Effect of a customized digital adherence tool on retention in care and adherence to antiretroviral treatment in breastfeeding women, children and adolescents living with HIV in Tanzania: a mixed-methods study followed by clinical trials

doi:10.21203/rs.3.rs-2604485/v1

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Research Article

Effect of a customized digital adherence tool on retention in care and adherence to antiretroviral treatment in breastfeeding women, children and adolescents living with HIV in Tanzania: a mixed-methods study followed by clinical trials

https://doi.org/10.21203/rs.3.rs-2604485/v1

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published 21 Apr, 2023

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Background

Adherence to antiretroviral (ARV) treatment for HIV infection is challenging because of many factors. The World Health Organization (WHO) has recommended using digital adherence technologies (DATs). However, there is limited evidence on how DATs improve adherence. Wisepill® is an internet enable medication dispenser found feasible and acceptable in several studies. However, limited evidence is available on its effectiveness in improving ART adherence, specifically among children and adolescents. Furthermore, DATs are often developed without involving the target groups. We propose a two-stage project consisting of a formative study to customize an existing Wisepill DAT intervention and a randomized clinical trial, to investigate the effectiveness of DAT combined with reminder cues and tailored feedback on adherence to ARV treatment among children and adolescents living with HIV and retention in care among breastfeeding women living with HIV in Kilimanjaro and Arusha Region, Tanzania.

Methods

We will conduct a formative study mixed-methods study and three sub-trials in Kilimanjaro and Arusha Regions among (1) children aged 0–14 years and their caregivers, (2) adolescents aged 15–19 years and (3) breastfeeding women and their HIV-negative infants. In the formative study, we will collect and analyse data on needs and contents for DATs, including the contents of short message service (SMS) texts and tailored feedback. The results will inform the customization of the DAT to be tested in the sub-trials. In the trials, participants will be randomized in the intervention arm, where the DAT will be implemented or the control arm, where standard care will be followed. Participants in the intervention arm will take their medication from the Wisepill-box and receive daily reminder texts and tailored feedback during clinic visits.

Discussion

If the intervention improves adherence to ART and the devices are acceptable, accurate and sustainable, the intervention can be scaled up within the National Aids Control Programmes.

Trial registration: PACTR202301844164954, date 27 January 2023

HIV

Adherence

Digital Health

Children

Adolescents

Breastfeeding Women

Children and adolescents form a significant part of the world population of people living with HIV, with WHO reporting 1.8 million children (age < 15) and 1.8 million adolescents (ages 10–19) in Sub-Saharan Africa in 2019.(1) In addition, new infections continue to occur. In 2019 an estimated 160,000 children and 160,000 adolescents got infected globally.(1) The ‘START FREE-STAY FREE-AIDS FREE’ ‘superfast’ framework developed by UNAIDS has set new targets for an AIDS-free generation focusing on those aged 0–24.(2) These targets highly depend on adherence to treatment and retention in care of pregnant and breastfeeding women, children and adolescents living with HIV. In 2017 Sub Saharan Africa (SSA), 81% of pregnant and breastfeeding women had access to treatment, with only 49% access for children aged 0–14 years.(3) A limited number of people in SSA is virologically suppressed, with an overall percentage of 53% in 2018.(4) This low percentage is mainly caused by limited treatment adherence and limited care retention.(3) High levels of adherence, i.e., taking more than 95% of prescribed doses, are needed to prevent treatment failure (defined as viral load becoming detectable, development of opportunistic infections or mortality), the development of HIV drug resistance and to prevent vertical transmission of HIV to the new-born child.(5, 6) Retention into care is a prerequisite for adherence to treatment. Reasons for non-retention are stigma, fear of disclosure, and lack of social support.(10)

Despite high access for pregnant women to HIV treatment of 92%, the percentage of infected infants has not decreased much since 2010.(7) In Tanzania, 11% of infants born to women living with HIV are HIV-positive. Five percent of infections in children happen during the first six weeks of life.(7) Although the National Aids Control Programme (NACP) of Tanzania encourages monthly Antenatal Care (ANC) visits for pregnant women living with HIV,(8) a study in Kilimanjaro, Tanzania, showed that retention in care is limited, with 59% lost to follow up, of whom 19% in the first month after HIV diagnosis, 12% during pregnancy and 70% after delivery.(9)

