BACKGROUND: Adherence to TB drugs is crucial for improving treatment outcomes. Digital adherence technologies can improve adherence; however, there is a lack of evidence on cost-effectiveness. This study aimed to explore the cost-effectiveness of medication event reminder monitors (MERM) in China compared with the standard of care, using results from a pragmatic, cluster-randomised superiority trial of an electronic MERM in China.
METHODS: We collected primary unit cost data from the societal perspective, both at and above the health facility level. We estimated the incremental cost-effectiveness of MERM using a Markov model with a 20-year time horizon; a 3% discount rate was applied to costs and outcomes. We explored uncertainty through a series of sensitivity and scenario analyses.
RESULTS: The incremental cost of MERM was $27.22 per patient. Probabilistic sensitivity analysis showed significant uncertainty about the intervention\'s cost-effectiveness. Changing assumptions around key parameters substantially affected our estimated incremental cost-effectiveness ratio.
CONCLUSIONS: Although the incremental cost of the MERM box was low, current evidence does not indicate that the intervention would be cost-effective. However, the intervention\'s cost-effectiveness could improve if implemented as part of a broader strategy, including enhanced patient management.
BACKGROUND: Il est crucial de respecter les médicaments antituberculeux pour améliorer les résultats du traitement. Les technologies numériques peuvent améliorer l\'observance, mais il existe un manque de preuves sur leur rapport coût-efficacité. Cette étude a examiné le rapport coût-efficacité des moniteurs de rappel d\'événements médicamenteux (MERM, pour l’anglais, « medication event reminder monitors ») en Chine par rapport aux soins standards, en se basant sur les résultats d\'un essai pragmatique randomisé en grappes d\'un MERM électronique en Chine.
UNASSIGNED: Les coûts unitaires primaires du point de vue de la société ont été collectés et analysés à la fois au niveau de l\'établissement de santé et au-delà. Pour évaluer le rapport coût-efficacité différentiel du MERM, nous avons utilisé un modèle de Markov sur une période de 20 ans, en appliquant un taux d\'actualisation de 3% aux coûts et aux résultats. Afin de prendre en compte les incertitudes, nous avons effectué plusieurs analyses de sensibilité et de scénarios.
UNASSIGNED: Le coût supplémentaire du MERM s\'élevait à 27,22 $ par patient. L\'analyse de sensibilité probabiliste a révélé une incertitude importante concernant le rapport coût-efficacité de l\'intervention. La variation des hypothèses liées aux paramètres clés a eu un impact significatif sur le rapport coût-efficacité différentiel estimé.
CONCLUSIONS: Bien que le coût différentiel de la boîte MERM soit faible, les données actuelles n\'indiquent pas que l\'intervention serait rentable. Toutefois, le rapport coût-efficacité de l\'intervention pourrait être amélioré si elle était mise en œuvre dans le cadre d\'une stratégie plus large, comprenant une meilleure prise en charge des patients.

