associated clinical outcomes. Standard digital advances, such as automated reminders in EAM and electronic pharmacy records, may also achieve improvements with relatively lower cost and easier implementation. Future research is needed to improve the functionality of these approaches, with attention paid to system-level issues through implementation science, as well as acceptability and ethical considerations at the individual level.

Ethical Questions in Medical Electronic Adherence Monitoring.

Electronic adherence monitors (EAMs) record and report an array of health behaviors, ranging from taking daily medications to wearing medical devices. EAMs are utilized in research worldwide and are being investigated for clinical use. However, there is also growing popular concern about the extent to which electronic devices may be used to monitor individuals, including allegations in the media that EAMs represent a move towards "Big Brother" in medicine. Here, we highlight the unique benefits as well as the potential ethical challenges that electronic adherence monitoring generates. These challenges surround autonomy, privacy and confidentiality, trust, and ancillary care obligations. We describe key questions within each of these domains that warrant further investigation, and present potential solutions to many of the concerns raised.

Can Short-Term Use of Electronic Patient Adherence Monitoring Devices Improve Adherence in Patients Failing Second-Line Antiretroviral Therapy? Evidence from a Pilot Study in Johannesburg, South Africa.

High levels of adherence are required to achieve the full benefit of ART. We assess the effectiveness of electronic adherence monitoring devices among patients failing second-line ART, as measured by viral load suppression. Cohort study of Wisepill™ real-time adherence monitoring in addition to intensified adherence counselling over 3 months in adults with a viral load ≥400 copies/ml on second-line ART in Johannesburg, South Africa between August 2013 and January 2014. Patients were sent SMS reminders upon missing a scheduled dose. We compared outcomes to earlier historical cohorts receiving either intensified adherence counselling or adherence counselling alone. Overall, 63 % of the participants (31/49) took >80 % of their prescribed medication; this dropped from 76 to 53 and 49 % at 1, 2 and 3 months post-enrolment respectively. Compared to those with good adherence (>80 %), participants with poor adherence (≤80 %) had a higher risk for a subsequently elevated viral load ≥400 copies/ml (relative risk (RR) 1.47 95 % CI 0.97-2.23). Participants found the intervention "acceptable and useful" but by 6 months after eligibility they were only slightly more likely to be alive, in care and virally suppressed compared to those who received intensified adherence counselling (44.9 vs. 38.5 %; RR 1.19; 95 % CI 0.85-1.67) or adherence counselling alone (44.9 vs. 40.9 %; RR 1.12; 95 % CI 0.81-1.56). In patients with an elevated viral load on second-line ART electronic adherence monitoring was associated with a modest, but not significant, improvement in viral suppression.

Cell Phone-Based and Adherence Device Technologies for HIV Care and Treatment in Resource-Limited Settings: Recent Advances.

Numerous cell phone-based and adherence monitoring technologies have been developed to address barriers to effective HIV prevention, testing, and treatment. Because most people living with HIV and AIDS reside in resource-limited settings (RLS), it is important to understand the development and use of these technologies in RLS. Recent research on cell phone-based technologies has focused on HIV education, linkage to and retention in care, disease tracking, and antiretroviral therapy adherence reminders. Advances in adherence devices have focused on real-time adherence monitors, which have been used for both antiretroviral therapy and pre-exposure prophylaxis. Real-time monitoring has recently been combined with cell phone-based technologies to create real-time adherence interventions using short message service (SMS). New developments in adherence technologies are exploring ingestion monitoring and metabolite detection to confirm adherence. This article provides an overview of recent advances in these two families of technologies and includes research on their acceptability and cost-effectiveness when available. It additionally outlines key challenges and needed research as use of these technologies continues to expand and evolve.

The differential impact of a 6-versus 12-month pharmacist-led interprofessional medication adherence program on medication adherence in patients with diabetic kidney disease: the randomized PANDIA-IRIS study.

