Adverse treatment outcomes in multidrug resistant tuberculosis go beyond the microbe-drug interaction: Results of a multiple correspondence analysis. / Los resultados adversos en el tratamiento de la tuberculosis resistente a múltiples fármacos sobrepasan la relación fármaco-microorganismo: resultados de un análisis de correspondencia múltiple

INTRODUCTION: Multidrug-resistant tuberculosis treatment is effective in 50% of patients due to several factors including antibiotic susceptibility of the microorganism, adverse treatment reactions, social factors, and associated comorbidities. OBJECTIVES: In this study, we describe the demographics, clinical characteristics, and factors associated with treatment outcomes in multidrug-resistant tuberculosis (MDR-TB) patients in Medellín, Colombia. MATERIALS AND METHODS: We conducted a retrospective analysis using data from patients diagnosed with MDR-TB attending Hospital La María in Medellín, Colombia, for treatment between 2010 and 2015. Patients were categorized as having successful (cured) or poor (failure, lost to follow-up, and death) treatment outcomes. Associations between demographic, clinical factors, laboratory results, treatment outcomes, and follow-up information were evaluated by univariate, multivariate, and multiple correspondence analyses. RESULTS: Of the 128 patients with MDR-TB, 77 (60%) had successful outcomes. Of those with poor outcomes, 26 were lost to follow-up, 15 died, and 10 were treatment failures. Irregular treatment, the presence of comorbidities, and positive cultures after more than two months of treatment were associated with poor outcomes compared to successful ones (p<0.05 for all). The multiple correspondence analyses grouped patients who were lost to follow-up, had HIV, and drug addiction, as well as patients with treatment failure, irregular treatment, and chronic obstructive pulmonary disease. CONCLUSION: The recognition of factors affecting treatment is essential and was associated with treatment outcomes in this series of patients. Early identification of these factors should increase the rates of treatment success and contribute to MDR-TB control.

Introducción. El tratamiento de la tuberculosis multirresistente tiene una efectividad del 50 %, afectado por múltiples factores como la sensibilidad del microorganismo, las reacciones secundarias, los factores sociales y las comorbilidades existentes. Objetivos. Describir la demografía, las características clínicas y los factores pronósticos asociados con los resultados del tratamiento en pacientes multirresistentes (TB-MDR) de Medellín, Colombia. Métodos. Se hizo un análisis retrospectivo de los datos de los pacientes con TB-MDR atendidos en el Hospital La María de Medellín, Colombia, que fueron tratados entre el 2010 y el 2015. Los pacientes se categorizaron con tratamiento exitoso (curados) o con tratamiento fallido (falla en el tratamiento, pérdida durante el seguimiento y muerte). Se determinó la asociación entre las características demográficas y clínicas, los resultados de los exámenes de laboratorio, los desenlaces del tratamiento y la información del seguimiento, utilizando análisis univariado, multivariado y de correspondencia múltiple. Resultados. De 128 pacientes con TB-MDR, 77 (60 %) tuvieron un tratamiento exitoso. De los que tuvieron un tratamiento fallido, 26 pacientes se perdieron en el seguimiento, 15 murieron y 10 tuvieron falla en el tratamiento. El tratamiento irregular, las comorbilidades y los cultivos positivos más allá de 2 meses de tratamiento se asociaron significativamente con los tratamientos fallidos (p<0,05). El análisis de correspondencia múltiple agrupó los pacientes con pérdida en el seguimiento, con HIV y tratamientos irregulares, y los pacientes con tratamientos irregulares y enfermedad pulmonar obstructiva crónica con falla en el tratamiento y muerte. Conclusión. El reconocimiento temprano de los factores que afectan el desenlace del tratamiento de los pacientes con TB-MDR es esencial; la identificación de dichos factores debería incrementar el éxito del tratamiento y contribuir al adecuado control de la TB-MDR.

Predictive factors for unfavourable treatment in MDR-TB and XDR-TB patients in Rio de Janeiro State, Brazil, 2000-2016.

SETTING: The State of Rio de Janeiro stands out as having the second highest incidence and the highest mortality rate due to TB in Brazil. This study aims at identifying the factors associated with the unfavourable treatment of MDR/XDR-TB patients in that State. METHOD: Data on 2269 MDR-TB cases reported in 2000-2016 in Rio de Janeiro State were collected from the Tuberculosis Surveillance System. Bivariate and multivariate logistic regressions were run to estimate the factors associated with unfavourable outcomes (failure, default, and death) and, specifically, default and death. RESULTS: The proportion of unfavourable outcomes was 41.9% among MDR-TB and 81.5% among XDR-TB. Having less than 8 years of schooling, and being an Afro-Brazilian, under 40 years old and drug user were associated with unfavourable outcome and default. Bilateral disease, HIV positive, and comorbidities were associated with death. XDR-TB cases had a 4.7-fold higher odds of an unfavourable outcome, with 29.3% of such cases being not treated for multidrug resistance in the past. CONCLUSION: About 30% of XDR-TB cases may have occurred by primary transmission. The high rates of failure and death in this category reflect the limitation of treatment options. This highlights the urgency to incorporate new drugs in the treatment.

Multidrug-resistant tuberculosis in Lisbon: unfavourable treatment and associated factors, 2000-2014.