BACKGROUND: Medication non-adherence is a significant problem in patients with Chronic Obstructive Pulmonary Disease (COPD). Efforts to address this issue are receiving increased attention. Simplifying treatment by prescribing single-inhaler triple therapy (SITT) as an alternative to multi-inhaler triple therapy (MITT) or with smart inhalers are often considered potential solutions. However, the actual impact of these innovations on adherence and clinical outcomes is unclear.
METHODS: To address this knowledge gap we first conducted a literature review focusing on two research questions: 1) the difference in adherence between SITT and MITT users in COPD, and 2) the effect of smart inhalers on adherence in COPD. Separate searches were conducted in PubMed and two authors independently assessed the articles. In addition, we present a protocol for a study to acquire knowledge for the gaps identified.
RESULTS: To address the first research question, 8 trials were selected for further review. All trials were observational, i.e. randomized controlled trials were lacking. Seven of these trials showed higher adherence and/or persistence in patients on SITT compared with patients on MITT. In addition, four studies showed a positive effect of SITT on various clinical outcomes. For the second research question, 11 trials were selected for review. While most of the studies showed a positive effect of smart inhalers on adherence, there was considerable variation in the results regarding their effect on other clinical outcomes. The TRICOLON (TRIple therapy COnvenience by the use of one or multipLe Inhalers and digital support in ChrONic Obstructive Pulmonary Disease) trial aims to improve understanding regarding the effectiveness of SITT and smart inhalers in enhancing adherence. This open-label, randomized, multi-center study will enroll COPD patients requiring triple therapy at ten participating hospitals. In total, 300 patients will be randomized into three groups: 1) MITT; 2) SITT; 3) SITT with digital support through a smart inhaler and an e-health platform. The follow-up period will be one year, during which three methods of measuring adherence will be used: smart inhaler data, self-reported data using the Test of Adherence to Inhalers (TAI) questionnaire, and drug analysis in scalp hair samples. Finally, differences in clinical outcomes between the study groups will be compared.
CONCLUSIONS: Our review suggests promising results concerning the effect of SITT, as opposed to MITT, and smart inhalers on adherence. However, the quality of evidence is limited due to the absence of randomized controlled trials and/or the short duration of follow-up in many studies. Moreover, its impact on clinical outcomes shows considerable variation. The TRICOLON trial aims to provide solid data on these frequently mentioned solutions to non-adherence in COPD. Collecting data in a well-designed randomized controlled trial is challenging, but the design of this trial addresses both the usefulness of SITT and smart inhalers while ensuring minimal interference in participants\' daily lives.
BACKGROUND: NCT05495698 (Clinicaltrials.gov), registered at 08-08-2022. Protocol version: version 5, date 27-02-2023.

Ensuring the completion of treatment for tuberculosis (TB) remains a key challenge in many high-burden countries. 99DOTS is a low-cost digital adherence technology that has emerged as a promising tool for monitoring and supporting TB treatment completion.
We aimed to understand the feasibility and acceptability of 99DOTS, a mobile phone-based TB treatment support method, and characterize barriers and facilitators to its implementation during a pragmatic trial in Uganda.
Between April 1 and August 31, 2021, we conducted in-depth interviews with people with TB and key informant interviews with health workers and district and regional TB officers involved in the implementation of 99DOTS at 18 health facilities in Uganda. Semistructured interview guides were informed by the capability, opportunity, motivation, and behavior (COM-B) model and explored perceptions of, and experiences with, 99DOTS, including barriers and facilitators to its use. Qualitative analysis was conducted using the framework approach.
Interviews were conducted with 30 people with TB, 12 health workers, and 7 TB officers. All people with TB, health workers, and TB officers noted that 99DOTS supported and encouraged people with TB to take their anti-TB medication, facilitated treatment monitoring, and improved relationships between people with TB and health workers. Participants also liked that the platform was free, easy to use, and improved TB treatment outcomes. Barriers to 99DOTS implementation for some people with TB were related to limited literacy, including technology literacy; limited access to electricity to charge their mobile phone to make dosing confirmation calls; and poor network connection. Gender differences in 99DOTS uptake also emerged. Specifically, women with TB were described to be more concerned that 99DOTS use would expose them to TB stigma and to be more likely to have mobile phone-access issues than men with TB. By contrast, men with TB not only had access to mobile phones but also received substantial support from their female partners to take their anti-TB medication and make 99DOTS dosing confirmation calls. Finally, although women with TB were described to face more barriers to 99DOTS use than men with TB, the women\'s narratives centered on the ways the platform facilitated and improved their adherence, whereas the men\'s narratives did not.
Overall, 99DOTS seems to be a feasible and acceptable strategy to support anti-TB medication adherence in Uganda. However, access to mobile phones, inability to charge mobile phones, and concerns about stigma should be considered and addressed as part of programmatic implementation to maximize uptake among all people with TB, particularly women and those with fewer financial resources.

