Acceptability and Feasibility of Real-Time Antiretroviral Therapy Adherence Interventions in Rural Uganda: Mixed-Method Pilot Randomized Controlled Trial

Background Wireless electronic adherence monitors can detect antiretroviral therapy (ART) adherence lapses and trigger interventions in real time, thus potentially avoiding unnecessary HIV viremia. Evidence about the acceptability and feasibility of these monitors and associated interventions, however, is limited. Objective The aim of this study was to assess the acceptability and feasibility of real-time adherence monitoring linked to text messaging (short message service, SMS) reminders and notifications to support adherence among individuals living with HIV who are taking ART in rural southwestern Uganda. Methods Individuals living with HIV who were initiating ART were enrolled in a pilot randomized controlled trial and followed up for 9 months. Participants received a real-time adherence monitor and were randomized to one of the following study arms: (1) scheduled SMS, (2) SMS triggered by missed or delayed doses, or (3) no SMS. SMS notifications were also sent to 45 patient-identified social supporters for sustained adherence lapses in the scheduled SMS and triggered SMS arms. Study participants and social supporters participated in qualitative semistructured in-depth interviews on acceptability and feasibility of this technology. An inductive, content analytic approach, framed by the unified theory of acceptance and use of technology model, was used to analyze qualitative data. Quantitative feasibility data, including device functionality and SMS tracking data, were recorded based upon device metrics collected electronically and summarized descriptively. Results A total of 63 participants participated in the study. Participants reported that real-time monitoring intervention linked to SMS reminders and notifications are generally acceptable; the predominant feedback was perceived utility—the intervention was beneficial in motivating and reminding patients to take medication, as well as enabling provision of social support. The intervention was found to be technically feasible, as data were obtained from most participants as expected most of the time. Potential challenges included the impact of the technology on confidentiality, shared phone ownership, usability skills, and availability of electricity. Conclusions Real-time adherence monitoring integrated with SMS reminders and social support notifications is a generally acceptable (based primarily on perceived utility) and feasible intervention in a resource-limited country. Future efforts should focus on optimized device design, user training to overcome the challenges we encountered, cost effectiveness studies, as well as studying the monitoring aspect of the device without accompanying interventions. Trial Registration ClinicalTrials.gov NCT01957865; https://clinicaltrials.gov/ct2/show/NCT01957865 (Archived by WebCite at http://www.webcitation.org/6zFiDlXDa)

mHealth technologies can potentially improve adherence to long-term medications through real-time medication and pill refill reminders, prompting social support and enabling medication monitoring [3]. Real-time wireless adherence monitors, for example, can detect adherence lapses as they occur, and interventions such as SMS reminders can be instituted before the loss of viral suppression [4]. The acceptability and feasibility of SMS reminders in Uganda, however, have not been well studied. Given the promise of real-time adherence monitoring and mobile-based interventions, the variability in effectiveness, and scarcity of literature, more thorough assessments of their acceptability and feasibility are needed. Does your paper address CONSORT subitem 2b?
The aim of this study was to assess the acceptability and feasibility of real-time adherence monitoring linked to text messaging (short message service, SMS) reminders and notifications to support adherence among individuals living with HIV who are taking ART in rural southwestern Uganda.

3a) CONSORT: Description of trial design (such as parallel, factorial) including allocation ratio
All study participants received a real-time adherence monitor (Wisepill Technologies, Cape Town, South Africa; see below) and training on its function and use (eg, filling and removing antiretroviral medications and device charging). Before enrollment in the study, potential participants were assessed for adequate cellular reception in their homes on a network supported by the technology used in this study (MTN or Airtel). Participants were given solar chargers and sent an SMS to charge the monitor as needed. A simple random number generator was used to determine study arm assignments. After screening and consenting, participants were randomized 1:1:1 as follows: 1. Scheduled SMS (also known as SMS reminders) plus real-time adherence monitoring (scheduled SMS arm)-Study participants received an SMS reminder daily for 1 month, then weekly for 2 months. For the next 6 months, study participants received an SMS only if no signal was received from the monitor within 2 hours of the expected dosing time, and an SMS notification was sent to one to two social supporters if no signal was received for more than 48 hours. 2. Triggered SMS (also known as SMS reminders) plus real-time adherence monitoring (triggered SMS arm)-For the entire 9-month study period, study participants received an SMS only if no signal was received from the monitor within 2 hours of the expected dosing time. For the latter 6 of the 9 months, an SMS notification was sent to one to two social supporters if no signal was received for >48 hours. 3. Real-time adherence monitoring only (called the control)-Study participants in this arm received no SMS reminders. 3b) CONSORT: Important changes to methods after trial commencement (such as eligibility criteria), with reasons n/a 3b-i) Bug fixes, Downtimes, Content Changes n/a 4a) CONSORT: Eligibility criteria for participants Inclusion Criteria for Patients Age ≥18 years • Personal cell phone ownership • Ability to read short message service (SMS) messages • Availability of mobile network at participants' homes • Willingness to receive SMS reminders • Ability and willingness to provide informed consent • Living within 20 km from Mbarara Regional Referral Hospital (to facilitate participant follow-up) • Ability to identify at least one social supporter to join the study Inclusion Criteria for Social Supporters Age ≥18 years • Ongoing relationships • Cell phone ownership • Knowledge of the study participant's HIV status • Willingness to provide informed consent • History of providing social support (eg, assistance to travel to the clinic and medication adherence advice) to the study participant 4a-i) Computer / Internet literacy n/a 4a-ii) Open vs. closed, web-based vs. face-to-face assessments: Face to face recruitment of participants from Mbarara Immune Suppression Syndrome(ISS) Clinic Mbarara, Mbarara District, Uganda 4a-iii) Information giving during recruitment Participants provided signed informed consent before study participation. As a cultural practice in Uganda, participants were given 10,000 Ugandan Shillings (per trip; equivalent of approximately US $4) to cover transportation costs if they came to the research offices for an interview).