SETTING: The incidence of tuberculosis (TB) has been decreasing in Portugal. Lisbon concentrates the largest number of cases of multidrug-resistant (MDR) TB in the country. This study aims at identifying clinical and demographic factors associated with unfavourable treatment results of patients with MDR-TB in the city.METHOD: The data on 265 MDR-TB cases, notified from 2000 to 2014 in the District of Lisbon, were collected from the Tuberculosis Surveillance System. Unfavourable cases were classified as failure, loss to follow-up (LTFU) and death. Bivariate and multivariate logistic regressions were undertaken to estimate the factors associated with unfavourable outcomes, LTFU and death.RESULTS: The proportion of unfavourable outcomes was 30.5%. These were associated mostly with being male, foreign-born and resistant to kanamycin. Death was associated with being human immunodeficiency virus-positive and resistant to kanamycin. Being foreign-born had a 4.46-fold higher odds of a LTFU outcome than did being Portuguese-born. The foreign-born patients were mostly African immigrants.CONCLUSION: The main finding in this study is that foreign-born patients are associated with a higher probability of unfavourable outcomes than Portuguese-born patients. Therefore, foreign-born patients need more careful monitoring in the control of MDR-TB.

Predictive model of unfavorable outcomes for multidrug-resistant tuberculosis.

OBJECTIVE: to analyze the temporal trend, identify the factors related and elaborate a predictive model for unfavorable treatment outcomes for multidrug-resistant tuberculosis (MDR-TB). METHODS: Retrospective cohort study with all cases diagnosed with MDR-TB between the years 2006 and 2015 in the state of São Paulo. The data were collected from the state system of TB cases notifications (TB-WEB). The temporal trend analyzes of treatment outcomes was performed through the Prais-Winsten analysis. In order to verify the factors related to the unfavorable outcomes, abandonment, death with basic cause TB and treatment failure, the binary logistic regression was used. Pictorial representations of the factors related to treatment outcome and their prognostic capacity through the nomogram were elaborated. RESULTS: Both abandonment and death have a constant temporal tendency, whereas the failure showed it as decreasing. Regarding the risk factors for such outcomes, using illicit drugs doubled the odds for abandonment and death. Besides that, being diagnosed in emergency units or during hospitalizations was a risk factor for death. On the contrary, having previous multidrug-resistant treatments reduced the odds for the analyzed outcomes by 33%. The nomogram presented a predictive model with 65% accuracy for dropouts, 70% for deaths and 80% for failure. CONCLUSIONS: The modification of the current model of care is an essential factor for the prevention of unfavorable outcomes. Through predictive models, as presented in this study, it is possible to develop patient-centered actions, considering their risk factors and increasing the chances for cure.

Mortality in hospitalized patients with tuberculous meningitis.

BACKGROUND: To evaluate the mortality in hospitalized patients with tuberculous meningitis and describe factors associated with an increased risk of mortality. METHODS: Retrospective study of hospitalized patients with tuberculous meningitis between 2006 and 2015 in Peru performing a generalized linear regression to identify factors predictive of in-hospital mortality. RESULTS: Of 263 patients, the median age was 35 years, 72.6% were men, 38% were positive for HIV upon admission, 24% had prior TB infections and 2.3% had prior MDR-TB infections. In-hospital mortality was 30.4% of all study patients with a final diagnosis of TBM. When multivariable analysis was applied, significant associations with in-hospital mortality were seen among patients with HIV (RR 2.06; Confidence Interval 95% (95% CI) 1.44-2.94), BMRC II (RR 1.78; 95% CI 1.07-2.97), BMRC III (RR 3.11; 95% CI 1.78-5.45) and positive CSF cultures (RR 1.95; 95% CI 1.39-2.74). CONCLUSIONS: In-hospital mortality is higher among patients with HIV infections, age over 40 years, positive CSF TB culture and BMRC stage II or III.

Predictive model of unfavorable outcomes for multidrug-resistant tuberculosis / Modelo preditivo dos desfechos desfavoráveis da tuberculose multidroga-resistente

ABSTRACT OBJECTIVE to analyze the temporal trend, identify the factors related and elaborate a predictive model for unfavorable treatment outcomes for multidrug-resistant tuberculosis (MDR-TB). METHODS Retrospective cohort study with all cases diagnosed with MDR-TB between the years 2006 and 2015 in the state of São Paulo. The data were collected from the state system of TB cases notifications (TB-WEB). The temporal trend analyzes of treatment outcomes was performed through the Prais-Winsten analysis. In order to verify the factors related to the unfavorable outcomes, abandonment, death with basic cause TB and treatment failure, the binary logistic regression was used. Pictorial representations of the factors related to treatment outcome and their prognostic capacity through the nomogram were elaborated. RESULTS Both abandonment and death have a constant temporal tendency, whereas the failure showed it as decreasing. Regarding the risk factors for such outcomes, using illicit drugs doubled the odds for abandonment and death. Besides that, being diagnosed in emergency units or during hospitalizations was a risk factor for death. On the contrary, having previous multidrug-resistant treatments reduced the odds for the analyzed outcomes by 33%. The nomogram presented a predictive model with 65% accuracy for dropouts, 70% for deaths and 80% for failure. CONCLUSIONS The modification of the current model of care is an essential factor for the prevention of unfavorable outcomes. Through predictive models, as presented in this study, it is possible to develop patient-centered actions, considering their risk factors and increasing the chances for cure.