BACKGROUND: Tuberculosis remains a leading infectious cause of death in resource-limited settings. Effective treatment is the cornerstone of tuberculosis control, reducing mortality, recurrence and transmission. Supporting treatment adherence through facility-based observations of medication taking can be costly to providers and patients. Digital adherence technologies (DATs) may facilitate treatment monitoring and differentiated care. The ASCENT-Ethiopia study is a three-arm cluster randomised trial assessing two DATs with differentiated care for supporting tuberculosis treatment adherence in Ethiopia. This study is part of the ASCENT consortium, assessing DATs in South Africa, the Philippines, Ukraine, Tanzania and Ethiopia. The aim of this study is to determine the costs, cost-effectiveness and equity impact of implementing DATs in Ethiopia.
METHODS: A total of 78 health facilities have been randomised (1:1:1) into one of two intervention arms or a standard-of-care arm. Approximately 50 participants from each health facility will be enrolled on the trial. Participants in facilities randomised to the intervention arms are offered a DAT linked to the ASCENT adherence platform for daily adherence monitoring and differentiated response for those who have missed doses. Participants at standard-of-care facilities receive routine care. Treatment outcomes and resource utilisation will be measured for each participant. The primary effectiveness outcome is a composite index of unfavourable end-of-treatment outcomes (lost to follow-up, death or treatment failure) or treatment recurrence within 6 months of end-of-treatment. For the cost-effectiveness analysis, end-of-treatment outcomes will be used to estimate disability-adjusted life years (DALYs) averted. Provider and patient cost data will be collected from a subsample of 5 health facilities per study arm, 10 participants per facility (n = 150). We will conduct a societal cost-effectiveness analysis using Bayesian hierarchical models that account for the individual-level correlation between costs and outcomes as well as intra-cluster correlation. An equity impact analysis will be conducted to summarise equity efficiency trade-offs.
CONCLUSIONS: Trial enrolment is ongoing. This paper follows the published trial protocol and describes the protocol and analysis plan for the health economics work package of the ASCENT-Ethiopia trial. This analysis will generate economic evidence to inform the implementation of DATs in Ethiopia and globally.
BACKGROUND: Pan African Clinical Trial Registry (PACTR) PACTR202008776694999. Registered on 11 August 2020,  https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=12241 .

[This corrects the article DOI: 10.3389/fpubh.2023.1033532.].

Digital technologies can improve adherence to tuberculosis (TB) treatment. We studied the impact of digitizing TB treatment monitoring on adherence among TB patients in Wuhan, China, during 2020-2021.
We compared an electronic system introduced to monitor TB medication adherence (e-Patient Service System; e-PSS) with the p paper-based standard of care (TB Control Information System; TCIS) in terms of prescribed TB treatment doses taken by patients and patient outcome after six months of follow up. We designed a cross sectional study using retrospective data for all drug susceptible pulmonary TB patients recorded on both systems. The main indicators were: compliant first follow up visit (within 3 days of start of treatment); medication adherence (80% or more of monthly doses taken); and end of treatment success ratio.
A total of 1,576 TB patients were recorded in TCIS in July September, 2020 and 1,145 TB cases were included in e-PSS in January March, 2021. The distribution of patient demographic and clinical features was similar between the two groups. A larger proportion from the e-PSS group visited the community doctor in the first three days compared with the TCIS group (48.91 versus 29. 76 % respectively). Medication adherence was also higher in the e-PSS group during the 6 months of treatment than in the TCIS group (84. 28 versus 80.3 3 % respectively). Treatment success was 92.52% in the e-PSS group and 92.07% in the TCIS group. Multivariate logistic regress ion analysis demonstrated that adjusted odds ratios for compliant first follow up visit, medication adherence and favorable treatment outcome in the e-PSS versus TCIS groups were 2.94 (95% 2.47 3.50), 1.33 (95% 1.08 1.63), and 1. 12 (95% CL: 0.79 1.57) respectively.
This study revealed improvements in TB care following an intervention to monitor treatment digitally in patients in Wuhan, China.