It is estimated that only 59% of children (0–14 years) living with HIV are on anti-retroviral (ARV) treatment in Eastern and Southern Africa.(3) In Tanzania, 110,000 children were living with HIV in 2019, with 56% on treatment.(1) Children living with HIV must take lifelong treatment; most depend on their parents/caretakers regarding adherence to treatment. A study in East Africa showed that parents of 90% of children reported good adherence, though this study only used self-report and pill counts. Therefore, it was recommended that consistent adherence monitoring with validated measures and attention to vulnerable groups is needed.(11) A study in Dar es Salaam among orphaned children aged 2–14 showed that 72% reached 95% adherence based on nevirapine plasma levels. Challenges for adherence were financial constraints, waiting times at clinics and limited knowledge about HIV among caretakers.(12) Another study in Mwanza, Tanzania, among children and adolescents also reported limited adherence of 65% based on pill counts.(13)

Adolescents (aged 15–19) are more independent than children below 14 years of age and depend less on their parents. Reports from nurse counsellors in our setting imply that older children, including adolescents, visit clinics independently and often do not have their parents/caregivers as treatment supporters. Virological suppression is more difficult in this group, and levels differ significantly between studies: 27–89%.(14) Adherence among adolescents shows a variety between 64–90%.(15) Factors associated with poor adolescent adherence are stigma, adverse effects to antiretroviral treatment, lack of assistance and forgetfulness.(15) In Kilimanjaro, a study reported that 40% of adolescents had virological failure, and about one-third reported poor adherence.(16) A study in Mwanza showed roughly the same, with only 65% of children and adolescents being able to reach adequate levels of adherence.(13) No single intervention has been proven effective among adolescents in low-to-middle-income countries.(17) It was shown that phone-based interventions might be promising, but more rigorous studies are needed.(18)

Digital Adherence Tools (DATs) have been proposed for monitoring adherence and have been investigated in several studies.(19–32) In the Kilimanjaro region, we have investigated the use of real-time medication monitoring by using the Wisepill® device/pillbox.(33) Wisepill® records the opening of the pillbox, a so-called medication event, and sends an SMS text to patients if the pillbox is not opened on time to remind them. We showed that using the pillbox is feasible and that adult HIV-infected patients saw it as a good means for helping them adhere to and store their medication.(19) Numerous studies have shown evidence of using SMS among pregnant women living with HIV to improve retention into care and adherence to treatment.(20, 25–30) Our pilot study among pregnant and breastfeeding women living with HIV has shown feasibility and confirms positive user experience with SMS reminder cues.(31, 32) In another study, we found that the percentage of participants reaching 90% adherence was significantly higher for those using DATs.(21) We also encountered concerns about unwanted disclosure and stigma due to SMS’s explicit contents.(22, 23) In addition, there have been technical challenges such as limited network availability.(24)

Using the common way of communication through SMS has a high potential for disease management. The number of mobile phone subscriptions per 100 inhabitants in Tanzania was 86% in 2020. Additionally, over 25 billion local SMS were sent in the second quarter of 2019.(34) In our previous studies, we found that using Real Time Medication Monitoring (RTMM) and SMS was feasible for reminding about medication intake among adults in Moshi, Tanzania.(19, 31, 32) In addition, studies in Kenya have shown SMS increased communication between patients and health care providers and retention in care and adherence to treatment.(35–37). Despite positive results, several studies have reported no clear effect on clinical outcomes.(38) In rural Malawi, an SMS trial could not show an effect of SMS on retention to care for people living with HIV.(39) Studies have suggested interventions to be developed through formative studies whereby the target population is engaged in designing the interventions early in the project.(40–42)

Only limited evidence exists for interventions improving adherence to treatment and retention in care for children and adolescents with HIV in SSA.(3) As the number of mobile phone users is high and still increasing, particularly in Tanzania, this creates a better avenue for digital health tools to be integrated with HIV care for improving adherence to treatment and retention into care. Therefore, in this study, we propose to investigate using a customized DAT to improve retention in care, adherence to treatment and subsequent treatment outcomes among infants of breastfeeding mothers living with HIV and children and adolescents living with HIV.

Study area

We will conduct our project in care and treatment clinics (CTC) and postnatal clinics serving clients on antiretroviral treatment in the Kilimanjaro region in Tanzania, which has an area of 13,250 km2. The region has seven districts, and its capital is Moshi. In the latest census of 2012, the region had a population of about 1.6 million. Seventy-six percent live in rural areas, and 38% are under 15.

Design

This project will evaluate a DAT consisting of real-time medication monitoring with the Wisepill® device and SMS messages, together with tailored feedback to participants on their adherence data. The project will consist of two stages (see Fig. 1). One is a formative stage in which we will determine the contents and timing of the DAT. This will consist of a mixed methods approach. We will conduct semi-structured interviews and qualitative data collection, including in-depth interviews and focus group discussions after using our DAT. The results of these data will inform the contents of the DAT to be used for each group. In the second stage, we will conduct three clinical trials to investigate the effect of the digital health intervention on adherence to treatment, retention into care and treatment outcomes among (1) breastfeeding women, (2) children and (3) adolescents.