RESUMO OBJETIVO Analisar a tendência temporal, identificar os fatores relacionados e elaborar um modelo preditivo para os desfechos desfavoráveis do tratamento da tuberculose multidroga-resistente. MÉTODOS Estudo de coorte retrospectiva com todos os casos diagnosticados com tuberculose multidroga-resistente entre os anos de 2006 e 2015 no estado de São Paulo. Os dados secundários foram provenientes do sistema estadual de notificações de casos de tuberculose, o TBWeb. Foi realizada a análise de tendência temporal dos desfechos de tratamento por meio da regressão de Prais-Winsten. Para verificar os fatores relacionados com os desfechos desfavoráveis (óbito com tuberculose como causa básica, abandono e falência do tratamento), foi empregada a regressão logística binária. Representações pictóricas dos fatores relacionados ao desfecho do tratamento e sua capacidade prognóstica foram elaboradas por meio de nomogramas. RESULTADOS Tanto o abandono como o óbito tiveram tendência temporal estacionária, enquanto a falência apresentou tendência decrescente. Em relação aos fatores de risco para tais desfechos, utilizar drogas ilícitas dobrou as chances de abandono e óbito. Além disso, ser diagnosticado em unidades de urgência ou emergência ou durante internações hospitalares foi um fator de risco para o óbito. Ao contrário, ter feito tratamentos prévios da multidroga-resistência reduziu as chances dos desfechos analisados. O nomograma apresentou um modelo preditivo com precisão de 65% para os abandonos, 70% para os óbitos e 80% para a falência. CONCLUSÕES A prevenção de desfechos desfavoráveis no tratamento da tuberculose multidroga-resistente implica a modificação do modelo de atenção vigente. Utilizando modelos preditivos, como o apresentado neste estudo, torna-se possível elaborar ações centradas nos pacientes, considerando seus fatores de risco e aumentando as chances de cura.

Rapid drug susceptibility testing and treatment outcomes for multidrug-resistant tuberculosis in Peru.

SETTING: The detection of multidrug-resistant tuberculosis (MDR-TB) using rapid drug susceptibility testing (DST) has increased steadily in recent years in Peru, from 9216 tests in 2010 to 27 021 tests in 2015. Research examining the impact of rapid DST on treatment outcomes is required. OBJECTIVE: To evaluate the association between rapid DST use (nitrate reductase assay, microscopic observation drug susceptibility assay [MODS] and GenoType® MTBDRplus) and treatment outcomes and mortality in MDR-TB patients in Peru. DESIGN: Retrospective cohort study of patients diagnosed with pulmonary MDR-TB between 2010 and 2013 (with treatment outcomes up to December 2015) using the electronic registry of the Peruvian National TB Programme. RESULTS: A total of 2671 MDR-TB patients were included; the median age was 27 years, 2.8% were co-infected with the human immunodeficiency virus. Use of rapid DST was associated with a 40% increase in the adjusted odds of treatment success (aOR 1.40, 95%CI 1.19-1.64) and a 54% reduction in mortality (aOR 0.46, 95%CI 0.33-0.64). Higher treatment success rates were driven by MODS and GenoType® MTBDRplus testing (aORs for unsuccessful outcomes respectively 0.68 and 0.66). CONCLUSION: The use of rapid DST (MODS and MTBDRplus) to diagnose MDR-TB was associated with a reduction in the odds of death and a substantial increase in the odds of treatment success.

Predictors of mortality in multidrug-resistant tuberculosis patients from Brazilian reference centers, 2005 to 2012.

OBJECTIVES: To determine the main predictors of death in multidrug-resistant (MDRTB) patients from Brazil. DESIGN: Retrospective cohort study, a survival analysis of patients treated between 2005 and 2012. RESULTS: Of 3802 individuals included in study, 64.7% were men, mean age was 39 (1-93) years, and 70.3% had bilateral pulmonary disease. Prevalence of human immunodeficiency virus (HIV) was 8.3%. There were 479 (12.6%) deaths. Median survival time was 1452 days (4 years). Factors associated with increased risk of death were age greater than or equal to 60 years (hazard rate [HR] = 1.6, confidence interval [CI] = 1.15-2.2), HIV co-infection (HR = 1.46; CI = 1.05-1.96), XDR resistance pattern (HR = 1.74, CI = 1.05-2.9), beginning of treatment after failure (HR = 1.72, CI = 1.27-2.32), drug abuse (HR = 1.64, CI = 1.22-2.2), resistance to ethambutol (HR = 1.30, CI = 1.06-1.6) or streptomycin (HR = 1.24, CI = 1.01-1.51). Mainly protective factors were presence of only pulmonary disease (HR = 0.57, CI = 0.35-0.92), moxifloxacin use (HR = 0.44, CI = 0.25-0.80), and levofloxacin use (HR = 0.75; CI = 0.60-0.94). CONCLUSION: A more comprehensive approach is needed to manage MDRTB, addressing early diagnostic, improving adhesion, and comorbidities, mainly HIV infection and drug abuse. The latest generation quinolones have an important effect in improving survival in MDRTB.

Predictors of mortality in multidrug-resistant tuberculosis patients from Brazilian reference centers, 2005 to 2012

ABSTRACT Objectives To determine the main predictors of death in multidrug-resistant (MDRTB) patients from Brazil. Design Retrospective cohort study, a survival analysis of patients treated between 2005 and 2012. Results Of 3802 individuals included in study, 64.7% were men, mean age was 39 (1-93) years, and 70.3% had bilateral pulmonary disease. Prevalence of human immunodeficiency virus (HIV) was 8.3%. There were 479 (12.6%) deaths. Median survival time was 1452 days (4 years). Factors associated with increased risk of death were age greater than or equal to 60 years (hazard rate [HR] = 1.6, confidence interval [CI] = 1.15-2.2), HIV co-infection (HR = 1.46; CI = 1.05-1.96), XDR resistance pattern (HR = 1.74, CI = 1.05-2.9), beginning of treatment after failure (HR = 1.72, CI = 1.27-2.32), drug abuse (HR = 1.64, CI = 1.22-2.2), resistance to ethambutol (HR = 1.30, CI = 1.06-1.6) or streptomycin (HR = 1.24, CI = 1.01-1.51). Mainly protective factors were presence of only pulmonary disease (HR = 0.57, CI = 0.35-0.92), moxifloxacin use (HR = 0.44, CI = 0.25-0.80), and levofloxacin use (HR = 0.75; CI = 0.60-0.94). Conclusion A more comprehensive approach is needed to manage MDRTB, addressing early diagnostic, improving adhesion, and comorbidities, mainly HIV infection and drug abuse. The latest generation quinolones have an important effect in improving survival in MDRTB.