UNASSIGNED: The success of a tuberculosis digital adherence technology relies on patients\' satisfaction with and the usability of the technology. This study aimed to evaluate treatment satisfaction and usability of a digital medication event reminder and monitor (MERM) device for patients with tuberculosis to address the prespecified secondary endpoint of the SELFTB trial.
UNASSIGNED: In this multicenter, randomised controlled trial, adults (≥18 years) with new or previously treated, bacteriologically-confirmed, drug-sensitive pulmonary tuberculosis who were eligible to start anti-tuberculosis therapy were recruited from 10 healthcare facilities in Ethiopia. With a computer-generated random number sequence, participants were randomly assigned 1:1 to receive a 15-day tuberculosis medication supply dispensed with an evriMED500® MERM device to self-administer and return every 15 days or the standard in-person DOT. Both arms were followed throughout the standard two-month intensive treatment phase. Treatment was based on the WHO-recommended two-month fixed-dose-combination of first-line anti-tuberculosis drug delivered as a single daily dose (2RHZE). Treatment Satisfaction Questionnaire for Medication version 4 (TSQM 1.4©) was used to measure and compare treatment satisfaction between arms. Adapted System Usability Scale (SUS) was used to assess the usability of the device, with emphasis on ease of use, challenges, benefits, motivation, popularity, and recommendation. The findings were correlated with adherence and clinical endpoints including sputum smear conversion and IsoScreen urine isoniazid test results. This trial is registered with ClinicalTrials.gov, NCT04216420.
UNASSIGNED: Between June 2, 2020, and June 15, 2021, 337 patients were screened for eligibility, of whom 109 participants enrolled and completed the satisfaction [control (n = 57) and intervention (n = 52) arms] and usability [intervention arm (n = 52)] questionnaires. TSQM 1.4© geometric mean scores were: Effectiveness 73.25 [geometric standard deviation (GSD) 1.28], Side Effects 100, Convenience 63.31 (GSD 1.45), and Global Satisfaction 77.29 (GSD 1.25). TSQM score was significantly higher in the intervention vs the control: Effectiveness [85.78 vs 63.43, 95% CI 1.35 (1.26-1.45), p < 0.001], Convenience [85.41 vs 48.18, 95% CI 1.77 (1.63-1.93), p < 0.001], and Global Satisfaction [90.19 vs 67.11, 95% CI 1.34 (1.26-1.43), p < 0.001]. There were significant associations between Global Satisfaction and medication adherence (p = 0.017). Average SUS score was 97.45%, which was close to the best imaginable SUS value of 100%. Likelihood to Recommend (LTR) value was ≥9, on a scale of 0-10, for 90.4% of MERM users, yielding higher net promoters. There was no significant association between usability and medication adherence (p = 0.691).
UNASSIGNED: Our findings suggested that treatment satisfaction scores were superior in the intervention vs control arms and across the domains of Effectiveness, Convenience, and Global Satisfaction. There was excellent usability of the MERM device and a significantly higher number of users likely to promote the device. High tuberculosis burden countries may transform patient-centered care through ongoing evaluation and scale-up of digital health innovations.
UNASSIGNED: U.S. National Institute of Health (NIH) Fogarty International Center and National Institute of Allergy and Infectious Diseases (D43 TW009127) and the Emory Center for AIDS Research (P30 AI050409).

Adherence to tuberculosis (TB) medication is one of the critical challenges to tuberculosis elimination in India. Digital adherence technologies (DAT) have the potential to facilitate medication adherence and monitor it remotely. Tuberculosis Monitoring Encouragement Adherence Drive (TMEAD) is one such DAT piloted in Nasik, Maharashtra, from April 2020 to December 2021. The study aims to assess the adherence and cost-effectiveness of TMEAD compared to the standard of care among patients with drug-sensitive tuberculosis (DSTB) residing in the urban areas of Nasik, Maharashtra, India.
A quasi-experimental study was conducted among new cases of TB as per the National TB Elimination Programme (NTEP) residing in the urban geography of Nasik. The intervention and control arms were purposively selected from non-contaminating TB units (TUs). A total of 400 DSTB patients (200 in the intervention group and 200 in the control group) were enrolled. After enrolment, patients in the intervention arm were provided with the TMEAD device and followed for 24 weeks to assess treatment outcomes. Adherence was measured as those patients who have completed 80% of prescribed doses, as reported during patient follow-up, and further validated by analyzing the trace of rifampicin in urine among 20% of patients from both arms. A budget impact analysis was done to assess the impact of the TMEAD program on the overall state health budget.
Out of 400 enrolled DSTB patients, 261 patients completed treatment, 108 patients were on treatment, 15 patients died, and 16 patients were defaulters over the study period. The study reported overall treatment adherence of 94% among those who completed treatment. Patient reports indicated high levels of treatment adherence in the intervention group (99%) as compared to the control group (90%). Adherence assessed through analyzing trace of rifampicin in the urine sample for the intervention arm was 84% compared to the control arm (80%). Per beneficiary (discounted) cost for TMEAD was Indian rupees (INR) 6,573 (USD 83). The incremental cost-effectiveness ratio of the intervention is INR 11,599 (USD 146), which shows that the intervention is highly cost-effective.
This study revealed that patient-reported treatment adherence was high in TMEAD when compared to standard therapy of care for DSTB patients and the intervention is cost-effective. TMEAD could complement the national strategy to end TB by improving adherence to the treatment regimen in India.