Background: For every 100 patients with diabetes, 40 will develop diabetic kidney disease (DKD) over time. This diabetes complication may be partly due to poor adherence to their prescribed medications. In this study, we aimed to evaluate the differential impact of a 6- versus 12-month pharmacist-led interprofessional medication adherence program (IMAP) on the components of adherence (i.e., implementation and discontinuation) in patients with DKD, during and after the intervention. Methods: All included patients benefited from the IMAP, which consists in face-to-face regular motivational interviews between the patient and the pharmacist based on the adherence feedback from electronic monitors (EMs), in which the prescribed treatments were delivered. Adherence reports were available to prescribers during the intervention period. Patients were randomized 1:1 into two parallel arms: a 12-month IMAP intervention in group A versus a 6-month intervention in group B. Adherence was monitored continuously for 24 months post-inclusion during the consecutive intervention and follow-up phases. In the follow-up phase post-intervention, EM data were blinded. Blood pressure was measured by the pharmacist at each visit. The repeated measures of daily patient medication intake outcomes (1/0) to antidiabetics, antihypertensive drugs, and statins were modeled longitudinally using the generalized estimated equation in both groups and in both the intervention and the follow-up phases. Results: EM data of 72 patients were analyzed (34 in group A and 38 in group B). Patient implementation to antidiabetics and antihypertensive drugs increased during the IMAP intervention phase and decreased progressively during the follow-up period. At 12 months, implementation to antidiabetics was statistically higher in group A versus group B (93.8% versus 86.8%; Δ 7.0%, 95% CI: 5.7%; 8.3%); implementation to antihypertensive drugs was also higher in group A versus B (97.9% versus 92.1%; Δ 5.8%, 95% CI: 4.8%; 6.7%). At 24 months, implementation to antidiabetics and antihypertensive drugs remained higher in group A versus B (for antidiabetics: 88.6% versus 85.6%; Δ 3.0%, 95% CI: 1.7%; 4.4% and for antihypertensive drugs: 94.4% versus 85.9%; Δ 8.5%, 95% CI: 6.6%; 10.7%). No difference in pharmacy-based blood pressure was observed between groups. Implementation to statins was comparable at each time point between groups. Three patients discontinued at least one treatment; they were all in group B. In total, 46% (16/35) of patients in the 12-month intervention versus 37% (14/38) of patients in the 6-month intervention left the study during the intervention phase, mainly due to personal reasons. Conclusion: The IMAP improves adherence to chronic medications in patients with DKD. The longer the patients benefit from the intervention, the more the implementation increases over time, and the more the effect lasts after the end of the intervention. These data suggest that a 12-month rather than a 6-month program should be provided as a standard of care to support medication adherence in this population. The impact on clinical outcomes needs to be demonstrated. Clinical Trial Registration: Clinicaltrials.gov, identifier NCT04190251_PANDIA IRIS.

Using a Semiautomated Procedure (CleanADHdata.R Script) to Clean Electronic Adherence Monitoring Data: Tutorial.

BACKGROUND: Patient adherence to medications can be assessed using interactive digital health technologies such as electronic monitors (EMs). Changes in treatment regimens and deviations from EM use over time must be characterized to establish the actual level of medication adherence. OBJECTIVE: We developed the computer script CleanADHdata.R to clean raw EM adherence data, and this tutorial is a guide for users. METHODS: In addition to raw EM data, we collected adherence start and stop monitoring dates and identified the prescribed regimens, the expected number of EM openings per day based on the prescribed regimen, EM use deviations, and patients' demographic data. The script formats the data longitudinally and calculates each day's medication implementation. RESULTS: We provided a simulated data set for 10 patients, for which 15 EMs were used over a median period of 187 (IQR 135-342) days. The median patient implementation before and after EM raw data cleaning was 83.3% (IQR 71.5%-93.9%) and 97.3% (IQR 95.8%-97.6%), respectively (Δ+14%). This difference is substantial enough to consider EM data cleaning to be capable of avoiding data misinterpretation and providing a cleaned data set for the adherence analysis in terms of implementation and persistence. CONCLUSIONS: The CleanADHdata.R script is a semiautomated procedure that increases standardization and reproducibility. This script has broader applicability within the realm of digital health, as it can be used to clean adherence data collected with diverse digital technologies.

Protocol for an evaluation of adherence monitoring and support interventions among people initiating antiretroviral therapy in Cape Town, South Africa-a multiphase optimization strategy (MOST) approach using a fractional factorial design.