Overall aim and objectives

We aim to investigate whether our customized digital adherence tool will improve retention in care among breastfeeding women and adherence to treatment among children and adolescents.

The specific objectives for the first stage are:

1. To identify the enablers and barriers to using DAT among children and their caregivers/parents, adolescents and breastfeeding women living with HIV in Kilimanjaro, Tanzania

2. To identify the needed content of SMS schemes based on the participants’ preferences.

3. To identify the preferred timing and frequency for SMS, including reminder cues to take medication and to visit the clinic.

4. To understand the need for additional information for different groups to be included in the SMS i.e., education on sexual and reproductive health importance of breastfeeding, amongst others.

5. To design the blueprint for the DAT to be tested in the second phase of the project

In the second stage of clinical trials, we will investigate the effectiveness of our developed DAT developed in the blueprint. This will be established through the following specific objectives:

1. Breastfeeding women: to assess the percentage retention in care at 18 months post-partum

2. Children: to assess the percentage of children being 95% adherent to treatment based on pharmacy refill counts and self-reported adherence

3. Adolescents: to assess the percentage of adolescents being 95% adherent to treatment based on pharmacy refill counts and self-reported adherence

Our secondary objectives for the second stage are:

1. To assess the percentage of breastfeeding women, children and adolescents living with HIV reporting 95% adherence at 18, 12 and 12 months, respectively

2. To assess the percentage of breastfeeding women, children and adolescents living with HIV being virologically suppressed (<20 copies/ml) at 18, 12 and 12 months, respectively

3. To determine the trend in adherence over time based on self-report and pharmacy refill counts for breastfeeding women, children and adolescents living with HIV

4. To establish a different cut off points of adherence levels and relation to virological suppression

5. To determine the HIV status of the infants of breastfeeding women living with HIV at 6 weeks, 9 months and 18 months.

6. To investigate the feasibility and acceptability of the DAT

7. To determine the implementation costs of the DAT

Formative stage

The objective of this stage is to evoke feedback from the key intervention stakeholders to guide on designing and development of the newly proposed DAT. We will first survey 142 participants from each group to investigate enablers and barriers to using DAT. This figure is based on selecting an arbitrary percentage of 50% experiencing barriers for using DAT with α = 0.05 and using a power of 80% for estimating a single proportion sample calculation.

Next, we will purposively select 20 participants from each group, considered enough to reach ‘saturation’ of information, to use the DAT for one month. After signing informed consent, we will provide mothers, parents/caregivers of children and adolescents with a Wisepill® box which they will use for a month. After a month, we will interview each of them, including the children whose status has been disclosed on their experience with the box and the need for SMS content to be developed for the customized digital tool. We will also hold two focus group discussions with each group of breastfeeding mothers, parents/caregivers and adolescents. The outcomes of the formative research will be as follows:

An overview of needs for SMS contents and timing for reminder cues to take medication
An overview of needs for SMS contents and timing for reminder cues for clinic visits
An overview of further needs for other SMSs, such as educational and informational texts, including timing and frequency
An overview of enablers and barriers to the success of the intervention

Quantitative data from the survey will be analysed descriptively using frequency tables, chi-square tests and t-tests to investigate differences between subgroups. We will do thematic content analyses of qualitative data to understand the context of adherence to treatment and the use of DAT in the different target groups. We will use NVivo® software for data organization and define themes and subthemes. Based on the qualitative and quantitative data outcomes, we will develop an SMS scheme containing customized content for each group.

Clinical Trials

We will conduct three clinical trials in each of the three target groups to investigate whether the developed DATs improve adherence to treatment and virological outcomes. The study procedures can be found in annex 1. We will conduct a non-blinded two-armed trial comparing DAT to standard care in each subgroup. Participants will be individually randomized to one of the arms in a 1:1 ratio and be exposed to the DAT for the study duration. After follow-up, we will compare the two arms’ retention in care for breastfeeding women and treatment adherence for children and adolescents.

Ethical approval

The formative study has been approved by the College Research and Ethical Review Committee (CRERC) of Kilimanjaro Christian Medical University College (KCMUCo) and the National Health Research Ethics Sub-Committee (NatHREC) of the National Medical Research Institute (NIMR) of Tanzania. Furthermore, the regional representatives of the Ministry of Health and the regional medical officer have been permitted to conduct the study. Once we have designed the customized DAT, we will apply for approval for the trials from the same bodies.

