Digital adherence technology for tuberculosis treatment supervision: A stepped-wedge cluster-randomized trial in Uganda

Background Adherence to and completion of tuberculosis (TB) treatment remain problematic in many high-burden countries. 99DOTS is a low-cost digital adherence technology that could increase TB treatment completion. Methods and findings We conducted a pragmatic stepped-wedge cluster-randomized trial including all adults treated for drug-susceptible pulmonary TB at 18 health facilities across Uganda over 8 months (1 December 2018-31 July 2019). Facilities were randomized to switch from routine (control period) to 99DOTS-based (intervention period) TB treatment supervision in consecutive months. Patients were allocated to the control or intervention period based on which facility they attended and their treatment start date. Health facility staff and patients were not blinded to the intervention. The primary outcome was TB treatment completion. Due to the pragmatic nature of the trial, the primary analysis was done according to intention-to-treat (ITT) and per protocol (PP) principles. This trial is registered with the Pan African Clinical Trials Registry (PACTR201808609844917). Of 1,913 eligible patients at the 18 health facilities (1,022 and 891 during the control and intervention periods, respectively), 38.0% were women, mean (SD) age was 39.4 (14.4) years, 46.8% were HIV-infected, and most (91.4%) had newly diagnosed TB. In total, 463 (52.0%) patients were enrolled on 99DOTS during the intervention period. In the ITT analysis, the odds of treatment success were similar in the intervention and control periods (adjusted odds ratio [aOR] 1.04, 95% CI 0.68-1.58, p = 0.87). The odds of treatment success did not increase in the intervention period for either men (aOR 1.24, 95% CI 0.73-2.10) or women (aOR 0.67, 95% CI 0.35-1.29), or for either patients with HIV infection (aOR 1.51, 95% CI 0.81-2.85) or without HIV infection (aOR 0.78, 95% CI 0.46-1.32). In the PP analysis, the 99DOTS-based intervention increased the odds of treatment success (aOR 2.89, 95% CI 1.57-5.33, p = 0.001). The odds of completing the intensive phase of treatment and the odds of not being lost to follow-up were similarly improved in PP but not ITT analyses. Study limitations include the likelihood of selection bias in the PP analysis, inability to verify medication dosing in either arm, and incomplete implementation of some components of the intervention. Conclusions 99DOTS-based treatment supervision did not improve treatment outcomes in the overall study population. However, similar treatment outcomes were achieved during the control and intervention periods, and those patients enrolled on 99DOTS achieved high treatment completion. 99DOTS-based treatment supervision could be a viable alternative to directly observed therapy for a substantial proportion of patients with TB. Trial registration Pan-African Clinical Trials Registry (PACTR201808609844917). Author summary Why was this study done? A PubMed search for publications prior to 1 January 2019 with the search terms "adherence technology AND tuberculosis" revealed 4 randomized trials and 14 observational studies of digital adherence technologies (DATs) being used to support tuberculosis (TB) treatment, most of which focused primarily on adherence rather than treatment outcome. A systematic review found limited evidence to support the effectiveness of DATs for improving TB treatment outcomes. What did the researchers do and find? We adapted 99DOTS, a low-cost DAT already widely used in India, with input from local stakeholders, and conducted a pragmatic randomized trial of the resulting 99DOTS-based intervention at 18 health facilities in Uganda. Only about half of patients were initiated on 99DOTS-based treatment supervision during the intervention period. The 99DOTS-based intervention did not increase treatment completion in the full study population. Treatment completion was high (>85%) among the nonrandom sample of patients initiated on 99DOTS-based treatment supervision during the intervention period. What do these findings mean? 99DOTS should not be used as a universal replacement for directly observed therapy for TB treatment supervision, with the aim of increasing population-level treatment completion. 99DOTS-based treatment supervision could enable a substantial proportion of patients with TB to complete treatment without the inconvenience and additional costs of directly observed therapy. Further research is needed to assess whether overall treatment outcomes can be improved by increasing uptake of 99DOTS or other low-cost DATs, and to identify additional measures needed to support all patients to complete treatment.