Factors associated with loss to follow-up and death in cases of drug-resistant tuberculosis (DR-TB) treated at a reference center in Rio de Janeiro, Brazil. / Fatores associados ao abandono e ao óbito de casos de tuberculose drogarresistente (TBDR) atendidos em um centro de referência no Rio de Janeiro, Brasil.

Drug-resistant tuberculosis (DR-TB) poses a serious threat to tuberculosis (TB) control in Brazil and worldwide. The current study investigated factors associated with loss to follow-up and death in the course of treatment for DR-TB in a tertiary reference center in the city of Rio de Janeiro, Brazil. This was a retrospective cohort study of cases reported to the Information System on Special Treatments for Tuberculosis (SITETB) from January 1, 2012, to December 31, 2013. A total of 257 patients were reported to the SITETB and initiated treatment for DR-TB. Of this total, 139 (54.1%) achieved treatment success as the outcome, 54 (21%) were lost to follow-up, and 21 (8.2%) died. Following a multiple multinomial logistic regression analysis, the age bracket older than 50 years was the only protective factor against loss to follow-up, whereas less than eight years of schooling and reentry after loss to follow-up were considered risk factors. Reentry after loss to follow-up, relapse, and treatment failure appeared as risk factors. Our data reinforce the concept that loss to follow-up in drug-resistant tuberculosis is a serious public health problem, and that adequate follow-up of treatment is necessary in patients with this history and low schooling. A social support network for patients is also indispensable for avoiding unfavorable outcomes.

A tuberculose drogarresistente (TBDR) representa hoje uma grave ameaça aos avanços no controle da tuberculose (TB) no Brasil e no mundo. Neste estudo, investigam-se fatores associados ao abandono e ao óbito de casos em tratamento para TBDR, em um centro de referência terciária do Município do Rio de Janeiro, Brasil. Trata-se de um estudo de coorte retrospectiva, a partir dos casos notificados no Sistema de Informação de Tratamentos Especiais de Tuberculose (SITETB), no período de 1º de janeiro de 2012 a 31 de dezembro de 2013. Um total de 257 pacientes foi notificado no SITETB e iniciou o tratamento para TBDR. Desse total, 139 (54,1%) tiveram sucesso terapêutico como desfecho, 54 (21%) abandonaram o tratamento e 21 (8,2%) evoluíram para óbito. Após análise de regressão logística multinomial múltipla, a faixa etária acima de cinquenta anos foi observada como único fator de proteção ao abandono, ao passo que ter menos de oito anos de escolaridade e reingresso após abandono foram considerados como fatores de risco. Reingresso após abandono, recidiva e falência indicaram fatores de risco. Nossos dados reforçam a concepção de que o abandono do tratamento de tuberculose resistente é um sério problema de saúde pública, sendo necessário um adequado acompanhamento no tratamento de pacientes com esse histórico e com baixa escolaridade. Além disso, uma rede de apoio social ao paciente é imprescindível para que desfechos desfavoráveis sejam evitados.

La tuberculosis farmacorresistente (TBFR) representa hoy una grave amenaza para los avances en el control de la tuberculosis (TB) en Brasil y en el mundo. En este estudio, se investigan factores asociados al abandono y al óbito de casos en tratamiento para TBDR, dentro de un centro de referencia de carácter terciario del municipio de Río de Janeiro, Brasil. Se trata de un estudio de cohorte retrospectiva, a partir de los casos notificados en el Sistema de Información de Tratamientos Especiales de Tuberculosis (SITETB), durante el período del 1 de enero de 2012 al 31 de diciembre de 2013. Un total de 257 pacientes fue notificado en el SITETB y comenzó el tratamiento para TBDR. De ese total, 139 (un 54,1%) tuvieron éxito terapéutico como desenlace, 54 (un 21%) abandonaron el tratamiento y un 21 (8,2%) evolucionaron hacia óbito. Tras el análisis de regresión logística multinomial múltiple, la franja de edad por encima de cincuenta años se observó como el único factor de protección al abandono, al mismo tiempo que tener menos de ocho años de escolaridad y reingresar en el sistema educativo tras el abandono fueron considerados como factores de riesgo. Reingreso tras abandono, recidiva e insolvencia indicaron factores de riesgo. Nuestros datos refuerzan la concepción de que el abandono del tratamiento de tuberculosis resistente es un serio problema de salud pública, siendo necesario un adecuado acompañamiento en el tratamiento de pacientes con este historial y con baja escolaridad. Además, una red de apoyo social entorno al paciente es imprescindible para que los desenlaces desfavorables sean evitados.