BACKGROUND: South Africa bears a large HIV burden with 7.8 million people with HIV (PWH). However, due to suboptimal antiretroviral therapy (ART) adherence and retention in care, only 66% of PWH in South Africa are virally suppressed. Standard care only allows for suboptimal adherence detection when routine testing indicates unsuppressed virus. Several adherence interventions are known to improve HIV outcomes, yet few are implemented in routinely due to the resources required. Therefore, determining scalable evidence-based adherence support interventions for resource-limited settings (RLS) is a priority. The multiphase optimization strategy (MOST) framework allows for simultaneous evaluation of multiple intervention components and their interactions. We propose to use MOST to identify the intervention combination with the highest levels of efficacy and cost-effectiveness that is feasible and acceptable in primary care clinics in Cape Town. METHODS: We will employ a fractional factorial design to identify the most promising intervention components for inclusion in a multi-component intervention package to be tested in a future randomized controlled trial. We will recruit 512 participants initiating ART between March 2022 and February 2024 in three Cape Town clinics and evaluate acceptability, feasibility, and cost-effectiveness of intervention combinations. Participants will be randomized to one of 16 conditions with different combinations of three adherence monitoring components: rapid outreach following (1) unsuppressed virus, (2) missed pharmacy refill collection, and/or (3) missed doses as detected by an electronic adherence monitoring device; and two adherence support components: (1) weekly check-in texts and (2) enhanced peer support. We will assess viral suppression (<50 copies/mL) at 24 months as the primary outcome; acceptability, feasibility, fidelity, and other implementation outcomes; and cost-effectiveness. We will use logistic regression models to estimate intervention effects with an intention-to-treat approach, employ descriptive statistics to assess implementation outcomes, and determine an optimal intervention package. DISCUSSION: To our knowledge, ours will be the first study to use the MOST framework to determine the most effective combination of HIV adherence monitoring and support intervention components for implementation in clinics in a RLS. Our findings will provide direction for pragmatic, ongoing adherence support that will be key to ending the HIV epidemic. TRIAL REGISTRATION: ClinicalTrials.gov NCT05040841. Registered on 10 September 2021.

Adherence to the CDK 4/6 Inhibitor Palbociclib and Omission of Dose Management Supported by Pharmacometric Modelling as Part of the OpTAT Study.

The cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib is administered orally and cyclically, causing medication adherence challenges. We evaluated components of adherence to palbociclib, its relationship with pharmacokinetics (PK), and drug-induced neutropenia. Patients with metastatic breast cancer (MBC) receiving palbociclib, delivered in electronic monitors (EM), were randomized 1:1 to an intervention and a control group. The intervention was a 12-month interprofessional medication adherence program (IMAP) along with monthly motivational interviews by a pharmacist. Implementation adherence was compared between groups using generalized estimating equation models, in which covariates were included. Model-based palbociclib PK and neutrophil profiles were simulated under real-life implementation scenarios: (1) optimal, (2) 2 doses omitted and caught up at cycle end. At 6 months, implementation was slightly higher and more stable in the intervention (n = 19) than in the control (n = 19) group, 99.2% and 97.3% (Δ1.95%, 95% CI 1.1−2.9%), respectively. The impact of the intervention was larger in patients diagnosed with MBC for >2 years (Δ3.6%, 95% CI 2.1−5.4%), patients who received >4 cycles before inclusion (Δ3.1%, 95% CI 1.7−4.8%) and patients >65 (Δ2.3%, 95% CI 0.8−3.6%). Simulations showed that 25% of patients had neutropenia grade ≥3 during the next cycle in scenario 1 versus 30% in scenario 2. Education and monitoring of patient CDK4/6i cycle management and adherence along with therapeutic drug monitoring can help clinicians improve prescription and decrease toxicity.

Implementation of Electronic Adherence Monitors and Associated Interventions for Routine HIV Antiretroviral Therapy in Uganda: Promising Findings.

