Effects of missed anti-tuberculosis therapy doses on treatment outcome: a multi-center cohort study

Abstract

Background: Tuberculosis (TB) remains a leading cause of infectious disease mortality globally. Although directly observed therapy (DOT) has been widely implemented to improve adherence, nonadherence continues to compromise treatment success rates, especially in real-world settings. Therefore, this study aims to assess the impact of missed doses on TB treatment outcomes.

Methods: Prospective study that followed adults with drug-sensitive TB for two years after TB treatment initiation at five clinical centers of the RePORT-Brazil cohort between June 2015 and June 2019. Participants not in DOT or followed for less than 30 days were excluded. Nonadherence was defined as the percentage of missed doses relative to the prescribed regimen, monitored daily through DOT. The primary composite outcome comprised treatment failure, disease recurrence, drug resistance, death, or loss to follow-up (LTFU) after 30 days of treatment. Associations were assessed with multivariable logistic regression.

Findings: Among the 578 participants analyzed, 218 (37·7%) experienced unfavorable outcomes. Overall, 23% of participants missed more than 10% of prescribed doses, and this group had an 81·2% likelihood of experiencing unfavorable outcomes, compared to only 21·6% among those with complete adherence. A significant association was observed between the percentage of missed doses and unfavorable outcomes (adjusted OR: 1·11, 95% CI: 1·07-1·14, p-value < 0·0001).

Interpretation: Even minor nonadherence in TB treatment was associated with an increased risk of unfavorable outcomes, highlighting the role of adherence in successful TB care.

Funding: Fundação Oswaldo Cruz, Fundação José Silveira, Departamento de Ciência e Tecnologia, US National Institute of Allergy and Infectious Diseases.

Keywords: Adherence; Compliance; Treatment; Tuberculosis; Unfavorable treatment outcome.

Fig. 1

Flowchart of the study.

Fig. 2

Distribution of missed doses and their relationship with treatment outcomes across phases of tuberculosis treatment. (A) Distribution of missed doses as a percentage of the prescribed therapy, stratified by favorable and unfavorable outcomes. (B) Proportion of unfavorable outcomes stratified by adherence levels total adherence, adherence above 90%, and nonadherence [missing more than 10% of prescribed doses]. (C) Heatmap of missed doses over months, divided into the intensive (months 1–2), maintenance (months 3–6), and extended phases of treatment. Warmer colors indicate higher percentages of missed doses. Gray areas represent months in which no doses were taken, which may reflect either complete treatment discontinuation or completion of the prescribed regimen.

Fig. 3

Associations between patient's characteristics and unfavorable treatment outcomes. (A) Binary logistic regression model assessing the association between patient's characteristics and unfavorable treatment outcomes. Odds ratios (OR) with 95% confidence intervals (CI) are presented for both unadjusted (white) and adjusted (black) models. The vertical dotted line represents an OR of 1, indicating no effect. Abbreviations: Tuberculosis (TB), Body Mass Index (BMI), People Living with HIV (PLWHIV). (B) Receiver operating characteristic (ROC) curve of the multivariable model, with an area under the curve (AUC) indicating strong discrimination. (C) Scatterplot of the predicted probability of unfavorable outcomes for each participant, plotted against their percentage of missed prescribed doses. Pink and blue dots represent participants with unfavorable and favorable outcomes, respectively. The black curve represents a locally weighted scatterplot smoothing (LOWESS) line, which visually illustrates the relationship between missed doses and predicted risk. A reference line illustrates a 10% absolute increase in risk for context.