Fatores associados ao abandono e ao óbito de casos de tuberculose drogarresistente (TBDR) atendidos em um centro de referência no Rio de Janeiro, Brasil / Factores asociados al abandono y al fallecimiento por casos de tuberculosis farmacorresistente (TBFR), atendidos en un centro de referencia en Río de Janeiro, Brasil / Factors associated with loss to follow-up and death in cases of drug-resistant tuberculosis (DR-TB) treated at a reference center in Rio de Janeiro, Brazil

Resumo: A tuberculose drogarresistente (TBDR) representa hoje uma grave ameaça aos avanços no controle da tuberculose (TB) no Brasil e no mundo. Neste estudo, investigam-se fatores associados ao abandono e ao óbito de casos em tratamento para TBDR, em um centro de referência terciária do Município do Rio de Janeiro, Brasil. Trata-se de um estudo de coorte retrospectiva, a partir dos casos notificados no Sistema de Informação de Tratamentos Especiais de Tuberculose (SITETB), no período de 1º de janeiro de 2012 a 31 de dezembro de 2013. Um total de 257 pacientes foi notificado no SITETB e iniciou o tratamento para TBDR. Desse total, 139 (54,1%) tiveram sucesso terapêutico como desfecho, 54 (21%) abandonaram o tratamento e 21 (8,2%) evoluíram para óbito. Após análise de regressão logística multinomial múltipla, a faixa etária acima de cinquenta anos foi observada como único fator de proteção ao abandono, ao passo que ter menos de oito anos de escolaridade e reingresso após abandono foram considerados como fatores de risco. Reingresso após abandono, recidiva e falência indicaram fatores de risco. Nossos dados reforçam a concepção de que o abandono do tratamento de tuberculose resistente é um sério problema de saúde pública, sendo necessário um adequado acompanhamento no tratamento de pacientes com esse histórico e com baixa escolaridade. Além disso, uma rede de apoio social ao paciente é imprescindível para que desfechos desfavoráveis sejam evitados.

Resumen: La tuberculosis farmacorresistente (TBFR) representa hoy una grave amenaza para los avances en el control de la tuberculosis (TB) en Brasil y en el mundo. En este estudio, se investigan factores asociados al abandono y al óbito de casos en tratamiento para TBDR, dentro de un centro de referencia de carácter terciario del municipio de Río de Janeiro, Brasil. Se trata de un estudio de cohorte retrospectiva, a partir de los casos notificados en el Sistema de Información de Tratamientos Especiales de Tuberculosis (SITETB), durante el período del 1 de enero de 2012 al 31 de diciembre de 2013. Un total de 257 pacientes fue notificado en el SITETB y comenzó el tratamiento para TBDR. De ese total, 139 (un 54,1%) tuvieron éxito terapéutico como desenlace, 54 (un 21%) abandonaron el tratamiento y un 21 (8,2%) evolucionaron hacia óbito. Tras el análisis de regresión logística multinomial múltiple, la franja de edad por encima de cincuenta años se observó como el único factor de protección al abandono, al mismo tiempo que tener menos de ocho años de escolaridad y reingresar en el sistema educativo tras el abandono fueron considerados como factores de riesgo. Reingreso tras abandono, recidiva e insolvencia indicaron factores de riesgo. Nuestros datos refuerzan la concepción de que el abandono del tratamiento de tuberculosis resistente es un serio problema de salud pública, siendo necesario un adecuado acompañamiento en el tratamiento de pacientes con este historial y con baja escolaridad. Además, una red de apoyo social entorno al paciente es imprescindible para que los desenlaces desfavorables sean evitados.

Abstract: Drug-resistant tuberculosis (DR-TB) poses a serious threat to tuberculosis (TB) control in Brazil and worldwide. The current study investigated factors associated with loss to follow-up and death in the course of treatment for DR-TB in a tertiary reference center in the city of Rio de Janeiro, Brazil. This was a retrospective cohort study of cases reported to the Information System on Special Treatments for Tuberculosis (SITETB) from January 1, 2012, to December 31, 2013. A total of 257 patients were reported to the SITETB and initiated treatment for DR-TB. Of this total, 139 (54.1%) achieved treatment success as the outcome, 54 (21%) were lost to follow-up, and 21 (8.2%) died. Following a multiple multinomial logistic regression analysis, the age bracket older than 50 years was the only protective factor against loss to follow-up, whereas less than eight years of schooling and reentry after loss to follow-up were considered risk factors. Reentry after loss to follow-up, relapse, and treatment failure appeared as risk factors. Our data reinforce the concept that loss to follow-up in drug-resistant tuberculosis is a serious public health problem, and that adequate follow-up of treatment is necessary in patients with this history and low schooling. A social support network for patients is also indispensable for avoiding unfavorable outcomes.

Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country / Avaliação do impacto das mudanças do tratamento da tuberculose implantadas em 2009 no controle da tuberculose pulmonar no Brasil

ABSTRACT Objective: To analyze the impact that the 2009 changes in tuberculosis treatment in Brazil had on the rates of cure, tuberculosis recurrence, mortality, treatment abandonment, and multidrug-resistant tuberculosis (MDR-TB). Methods: An ordinary least squares regression model was used in order to perform an interrupted time series analysis of secondary data collected from the Brazilian Tuberculosis Case Registry Database for the period between January of 2003 and December of 2014. Results: The 2009 changes in tuberculosis treatment in Brazil were found to have no association with reductions in the total number of cases (β = 2.17; 95% CI: −3.80 to 8.14; p = 0.47) and in the number of new cases (β = −0.97; 95% CI: −5.89 to 3.94; p = 0.70), as well as having no association with treatment abandonment rates (β = 0.40; 95% CI: −1.12 to 1.93; p = 0.60). The changes in tuberculosis treatment also showed a trend toward an association with decreased cure rates (β = −4.14; 95% CI: −8.63 to 0.34; p = 0.07), as well as an association with increased mortality from pulmonary tuberculosis (β = 0.77; 95% CI: 0.16 to 1.38; p = 0.01). Although there was a significant increase in MDR-TB before and after the changes (p < 0.0001), there was no association between the intervention (i.e., the changes in tuberculosis treatment) and the increase in MDR-TB cases. Conclusions: The changes in tuberculosis treatment were unable to contain the decrease in cure rates, the increase in treatment abandonment rates, and the increase in MDR-TB rates, being associated with increased mortality from pulmonary tuberculosis during the study period. Keywords: Tuberculosis, pulmonary/epidemiology; Tuberculosis, pulmonary/drug therapy; Tuberculosis, pulmonary/mortality; Interrupted time series analysis; Drug resistance, multiple; Drug compounding.

