Temporal Factors and Missed Doses of Tuberculosis Treatment. A Causal Associations Approach to Analyses of Digital Adherence Data

Rationale: Tuberculosis treatment lasts for 6 months or more. Treatment adherence is critical; regimen length, among other factors, makes this challenging. Globally, analyses mapping common types of nonadherence are lacking. For example, is there a greater challenge resulting from early treatment cessation (discontinuation) or intermittent missed doses (suboptimal dosing implementation)? This is essential knowledge for the development of effective interventions and more “forgiving” regimens, as well as to direct national tuberculosis programs. Objectives: To granularly describe how patients take their tuberculosis medication and the temporal factors associated with missed doses. Methods: The present study included patients with pulmonary tuberculosis enrolled in the control arm of a pragmatic, cluster-randomized trial in China of electronic reminders to improve treatment adherence. Treatment was the standard 6-month course (180 d), dosed every other day (90 doses). Medication monitor boxes recorded adherence (box opening) without prompting reminders. Patterns of adherence were visualized and described. Mixed-effects logistic regression models examined the temporal factors associated with per-dose suboptimal dosing implementation, adjusting for clustering within a participant. Cox regression models were used to examine the association between early suboptimal dosing implementation and permanent discontinuation. Results: Across 780 patients, 16,794 (23.9%) of 70,200 doses were missed, 9,487 of which were from suboptimal dosing implementation (56.5%). By 60 days, 5.1% of participants had discontinued, and 14.4% had discontinued by 120 days. Most participants (95.9%) missed at least one dose. The majority of gaps were of a single dose (71.4%), although 22.6% of participants had at least one gap of 2 weeks or more. In adjusted models, the initiation–continuation phase transition (odds ratio, 3.07 [95% confidence interval, 2.68–3.51]) and national holidays (1.52 [1.39–1.65]) were associated with increased odds of suboptimal dosing implementation. Early-stage suboptimal dosing implementation was associated with increased discontinuation rates. Conclusions: Digital tools provide an unprecedented step change in describing and addressing nonadherence. In our setting, nonadherence was common; patients displayed a complex range of patterns. Dividing nonadherence into suboptimal dosing implementation and discontinuation, we found that both increased over time. Discontinuation was associated with early suboptimal dosing implementation. These apparent causal associations between temporal factors and nonadherence present opportunities for targeted interventions. Clinical trial registered with the ISRCTN Registry (ISRCTN46846388).