UNASSIGNED: Digital adherence technologies hold promise to improve patient-centered tuberculosis (TB) monitoring, yet few studies have incorporated direct adherence monitoring or assessed patients\' experiences with these technologies. We explored acceptability, feasibility, and refinement needs of the TB Treatment Support Tools (TB-TSTs) intervention linking a mobile app, a urine drug metabolite test, and interactive communication with a treatment supporter.
UNASSIGNED: This pilot study was a parallel-designed single-center randomized controlled trial with exit interviews. Newly diagnosed TB patients were randomized 1:1 using a treatment allocation button in the REDCap software preloaded with a random allocation sequence to usual care or usual care plus the TB-TSTs intervention from a respiratory medicine hospital in the province of Buenos Aires, Argentina and followed for 6-months. Due to the nature of the intervention, blinding to the group allocation could not be achieved for the recruiter or patients. The treatment outcome data extractor was blinded to the group allocation of the participants. Intervention participants used the app to report self-administering medication, potential side effects, submit photos of the urine test, and interact with a treatment supporter. Outcomes were feasibility, acceptability, and treatment outcomes.
UNASSIGNED: Forty-two patients were enrolled and evenly assigned to each group. Intervention participants submitted 147·2±58 (mean, SD) medication self-administration and 144·5±55 side effect reports out of 180 and 47.5±38·4 photos of the urine test out of 77. Treatment success for usual care was 81% [17/21] and 95% [20/21] for the TB-TSTs intervention. Thirty-three themes were identified within the main categories of motivation, what worked, issues experienced, and recommendations. Participants (n=12) rated it as \'easy to use\' (4.57/5), \'would highly recommend to others\' (4·43/5) and reported that access to the treatment support was a critical component. Recommendations included adding an alarm, appointment reminders, and off-line functionality.
UNASSIGNED: Findings suggest that the TB-TSTs intervention was feasible and acceptable and further refinement and testing is warranted.
UNASSIGNED: National Institute of Health K23NR017210.

Digital adherence technologies like 99DOTS are increasingly considered as an alternative to directly observed therapy for tuberculosis (TB) treatment supervision. We evaluated the cost and cost-effectiveness of 99DOTS in a high-TB-burden setting.
We assessed the costs of implementing 99DOTS in Uganda through a pragmatic, stepped-wedge randomized trial. We measured costs from the health system perspective at 5 of 18 study facilities. Self-reported service activity time data were used to assess activity-based service costs; other costs were captured from budgets and key informant discussions using standardized forms. We estimated costs and effectiveness considering the 8-month study period (\"trial specific\") and using a 5-year time horizon (\"extended activities\"), the latter including a \"marginal clinic\" expansion scenario that ignored above-site implementation costs. Cost-effectiveness was assessed as cost per patient successfully completing treatment, using Monte Carlo simulation, cost-effectiveness acceptability curves, and sensitivity analyses to evaluate uncertainty and robustness of results.
The total cost of implementing 99DOTS in the \"trial-specific\" scenario was $99 554 across 18 clinics (range $3771-$6238 per clinic). The cost per treatment success in the \"trial-specific\" scenario was $355 (range $229-$394), falling to $59 (range $50-$70) assuming \"extended activities,\" and $49 (range $42-$57) in the \"marginal clinic\" scenario. The incremental cost-effectiveness of 99DOTS in the \"extended-activity\" scenario was $355 per incremental treatment success.
Costs and cost-effectiveness of 99DOTS were influenced by the degree to which infrastructure is scaled over time. If sustained and scaled up, 99DOTS can be a cost-effective option for TB treatment adherence support in high-TB-burden settings like Uganda.