4b) CONSORT: Settings and locations where the data were collected
This study involved two types of participants: PLWHA (called study participants) and their social supporters. Study participants initiating ART were recruited from the Immune Suppression Syndrome Clinic at Mbarara Regional Referral Hospital (MRRH), a rural public hospital that dispenses free ART to over 10,000 people living with HIV in southwestern Uganda. We focused on ART initiators because they are not yet accustomed to taking medication; intervening at this level could potentially result in developing medication adherence habits. HIV status was identified by checking participants' medical records. 4b-i) Report if outcomes were (self-)assessed through online questionnaires n/a 4b-ii) Report how institutional affiliations are displayed Massachusetts General Hospital Mbarara University of Science and Technology 5) CONSORT: Describe the interventions for each group with sufficient details to allow replication, including how and when they were actually administered 5-i) Mention names, credential, affiliations of the developers, sponsors, and owners

5-iii) Revisions and updating
no major revisions and updates were done 5-iv) Quality assurance methods Following each interview, the research investigators reviewed transcripts for quality, clarity, and detail. 5-v) Ensure replicability by publishing the source code, and/or providing screenshots/screen-capture video, and/or providing flowcharts of the algorithms used n/a 5-vi) Digital preservation n/a 5-vii) Access All study participants received a real-time adherence monitor (Wisepill Technologies, Cape Town, South Africa; see below) and training on its function and use (eg, filling and removing antiretroviral medications and device charging). Before enrollment in the study, potential participants were assessed for adequate cellular reception in their homes on a network supported by the technology used in this study (MTN or Airtel). Participants were given solar chargers and sent an SMS to charge the monitor as needed. A simple random number generator was used to determine study arm assignments.

5-viii) Mode of delivery, features/functionalities/components of the intervention and comparator, and the theoretical framework
After screening and consenting, participants were randomized 1:1:1 as follows: 1. Scheduled SMS (also known as SMS reminders) plus real-time adherence monitoring (scheduled SMS arm)-Study participants received an SMS reminder daily for 1 month, then weekly for 2 months. For the next 6 months, study participants received an SMS only if no signal was received from the monitor within 2 hours of the expected dosing time, and an SMS notification was sent to one to two social supporters if no signal was received for more than 48 hours. 2. Triggered SMS (also known as SMS reminders) plus real-time adherence monitoring (triggered SMS arm)-For the entire 9-month study period, study participants received an SMS only if no signal was received from the monitor within 2 hours of the expected dosing time. For the latter 6 of the 9 months, an SMS notification was sent to one to two social supporters if no signal was received for >48 hours. 3. Real-time adherence monitoring only (called the control)-Study participants in this arm received no SMS reminders. The Unified Theory of acceptance and use of Technology model guided the design of the data collection tools collection and analysis of data.

5-ix) Describe use parameters
Device: Fixed SMS, real-time monitoring Device: Triggered SMS, real-time monitoring

5-x) Clarify the level of human involvement
Research assistants: -training the participants on using the devices -Replacement of the malfunctioning devices -Data Collection -Interview transcription

5-xi) Report any prompts/reminders used
Text messaging (short message service, SMS) reminders and notifications to support adherence among individuals living with HIV who are taking ART in rural southwestern Uganda.