RESUMO Objetivo: Analisar o impacto das mudanças do tratamento da tuberculose implantadas no Brasil em 2009 no número de casos de cura, de recidiva, de óbitos, de abandono e de tuberculose multirresistente (TBMR). Métodos: Foi realizada uma análise de séries temporais interrompida utilizando o modelo de regressão pelo método dos mínimos quadrados ordinários a partir de dados secundários coletados do Sistema de Informação de Agravos de Notificação da Tuberculose entre janeiro de 2003 e dezembro de 2014. Resultados: A análise mostrou independência entre as mudanças do tratamento e a redução do número total de casos (β = 2,17; IC95%: −3,80 a 8,14; 189 p = 0,47), a redução do número de novos casos (β = −0,97; IC95%: −5,89 a 3,94; p =190 0,70) e do abandono do tratamento (β = 0,40; IC95%: 199 −1,12 a 1,93; p = 0,60). Demonstrou ainda tendência à associação com a diminuição da cura (β = −4,14; IC95%: −8,63 a 0,34; p = 0,07) e associação com aumento da mortalidade por tuberculose pulmonar (β = 0,77; IC95%: 0,16 a 1,38; p = 0,01). A TBMR aumentou significativamente tanto no período anterior quanto no período posterior às mudanças do tratamento (p < 0,0001), embora de forma independente da intervenção (β = 0,13; IC95%: −0,03 a 0,29; p = 0,12). Conclusões: As mudanças no tratamento não impediram nem a diminuição na taxa de cura e nem o aumento do abandono e da TBMR; por outro lado, se associaram ao aumento de óbitos por tuberculose pulmonar durante o período do estudo.

Predicting treatment failure, death and drug resistance using a computed risk score among newly diagnosed TB patients in Tamaulipas, Mexico.

The purpose of this study was to develop a method for identifying newly diagnosed tuberculosis (TB) patients at risk for TB adverse events in Tamaulipas, Mexico. Surveillance data between 2006 and 2013 (8431 subjects) was used to develop risk scores based on predictive modelling. The final models revealed that TB patients failing their treatment regimen were more likely to have at most a primary school education, multi-drug resistance (MDR)-TB, and few to moderate bacilli on acid-fast bacilli smear. TB patients who died were more likely to be older males with MDR-TB, HIV, malnutrition, and reporting excessive alcohol use. Modified risk scores were developed with strong predictability for treatment failure and death (c-statistic 0·65 and 0·70, respectively), and moderate predictability for drug resistance (c-statistic 0·57). Among TB patients with diabetes, risk scores showed moderate predictability for death (c-statistic 0·68). Our findings suggest that in the clinical setting, the use of our risk scores for TB treatment failure or death will help identify these individuals for tailored management to prevent these adverse events. In contrast, the available variables in the TB surveillance dataset are not robust predictors of drug resistance, indicating the need for prompt testing at time of diagnosis.

The effect size of type 2 diabetes mellitus on tuberculosis drug resistance and adverse treatment outcomes.

OBJECTIVE: To evaluate the effect size of type 2 diabetes mellitus (T2DM) on tuberculosis (TB) treatment outcomes and multi drug resistance (MDR). METHODS: A cohort with 507 individuals with diagnosed TB included 183 with coexistence of T2DM and TB (TB-T2DM). Participants were identified at the time of TB diagnosis and followed during the course of TB treatment. Then we computed relative risks and adjustments by Cox proportional hazards for outcome variables (drug resistance, death, relapse, treatment failure), and the size of their effect as Cohen's-d. RESULTS: Patients with TB-T2DM were more likely to remain positive for acid-fast bacilli after two months of anti-TB treatment RR = [2.01 (95% CI: 1.3, 3.1)], to have drug resistant (DR) [OR 3.5 (95% CI: 1.8, 6.7)] and multi-drug resistant (MDR) TB [OR 3.5 (95% CI: 1.8, 7.1)]. The Cohen's-d for DR or MDR in T2DM was 0.69 when compared with non-DM subjects. The T2DM patients had higher odds of resistance to isoniazid (OR 3.9, 95% CI: 2.01, 7.9), rifampicin (OR 3.4, 95% CI: 1.6, 7.2) and pyrazinamide (OR 9.4, 95% CI: 2.8, 25.6), and their effect sizes were ≥0.67. Patients with TB-T2DM (versus no DM) were more likely to present with MDR TB (HR 3.1; 95% CI: 1.7, 5.8; p < 0.001), treatment failure (HR 2.04; 95% CI: 1.07, 3.8; p = 0.02) and relapse (HR 1.86; 95% CI: 1.09, 3.1; p = 0.02), with effect size ≥0.34. CONCLUSION: T2DM showed a substantial contribution to the presence of DR or MDR-TB and to adverse clinical outcomes during and after TB treatment. Our findings support the importance for routine screening of T2DM among newly-diagnosed TB patients in order to stratify them for immediate DR assessment, and highlight the need for clinical trials to evaluate variations to the standard TB treatment in TB-T2DM to prevent adverse treatment outcomes.