Background: High, sustained adherence is critical for achieving the individual and public health benefits of HIV antiretroviral therapy (ART). Electronic monitors provide detailed adherence information and can enable real-time interventions; however, their use to date has largely been confined to research. This pilot study (NCT03825952) sought to understand feasibility and acceptability a relatively low-cost version of this technology and associated interventions for routine ART delivery in sub-Saharan Africa. Methods: We provided two ART clinics in rural, southwestern Uganda with electronic adherence monitors for data-informed counseling as well as optional SMS messages to clients and/or social supporters (daily or triggered by missed or delayed doses) and/or an alarm. Clinic and ART client experiences were observed for 3 months per client, including time and motion studies. Qualitative interviews among clients, clinicians, and healthcare administrators were informed by the Consolidated Framework for Implementation Research. Results: Fifty-one ART clients were enrolled; 57% were male and the median age was 34 years. Choice of associated intervention varied among participants. The median number of visits during follow-up was two per client. Counselors reviewed the adherence data with 90% of clients at least once; 67% reviewed data at all visits. Average adherence was 94%; four clients had adherence gaps >1 week. Acceptability was high; all but one client found the monitor "very useful" and all found SMS "very useful." Clinic visits among clients with the intervention lasted 4 min longer on average than those in standard care. The monitors and daily SMS generally functioned well, although excess SMS were triggered, primarily due to cellular network delays. Overall, participants felt the technology improved adherence, clinic experiences, and clinician-client relationships. Few worried about stigma and privacy. Cost was a concern for implementation, particularly at scale. Conclusion: We successfully implemented a relatively low-cost electronic ART adherence monitor and associated interventions for routine care in rural Uganda. Feasibility and acceptability were generally high, and individuals were identified who could benefit from adherence support. Future work should involve longitudinal follow-up of diverse populations, clinical outcomes, and detailed cost-effectiveness analysis to help drive policy decisions around the uptake of this technology for routine clinical care. Clinical Trial Registration: identifier: NCT03825952.

Medication Adherence Evaluated Through Electronic Monitors During the 2020 COVID-19 Pandemic Lockdown in Switzerland: A Longitudinal Analysis.

Background: During the 2020 COVID-19 lockdown, patients included in the Interprofessional Medication Adherence Program (IMAP) in Switzerland continued to use electronic monitors (EMs) that registered daily drug-dose intake. We aimed to understand to what extent patients' medication implementation (ie, the extent to which the patient took the prescribed medicine), measured with EMs, was impacted by the lockdown. Methods: Patients participating in the IMAP were diagnosed with diabetic kidney disease (DKD), solid cancer, human immunodeficiency virus (HIV) and miscellaneous long-term diseases (MLTD). Patient implementation was defined through a proxy: if all patient EMs were opened at least once daily, implementation was considered active (=1), and no implementation was considered (=0) otherwise. Implementation before (from December 2019 to March 2020), during (March to June 2020) and after (June to September 2020) the lockdown was compared. Subanalyses were performed according to the patients' diseases. Subanalyses were performed in patients who used at least one EM in 2018-2019 during the same periods (defined as winter, spring and summer). The logistic regression models used to estimate medication implementation according to the period were fitted using generalized estimating equations. Results: In 2020, patient implementation (n = 118) did not differ significantly before versus during (OR = 0.98, 95% CI: 0.84-1.15, p = 0.789) and before versus after (OR = 0.91, 95% CI: 0.79-1.06, p = 0.217) the lockdown. These findings remained stable when separately analyzing the implementation of patients with HIV (n = 61), DKD (n = 25) or MLTD (n = 22). Too few patients with cancer were included (n = 10) to interpret the results. In 2019, the implementation of 61/118 (51.7%) patients was significantly lower during summertime versus wintertime (OR = 0.73, 95% CI: 0.60-0.89, p = 0.002). Conclusion: Medication implementation remained steady before, during and after the lockdown in 2020. The IMAP before, during and after the lockdown may have supported the adherence of most patients, by ensuring continuity of care during periods of routine disturbances.

Understanding reasons and factors for participation and non-participation to a medication adherence program for patients with diabetic kidney disease in Switzerland: a mixed methods study.

