Predictors of unsuccessful tuberculosis treatment outcomes in Brazil: an analysis of 259,484 patient records – BMC Infectious Diseases

In this study we examined the relationship between treatment outcomes and individual demographics, pre-existing conditions, health-related behaviors, membership of special populations, clinical examination results, and features of health services among individuals treated for TB in Brazil between 2015 and 2018. These analyses revealed elevated risks of unsuccessful TB treatmen associated with a range of demographic, clinical and behavioral factors.

In terms of socio-demographic and behavioral factors, the strongest relationships with unsuccessful treatment outcomes were estimated for old age, no education or limited education, HIV infection, illicit drug use, and homelessness. Elevated mortality on treatment was found to be the primary cause of poor treatment outcomes for individuals with HIV and old age, while elevated loss to follow-up was the most important factors for homeless individuals and those with illicit drug use. Both factors were found to be important for individuals with no education or limited education. These findings are consistent with previous systematic reviews and meta-analyses [11,12,13], and point to the greater challenges of achieving successful treatment outcomes for medically fragile individuals, and for individuals with vulnerable circumstances or health behaviors that make it more difficult to complete the extended treatment regimens required for TB disease. Treatment completion was found to be higher among incarcerated patients, consistent with earlier studies [12, 14, 15]. However, TB treatment completion among incarcerated individuals may be negatively impacted when patients are transferred between facilities or released during treatment, as coordination of care is often challenging [15]. For individuals with diagnosed diabetes, we estimated a lower risk of unsuccessful treatment outcomes. This finding is in conflict with earlier studies that have reported worse treatment outcomes for individuals with diabetes [16]. In our study, it is possible that the subset of individuals with diagnosed diabetes could represent a group that was healthier and with better healthcare access compared to the overall diabetic population, and that different results may have been obtained if the diabetic category also included individuals with undiagnosed diabetes.

In terms of clinical factors, our results revealed a strong relationship between the risk of unsuccessful treatment outcomes and enrollment in DOT. Individuals who enrolled in DOT were substantially more likely to experience a successful treatment outcome, and DOT treatment was associated with lower risks of both loss to follow-up and death on treatment. It is possible these relationships are not consistent across Brazil, as the approach to providing DOT differ at the state level [17, 18]. The greater success rates experienced with DOT treatment must be interpreted carefully, as it will reflect both the impact of DOT through supporting better treatment adherence and completion (the causal effect), as well as differences in treatment outcomes resulting from differences in the characteristics of patients enrolled versus not enrolled in DOT (the non-casual effect). However, the large magnitude of this effect demonstrates the importance of DOT enrollment in understanding TB treatment outcomes in this setting. This is also shown in the results for the variable importance analysis, which found DOT to be the most important single factor for predicting treatment outcomes in this study population. As traditional DOT requires patients to consume drugs on-site multiple times per week, this can cause challenges for some patients (particularly those in vulnerable situations) and limit the proportion of patients enrolled in DOT. To address this challenge, the Brazilian health system is considering alternative DOT modalities that do not require in-person attendance (e.g., video-based DOT). If successful, these new DOT modalities could raise DOT enrollment and enhance treatment adherence (particularly in groups with currently low rates of treatment success), as well as giving patients greater autonomy over when and where they take their medication. However, it is unclear whether video DOT will meet the needs of individuals with low digital access or literacy. Additional resources and strategies may be required for these groups.

The health system level at which TB treatment is provided was also found to be strongly related to the risk of unsuccessful treatment. Controlling for other factors, patients treated in primary facilities were less likely to experience an unsuccessful treatment outcome compared to those treated in secondary or tertiary facilities. As higher-level clinical facilities typically treat individuals with more complex disease cases, it is likely the results for this variable reflect differences in case-mix between health system levels, not sufficiently captured by the other variables included in the analysis [9]. However, the high levels of unsuccessful outcome experienced by patients at higher-level facilities indicates the potential for greater absolute improvements in outcomes in these settings.

This study revealed substantial variation in treatment outcomes between states. While these differences were partially explained by inter-state variation in the patient-level factors examined in the analyses, large differences remained after controlling for these factors. Rio De Janeiro, Rio Grande do Sul, Paraná, Mato Grosso do Sul, and Roraima each had adjusted odds of unsuccessful treatment > 25% greater than the reference, while Acre, Piauí, and Rio Grande do Norte had adjusted odds of unsuccessful treatment > 25% lower than the reference. Additional studies are needed to understand the factors determining differences in treatment outcomes across states. When analyses were stratified by year, we found the estimated relationships to be generally stable over time, although ORs appeared to be declining for individuals with HIV.

Several previous studies conducted in low- and middle-income countries have focused on specific factors associated with the TB treatment outcome, such as HIV co-infection, TB drug resistance, and social vulnerability [19,20,21]. Our study adds to this literature by using national registry data to identify the patient subgroups that are at greater risk of poor treatment outcomes. Strengths of this study include the large sample size—allowing precise inferences—and the wide range of clinical and demographic factors available for analysis. However, this study has several limitations. Most importantly, the relationships estimated in this analysis represent statistical associations rather than causal relationships. As a consequence, while the results can be used to describe patient subgroups that are at high risk of poor outcomes—and that would potentially benefit from greater clinical attention—they do not describe the improvements in outcomes that could be achieved by changes in patient care, such as by devolving more TB care to the primary facilities or increasing DOT enrollment. Second, the outcome examined (treatment success) has limitations as an indicator of treatment effectiveness. In particular, some individuals coded as treatment success will not have achieved sterilizing cure and will go on to relapse in the years following treatment. While these relapse cases may be identified in research cohorts, they are not linked to the original treatment episode in the disease registry data. Third, we did not investigate interactions between exposure variables, or how the estimated relationships varied across states. Given the differences in TB care and populations characteristics across Brazil, it is possible such variation exists. Finally, the analysis revealed some unexpected relationships that are difficult to explain with available data (for example, the better treatment outcomes estimated for TB with both pulmonary and extrapulmonary involvement). Understanding these findings will require additional research.