Evaluation of the impact that the changes in tuberculosis treatment implemented in Brazil in 2009 have had on disease control in the country.

OBJECTIVE: To analyze the impact that the 2009 changes in tuberculosis treatment in Brazil had on the rates of cure, tuberculosis recurrence, mortality, treatment abandonment, and multidrug-resistant tuberculosis (MDR-TB). METHODS: An ordinary least squares regression model was used in order to perform an interrupted time series analysis of secondary data collected from the Brazilian Tuberculosis Case Registry Database for the period between January of 2003 and December of 2014. RESULTS: The 2009 changes in tuberculosis treatment in Brazil were found to have no association with reductions in the total number of cases (ß = 2.17; 95% CI: -3.80 to 8.14; p = 0.47) and in the number of new cases (ß = -0.97; 95% CI: -5.89 to 3.94; p = 0.70), as well as having no association with treatment abandonment rates (ß = 0.40; 95% CI: -1.12 to 1.93; p = 0.60). The changes in tuberculosis treatment also showed a trend toward an association with decreased cure rates (ß = -4.14; 95% CI: -8.63 to 0.34; p = 0.07), as well as an association with increased mortality from pulmonary tuberculosis (ß = 0.77; 95% CI: 0.16 to 1.38; p = 0.01). Although there was a significant increase in MDR-TB before and after the changes (p < 0.0001), there was no association between the intervention (i.e., the changes in tuberculosis treatment) and the increase in MDR-TB cases. CONCLUSIONS: The changes in tuberculosis treatment were unable to contain the decrease in cure rates, the increase in treatment abandonment rates, and the increase in MDR-TB rates, being associated with increased mortality from pulmonary tuberculosis during the study period.Keywords: Tuberculosis, pulmonary/epidemiology; Tuberculosis, pulmonary/drug therapy; Tuberculosis, pulmonary/mortality; Interrupted time series analysis; Drug resistance, multiple; Drug compounding.

Isoniazid Mono-Resistant Tuberculosis: Impact on Treatment Outcome and Survival of Pulmonary Tuberculosis Patients in Southern Mexico 1995-2010.

BACKGROUND: Isoniazid mono-resistance (IMR) is the most common form of mono-resistance; its world prevalence is estimated to range between 0.0 to 9.5% globally. There is no consensus on how these patients should be treated. OBJECTIVE: To describe the impact of IMR tuberculosis (TB) on treatment outcome and survival among pulmonary TB patients treated under programmatic conditions in Orizaba, Veracruz, Mexico. MATERIALS AND METHODS: We conducted a prospective cohort study of pulmonary TB patients in Southern Mexico. From 1995 to 2010 patients with acid-fast bacilli or culture proven Mycobacterium tuberculosis in sputum samples underwent epidemiological, clinical and microbiological evaluation. We included patients who harbored isoniazid mono-resistant (IMR) strains and patients with strains susceptible to isoniazid, rifampicin, ethambutol and streptomycin. All patients were treated following Mexican TB Program guidelines. We performed annual follow-up to ascertain treatment outcome, recurrence, relapse and mortality. RESULTS: Between 1995 and 2010 1,243 patients with pulmonary TB were recruited; 902/1,243 (72.57%) had drug susceptibility testing; 716 (79.38%) harbored pan-susceptible and 88 (9.75%) IMR strains. Having any contact with a person with TB (adjusted odds ratio (aOR)) 1.85, 95% Confidence interval (CI) 1.15-2.96) and homelessness (adjusted odds ratio (aOR) 2.76, 95% CI 1.08-6.99) were associated with IMR. IMR patients had a higher probability of failure (adjusted hazard ratio (HR) 12.35, 95% CI 3.38-45.15) and death due to TB among HIV negative patients (aHR 3.30. 95% CI 1.00-10.84). All the models were adjusted for socio-demographic and clinical variables. CONCLUSIONS: The results from our study provide evidence that the standardized treatment schedule with first line drugs in new and previously treated cases with pulmonary TB and IMR produces a high frequency of treatment failure and death due to tuberculosis. We recommend re-evaluating the optimal schedule for patients harboring IMR. It is necessary to strengthen scientific research for the evaluation of alternative treatment schedules in similar settings.

Tuberculosis-diabetes epidemiology in the border and non-border regions of Tamaulipas, Mexico.

Type 2 diabetes mellitus (DM) is a re-emerging risk factor for TB development and adverse TB outcomes. As a follow-up of our previous study in 1998-2004, we reassessed prevalence of DM and its associated factors among 8431 TB patients using surveillance data from 2006 to 2013 for the Mexican state of Tamaulipas, across the border with Texas. Prevalence of DM was 25.2%, with an increase of at least 2.8% over the study period. Newly discovered factors associated with TB-DM (versus no DM) were lower education and higher unemployment (p < 0.001), which are reportedly associated with poorer DM management. At least 15% of the DM patients were newly-diagnosed and younger than those previously diagnosed, showing the importance of early DM diagnosis at TB clinics. TB-DM patients were more likely to have smear-positive, pulmonary (versus extra-pulmonary) and drug-resistant TB (1.9-, 3.8- and 1.4-fold, respectively). During treatment, TB-DM patients were more likely to be smear-positive, and less likely to die or abandon TB treatment. Thus, the increasing prevalence of DM among TB, and its association with low education, features of a more contagious TB, and drug resistance, highlight the need for design of TB management programs in DM patients, blood testing of all new TB patients for DM, and if positive for DM, testing for drug resistance.