Participants

We will have three different study populations, which are the following:

Breastfeeding mothers living with HIV with their uninfected infants (for the survey of the formative phase, we will also include pregnant women to understand their views)
Children aged 0-14 and their caregivers/parents
Adolescents aged 15-19

The inclusion criteria are as follows:

Mother (of HIV-exposed infant)/child/adolescent being HIV positive, with the infant of the mother not being positive
attending Care and Treatment Centres (CTC) or postnatal clinics in the Kilimanjaro region at the start of the study
age of mother between 18-50 years, age of children living with HIV 0-14 years and adolescents living with HIV between 15-19 years
mother, caregiver/parents and adolescents willing to use RTMM and/or receive SMS
mother, caregiver/parent and adolescents able to read and understand SMS
mother, caregiver/parent and adolescents aged 18-19 able to understand and willing to sign the informed consent
adolescents aged 15-17 able and willing to sign informed assent.

The exclusion criteria are:

admission to a hospital at study entry
participation in other trials related to adherence and retention in care
previous participation in digital health research

Intervention

The basis for the intervention is the Wisepill® device and our previously developed SMS scheme.(21) Customized SMS will be sent on a daily basis to remind taking medication. The Wisepill® device (Wisepill RT2000®), also known as an internet-enabled medication dispenser, enables real-time and remote medication monitoring. The device consists of a box the size of a compact camera, which holds up to 30 large pills or 60 small pills in a two-partitioned container. It is manufactured by the Wisepill® company in Cape Town, South Africa. It has features to suit research and clinical trials on adherence.(33,43) Participants will always receive a first reminder SMS half an hour before the agreed usual time of intake. A second reminder will be sent one hour after the agreed usual time of intake in case there is no signal of the box being opened.

Attending the nurse; feedback on adherence data

Participants will be recruited by nurse counsellors at their respective care and treatment clinics. follow standard care according to their normal schedule of care. After signing informed consent, we will provide parents/caregivers of children and adolescents with a Wisepill® box which they will use for 12 months, while mothers will use it for 18 months.

Study nurses will attend extensive training on all study procedures. Participants will receive feedback on their adherence to ART during their clinic visit. Study nurses will share and discuss adherence reports generated by the device with the participant during the clinic visit. We will use the ‘stages of change’ model by Prochaska and Velicer (44,45) to give tailored feedback on these reports. Feedback will be divided into phases. In the first part of the feedback session, awareness will be generated by showing the adherence report from the DAT. Study nurses will provide basic education on the importance of adherence and the potential risks of poor adherence. Participants will be given an opportunity to share any issues they experienced during this period of using the DAT. After this phase, the nurse and participant will discuss the possible pros and cons of changing behaviour and barriers to improving adherence. Nurses may offer possible solutions, such as daily life cues that can be coupled with medication intake. The third phase of a feedback session consists of the participant setting goals for improving adherence with the nurse (goal setting). For the formative phase, a feedback session will be done once at the end of the month of using the DAT. More extensive sessions will be done in the trial phase of the study. The information about sharing of Wisepill® data will be included in the informed consent.

Sample size calculation and randomization

We calculated the sample size for each group separately as the outcomes differed. In a previous study, the proportion of breastfeeding women that stayed in care was 41% in Kilimanjaro.(10) We want to show an improvement in retention of 20%. We will use 1:1 randomization in the two arms. We will use 1:1 randomization in the two arms. Using the two-sided test for proportions with α=0.05 and Power=80%, we will need 102 women in each arm.

The proportion of children reaching 95% adherence was 72% in a study among orphans in Dar es Salaam.(2) We want to show an improvement in this proportion of 20%. We will use 1:1 randomization in the two arms. Using the one-sided test for proportions with a=0.05 and power=80%, we will need 52 children in each arm. Considering a drop-out of 20%, we will need 65 children with their caregivers in each arm.

The proportion of adolescents reaching 95% was 67% in a study among adolescents in the Kilimanjaro region.(3) We want to show an improvement in this proportion of 20%. We will use 1:1 randomization in the two arms. Using the two-sided test for proportions with α=0.05 and Power=80%, we will need 76 adolescents in each arm. Considering a drop-out of 20%, we will need 91 adolescents in each arm.

Study outcomes

The primary study outcome for breastfeeding women is percentage retained in care at 18 month post-partum. For children and adolescents, the primary outcomes is mean adherence to ARV treatment.