BACKGROUND: An interprofessional medication adherence intervention led by pharmacists, combining motivational interviews and feedback with electronic monitor (EM) drug assessment, was offered to all consecutive patients with diabetic kidney disease (DKD) (estimated glomerular filtration rate < 60 mL/min/1.73 m2) visiting their nephrologist or endocrinologist. Approximately 73% (202/275) of eligible patients declined to participate, and the factors and reasons for refusal were investigated. METHODS: Sociodemographic and clinical data of included patients and those who refused were collected retrospectively for those who had previously signed the general consent form. Multivariate logistic regression analysis was performed to identify independent variables associated with non-participation. Patients who refused or accepted the adherence study were invited to participate in semi-structured interviews. Verbatim transcription, thematic analysis, and inductive coding were performed. RESULTS: Patients who refused to participate were older (n = 123, mean age 67.7 years, SD:10.4) than those who accepted (n = 57, mean age 64.0 years, SD:10.0, p = 0.027) and the proportion of women was higher among them than among patients who accepted it (30.9% vs 12.3%, p = 0.007). The time from diabetes diagnosis was longer in patients who refused than in those who accepted (median 14.2 years IQR 6.9-22.7 vs. 8.6 years, IQR 4.5-15.9, p = 0.003). Factors associated with an increased risk of non-participation were female sex (OR 3.8, 95% CI 1.4-10.0, p = 0.007) and the time from diabetes diagnosis (OR 1.05, 95% CI 1.01-1.09, p = 0.019). The included patients who were interviewed (n = 14) found the interprofessional intervention useful to improve their medication management, support medication literacy, and motivation. Patients who refused to participate and who were interviewed (n = 16) explained no perceived need, did not agree to use EM, and perceived the study as a burden and shared that the study would have been beneficial if introduced earlier in their therapeutic journey. Other barriers emerged as difficult relationships with healthcare providers, lack of awareness of the pharmacist's role, and negative perception of clinical research. CONCLUSIONS: Investigating the factors and reasons for participation and non-participation in a study helps tailor intervention designs to the needs of polypharmacy patients. Patients who refused the adherence intervention may not be aware of the benefits of medication management and medication literacy. There is an urgent need to advocate for interprofessional outpatient collaborations to support medication adherence in patients with DKD. Trial registration Clinicaltrials.gov NCT04190251_PANDIA IRIS.

Development of an algorithm for analysing the electronic measurement of medication adherence in routine HIV care.

Background Medication adherence is crucial for successful treatment. Various methods exist for measuring adherence, including electronic drug monitoring, pharmacy refills, pill count, and interviews. These methods are not equivalent, and no method can be considered as the gold standard. A combination of methods is therefore recommended. Objective To develop an algorithm for the management of routinely collected adherence data and to compare persistence and implementation curves using post-algorithm data (reconciled data) versus raw electronic drug monitoring data. Setting A community pharmacy located within a university medical outpatient clinic in Lausanne, Switzerland. Methods The algorithm was developed to take advantage of the strengths of each available adherence measurement method, with electronic drug monitoring as a cornerstone to capture the dynamics of patient behaviour, pill count as a complementary objective method to detect any discrepancy between the number of openings measured by electronic monitoring and the number of pills ingested per opening, and annotated interviews to interpret the discrepancy. The algorithm was tested using data from patients taking lopinavir/r and having participated in an adherence-enhancing programme for more than 3 months. Main outcome measure Adherence was calculated as the percentage of persistent patients (persistence) and the proportion of days with correct dosing over time (implementation) from inclusion to the end of the median follow-up period. Results A 10-step algorithm was established. Among 2041 analysed inter-visit periods, 496 (24 %) were classified as inaccurate, among which 372 (75 %) could be reconciled. The average implementation values were 85 % (raw data) and 91 % (reconciled data) (p < 0.0001). At day 544, persistence values were 68 % (raw) and 82 % (reconciled) (p = 0.11), and adherence values were 74 % (raw) and 82 % (reconciled) (p < 0.0001). Conclusion Combining electronic drug monitoring, pill count and patient interviews is possible within the setting of a medication adherence clinic. Electronic drug monitoring underestimates medication adherence, affecting subsequent analysis of routinely collected adherence data. To ensure a set of reliable electronic drug monitoring data, structured and timely electronic drug monitoring management should be reinforced.