Baseline Predictors of Treatment Outcomes in Children With Multidrug-Resistant Tuberculosis: A Retrospective Cohort Study.

BACKGROUND: Globally, >30 000 children fall sick with multidrug-resistant (MDR) tuberculosis every year. Without robust pediatric data, clinical management follows international guidelines that are based on studies in adults and expert opinion. We aimed to identify baseline predictors of death, treatment failure, and loss to follow-up among children with MDR tuberculosis disease treated with regimens tailored to their drug susceptibility test (DST) result or to the DST result of a source case. METHODS: This retrospective cohort study included all children ≤15 years old with confirmed and probable MDR tuberculosis disease who began tailored regimens in Lima, Peru, between 2005 and 2009. Using logistic regression, we examined associations between baseline patient and treatment characteristics and (1) death or treatment failure and (2) loss to follow-up. RESULTS: Two hundred eleven of 232 (90.9%) children had known treatment outcomes, of whom 163 (77.2%) achieved cure or probable cure, 29 (13.7%) were lost to follow-up, 10 (4.7%) experienced treatment failure, and 9 (4.3%) died. Independent baseline predictors of death or treatment failure were the presence of severe disease (adjusted odds ratio [aOR], 4.96; 95% confidence interval [CI], 1.61-15.26) and z score ≤-1 (aOR, 3.39; 95% CI, 1.20-9.54). We did not identify any independent predictors of loss to follow-up. CONCLUSIONS: High cure rates can be achieved in children with MDR tuberculosis using tailored regimens containing second-line drugs. However, children faced significantly higher risk of death or treatment failure if they had severe disease or were underweight. These findings highlight the need for early interventions that can improve treatment outcomes for children with MDR tuberculosis.

Mortality among MDR-TB cases: comparison with drug-susceptible tuberculosis and associated factors.

BACKGROUND: An increase in multidrug-resistant tuberculosis (MDR-TB) cases is evident worldwide. Its management implies a complex treatment, high costs, more toxic anti-tuberculosis drug use, longer treatment time and increased treatment failure and mortality. The aims of this study were to compare mortality between MDR and drug-susceptible cases of tuberculosis, and to determine risk factors associated with mortality among MDR-TB cases. METHODS AND RESULTS: A retrospective cohort study was performed using data from clinical records of the National Strategy for Prevention and Control of Tuberculosis in Lima, Peru. In the first objective, MDR-TB, compared to drug-susceptible cases, was the main exposure variable and time to death, censored at 180 days, the outcome of interest. For the second objective, different variables obtained from clinical records were assessed as potential risk factors for death among MDR-TB cases. Cox regression analysis was used to determine hazard ratios (HR) and 95% confidence intervals (95%CI). A total of 1,232 patients were analyzed: mean age 30.9 ±14.0 years, 60.0% were males. 61 patients (5.0%) died during treatment, whereas the MDR-TB prevalence was 19.2%. MDR-TB increased the risk of death during treatment (HR = 7.5; IC95%: 4.1-13.4) when compared to presumed drug-susceptible cases after controlling for potential confounders. Education level (p = 0.01), previous TB episodes (p<0.001), diabetes history (p<0.001) and HIV infection (p = 0.04) were factors associated with mortality among MDR-TB cases. CONCLUSIONS: MDR-TB is associated with an increased risk of death during treatment. Lower education, greater number of previous TB episodes, diabetes history, and HIV infection were independently associated with mortality among MDR-TB cases. New strategies for appropriate MDR-TB detection and management should be implemented, including drug sensitivity tests, diabetes and HIV screening, as well as guarantee for a complete adherence to therapy.

Diabetes and Other Risk Factors for Multi-drug Resistant Tuberculosis in a Mexican Population with Pulmonary Tuberculosis: Case Control Study.

BACKGROUND AND AIMS: Multidrug resistant tuberculosis (MDR-TB) poses problems in treatment, costs and treatment outcomes. It is not known if classically described risk factors for MDR-TB in other countries are the same in Mexico and the frequency of the association between diabetes mellitus (DM) and MDR-TB in our country is not clear. We undertook this study to analyze risk factors associated with the development of MDR-TB, with emphasis on DM. METHODS: A case-control study in the state of San Luis Potosi (SLP), Mexico was carried out. All pulmonary MDR-TB patients diagnosed in the state of SLP between 1998 and 2013 (36 cases) evaluated at a state pharmacoresistant tuberculosis (TB) clinic and committee; 139 controls were randomly selected from all pulmonary non-multidrug-resistant tuberculosis (non-MDR-TB) cases identified between 2003 and 2008. Cases and controls were diagnosed and treated under programmatic conditions. RESULTS: Age, gender, malnutrition, being a health-care worker, HIV/AIDS status, and drug abuse were not significantly different between MDR-TB and non-MDR-TB patients. Significant differences between MDR-TB and non-MDR-TB patients were DM (47.2 vs. 28.1%; p = 0.028); previous anti-TB treatments (3 vs. 0, respectively; p <0.001), and duration of first anti-TB treatment (8 vs. 6 months, respectively; p <0.001). CONCLUSIONS: MDR-TB and DM are associated in 47.2% of MDR TB cases (17/36) in this study. Other recognized factors were not found to be significantly different in MDR-TB compared to non-MDR-TB in this study. Cost-feasible strategies must be implemented in the treatment of DM-TB in order to prevent the selection of MDR-TB.