Data Management and analyses

We will develop a case report form (CRF) that contains information needed for study visits. During the screening, we will collect data on the date of informed consent, demographics, disease and treatment, including current antiretroviral regimen and dosing schemes. Furthermore, the phone number of the participants and treatment supporters will be recorded. In follow-up visits, we will collect data about a change in the ARV regimen. In addition, we will collect information about pharmacy refills and self-reported adherence. Viral load will be measured and recorded at study entry and after follow-up. In addition, the infant of breastfeeding mothers will be tested for HIV according to standard care at week 6, month 9 and month 18. We will use Redcap®, an open-source database management system for randomization and data management. Data will be stored anonymously whereby personal identifiers are stored on the participant screening log. The study’s datamanager is in charge of all procedures considering data management and randomization. In each sub-study, we will use intention-to-treat analyses comparing the two arms on the mentioned outcomes. We will also use intention-to-treat analyses comparing the two arms on the mentioned primary study outcomes. Therefore, we will use chi-square analyses to compare the percentage of women retained in care at 18 months and the percentage of children and adolescents having 95% adherence during the study period of 12 months. Also, we will do Student’s t-tests to compare continuous variables of adherence between arms. We will compare the percentage of infants found to be HIV positive between arms by using chi-square tests.

Introduction

We believe our study will demonstrate the effectiveness of a customized DAT among breastfeeding women, children and adolescents living with HIV in Kilimanjaro, Tanzania. Furthermore, it will give more insights into the acceptability of the tools in specific groups. These results will inform policymakers to advocate for using DAT to improve adherence to treatment.

Limitations

Opening the Wisepill® box does not necessarily imply ingestion of pills. Furthermore, the pillbox can only contain a limited number of pills. That would mean a participant will have to refill it every two weeks. Although we will be able to show a possible effect, there are a number of groups for which the effect will be difficult to extrapolate. One group is those who are not able to read and understand SMS. Later, we may develop an interactive voice response calling system to overcome this problem. In addition, those without a phone will not be able to participate. This will be mitigated by providing them with a simple mobile phone feature. Another limitation is that in the currently proposed study, we will still work with a pre-defined SMS structure whereby participants will receive the same messages over a given period that only intervenes on missed intakes. Messages could be more personalized and tailored by using a learning mechanism that will send messages completely tailored towards the adherence pattern of a participant.

Strengths

Strengths of our study include the formative part, in which we investigate the user’s experience of the DAT, their preference for the type of SMS to be received, and the timing of such SMS. Another strength is that we will conduct the study in three groups, considered vulnerable and often overlooked in research.

Dissemination

We plan to disseminate our study at different levels starting with the target group through the participants and community advisory boards. We will also disseminate results to the scientific community through peer-reviewed manuscripts and abstract presentations at conference proceedings. Nationally, we will disseminate to the Ministry of Health and National Aids Control Programme and regionally through the East African Consortium on Clinical Research (EACCR). On an international level, we will inform the World Health Organization of our results. We will develop different kinds of policy briefs for all levels to communicate and disseminate our study. In addition, the data management plan will provide for accessibility of data and sharing.

Our study will give clear insights into the needs and contents of a digital tool and the effect of customization of that tool on adherence to treatment among breastfeeding women, children and adolescents living with HIV.

Current status: data was analysed for the formative study. We have started recruitment for the trial and expect to finalize recruitment by February 2024 and follow-up by August 2024.

Trial sponsor in terms of GCP

KCRI, Moshi, Tanzania

Ethics approval and consent to participate: Our proposal has been approved by the College Research and Ethical Review Committee (CRERC) of Kilimanjaro Christian Medical University College (KCMUCo), the National Health Research Ethics Sub-Committee (NatHREC) of the National Medical Research Institute (NIMR) of Tanzania. Informed consent will be obtained from all study participants.

Consent for publication: Not applicable

Availability of data and material: Not applicable

Competing interests: The authors declare that they have no competing interests

Funding: The project is funded through a senior fellowship plus from the European and Developing Countries Clinical Trials Partnership awarded to Marion Sumari-de Boer

Authors' contributions: MSB wrote the initial paper together with KM. PN and RA were involved in mentorship during the design of the research proposal and write-up of the paper. All authors read and approved the final manuscript.

Acknowledgements: We thank the administration of Kilimanjaro Clinical Research Institute for assisting us to conduct this study. We are grateful to EDCTP who have agreed to fund this study under the Senior Fellowship Plus TMA2818 of Marion Sumari-de Boer.

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published 21 Apr, 2023

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Effect of a customized digital adherence tool on retention in care and adherence to antiretroviral treatment in breastfeeding women, children and adolescents living with HIV in Tanzania: a mixed-methods study followed by clinical trials

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Intervention

Attending the nurse; feedback on adherence data

Sample size calculation and randomization

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