5-xii) Describe any co-interventions (incl. training/support)
All study participants were trained to use the realtime adherence monitors (Filling and removing medication and device charging) 6a) CONSORT: Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed Antiretroviral Therapy (ART) Adherence Levels [ Time Frame: real time (for 9 months) ] ART adherence in each study arms. Adherence was measured by the Wisepill real-time adherence monitor and calculated as the number of monitor opening signals received divided by the number of monitor opening signals expected, capped at 100%.

6a-i) Online questionnaires: describe if they were validated for online use and apply CHERRIES items to describe how the questionnaires were designed/deployed
We never used online questionnaires 6a-ii) Describe whether and how "use" (including intensity of use/dosage) was defined/measured/monitored Powered by a rechargeable battery, the real-time adherence monitor (Figure 1) is a medication container that can hold up to sixty small pills. When an individual opens it to take pills, the device records a date-and-time stamp. An internal modem and subscriber identity module card enable the device to send a real-time mobile signal to a secure Web server (hosted in South Africa) by General Packet Radio Service (GPRS). Receipt of this signal was taken as a proxy for taking medication. GPRS maintains the data in transit until acknowledgment of receipt by the Web server, which minimizes possible data loss because of power failure or lack of Internet connectivity. Data transmission is backed up by the SMS to mitigate possible temporal GPRS network disconnections. In the event of inadequate mobile network coverage, the monitor stores openings in flash memory and sends them when the network becomes available. The monitor also transmits a daily heart beat that indicates current battery life, remaining airtime balance, and signal strength as indication of its functionality. The monitor can be charged using electricity or a solar device. Its battery life was 3 months at the time of the study but has since been improved to 6 months. 6a-iii) Describe whether, how, and when qualitative feedback from participants was obtained Semistructured qualitative interviews were conducted after month 3 (known as interview 1) and after the first 48-hour lapse (known as interview 2), or at study exit if there was no such lapse (also known as interview 2), reflecting two planned interviews per participant. In-depth semistructured interviews with a purposeful sample of social supporters were conducted within 2 weeks of a lapse by their respective study participant. Their selection was based on the study participant's explanation for the lapse, social support characteristics, and variations in the types of social support provided. Closed and open-ended questions were asked of social supporters at exit exploring various aspects such as challenges and experiences to social support and understanding of and responses to the intervention SMS notifications and the type of voluntary and requested help or support presently given to the study participant toward adherence. 6b) CONSORT: Any changes to trial outcomes after the trial commenced, with reasons This study involved two types of participants: PLWHA (called study participants) and their social supporters. Study participants initiating ART were recruited from the Immune Suppression Syndrome Clinic at Mbarara Regional Referral Hospital (MRRH), a rural public hospital that dispenses free ART to over 10,000 people living with HIV in southwestern Uganda. We focused on ART initiators because they are not yet accustomed to taking medication; intervening at this level could potentially result in developing medication adherence habits. HIV status was identified by checking participants' medical records. 7a) CONSORT: How sample size was determined 7a-i) Describe whether and how expected attrition was taken into account when calculating the sample size 7b) CONSORT: When applicable, explanation of any interim analyses and stopping guidelines Antiretroviral Therapy (ART) Adherence Levels [ Time Frame: real time (for 9 months) ] ART adherence in each study arms. Adherence was measured by the Wisepill real-time adherence monitor and calculated as the number of monitor opening signals received divided by the number of monitor opening signals expected, capped at 100%. 8a) CONSORT: Method used to generate the random allocation sequence Randomized using 1:1:1 ration into three arms 8b) CONSORT: Type of randomisation; details of any restriction (such as blocking and block size) Participants received a real-time adherence monitor and were randomized to one of the following study arms: (1) scheduled SMS, (2) SMS triggered by missed or delayed doses, or (3) no SMS. 9) CONSORT: Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned Participants received a real-time adherence monitor and were randomized to one of the following study arms: (1) scheduled SMS, (2) SMS triggered by missed or delayed doses, or (3) no SMS. 10) CONSORT: Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions The research Assistants at the clinic generated the sequence, enrolled the participants and allocated the participants to the different intervention arms 11a) CONSORT: Blinding -If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how 11a-i) Specify who was blinded, and who wasn't participants were not blinded 11a-ii) Discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator" The participants were choosen randomly to different study arms 11b) CONSORT: If relevant, description of the similarity of interventions n/a 12a) CONSORT: Statistical methods used to compare groups for primary and secondary outcomes n/a 12a-i) Imputation techniques to deal with attrition / missing values n/a 12b) CONSORT: Methods for additional analyses, such as subgroup analyses and adjusted analyses