Defining Outcomes of Tuberculosis (Treatment): From the Past to the Future

Abstract

Untreated active tuberculosis (TB) has a very high long-term mortality. Treatment of TB reduces mortality dramatically and should maximize cure, preventing ongoing transmission and TB sequelae. However, predicting the risk of failure and relapse is crucial for the management of individual patients and for the evaluation of effectiveness of programs. Various outcome definitions for drug-sensitive and drug-resistant TB were developed, implemented, and endorsed since introduction of TB chemotherapy by the World Health Organization (WHO), mostly based on culture and smear results. They should be applicable for individual patient care, surveillance, and research. Definitions with focus on program evaluation differ from definitions to evaluate the efficacy and effectiveness of regimens. Lack of sputum production at the later stage of treatment reduces the easy applicability of current definitions. Definitions of failure and cure are sometimes difficult to apply. Alternative approaches suggest culture positivity at 6 months or more of treatment as an indicator for failure. New definitions for cure including a relapse-free period posttreatment and reduced number of culture and smear results are considered. Increasing variation and individualization of treatment and its duration urgently require new approaches using pathogen- or host-specific biomarkers, which indicate risk of failure and define cure. Such biomarkers are under evaluation but still far from translation in clinical routine practice.

Concordance of three approaches for operationalizing outcome definitions for multidrug-resistant TB

“…The approach used for outcome assignment should align with the intended purpose. 6 , 10 – 12 Calculated outcomes may reduce heterogeneity across time and place while allowing flexibility to contend with changing outcome definitions and address specific research objectives. 10 – 12 For example, the failure-dominant algorithm may be most appropriate for evaluating the effectiveness of an initial regimen because treatment failure is defined as soon as it is identified at the end of 8 months.…”

“…Missingness of culture results could be due to reagent stock-outs, limited laboratory capacity, or a patient’s inability to produce an adequate sputum sample (especially during the later stages of treatment). 6 For patients who were unable to produce sputum samples, missing cultures could be considered negative. 12 Recording the reasons for missing sputum samples or culture results, and reasons for necessary deviations from standardized definitions may facilitate further honing of WHO outcome definitions and associated algorithms for calculated outcomes.…”

“… 2 – 5 In practice, however, applying standardized definitions, which include the consideration of both quantity and timing of culture results, may be challenging. 1 , 6 In clinical settings, consistent outcome assignment may be complicated by differences in treatment duration; availability of microbiological results (relative to the timing of cessation of treatment); availability and use of clinical and radiographic data; adherence to treatment; and information on reasons for treatment change. 6 To enhance standardization, algorithms can be used to calculate outcomes based on pre-specified criteria.…”

“…1 , 6 In clinical settings, consistent outcome assignment may be complicated by differences in treatment duration; availability of microbiological results (relative to the timing of cessation of treatment); availability and use of clinical and radiographic data; adherence to treatment; and information on reasons for treatment change. 6 To enhance standardization, algorithms can be used to calculate outcomes based on pre-specified criteria. Algorithms can also be adapted for different purposes, such as evaluating the effectiveness of an initial regimen without considering the effects of subsequent treatment adjustments or the effectiveness of overall treatment strategies after considering such effects.…”

Bedaquiline containing regimen showed excellent efficacy and safety for the treatment of pre-extensively drug-resistant tuberculosis

“…So we could only apply the suboptimal outcome de nition. This de nition kept in line with the outcome de nition of WHO, but may be inferior to criteria of TB net, since the later took into consideration of the recurrence rate within one year after treatment completion [22]. Until this manuscript was submitted, a total of 34 cases in Bdq group had been followed in clinic or by telephone for more than 12 months after completion.…”