Is the Pharmacokinetics of First-Line Anti-TB Drugs a Cause of High Mortality Rates in TB Patients Admitted to the ICU? A Non-Compartmental Pharmacokinetic Analysis.

BACKGROUND: Patients with tuberculosis (TB) may develop multi-organ failure and require admission to intensive care. In these cases, the mortality rates are as high as 78% and may be caused by suboptimal serum concentrations of first-line TB drugs. This study aims to compare the pharmacokinetics of oral rifampin, isoniazid, pyrazinamide and ethambutol patients in intensive care units (ICU) to outpatients and to evaluate drug serum concentrations as a potential cause of mortality. METHODS: A prospective pharmacokinetic (PK) study was performed in Amazonas State, Brazil. The primary PK parameters of outpatients who achieved clinical and microbiological cure were used as a comparative target in a non-compartmental analysis. RESULTS: Thirteen ICU and twenty outpatients were recruited. The clearance and volume of distribution were lower for rifampin, isoniazid, pyrazinamide and ethambutol. ICU thirty-day mortality was 77% versus a cure rate of 89% in outpatients. CONCLUSIONS: ICU patients had a lower clearance and volume of distribution for rifampin, isoniazid, pyrazinamide and ethambutol compared to the outpatient group. These may reflect changes to organ function, impeded absorption and distribution to the site of infection in ICU patients and have the potential to impact clinical outcomes.

Determinants of losses in the latent tuberculosis infection cascade of care in Brazil.

INTRODUCTION: Factors associated with losses in the latent tuberculosis infection (LTBI) cascade of care in contacts of patients with tuberculosis (TB) were investigated in a multicentre prospective cohort from highly endemic regions in Brazil. METHODS: Close contacts of 1187 patients with culture-confirmed pulmonary TB were prospectively studied between 2015 and 2019, with follow-up of 6-24 months. Data on TB screening by clinical investigation, radiographic examination and interferon-gamma release assay (IGRA) were collected. Multivariable regressions were used to identify determinants of losses in the LTBI cascade. RESULTS: Among 4145 TB contacts initially identified, 1901 were examined (54% loss). Among those examined, 933 were people living with HIV, ≤5 years old and/or had positive IGRA results, and therefore had a recommendation to start TB preventive treatment (TPT). Of those, 454 (23%) initiated treatment, and 247 (54% of those initiating; 26% of those in whom treatment was recommended) completed TPT. Multivariable regression analysis revealed that living with HIV, illiteracy and black/pardo (brown) race were independently associated with losses in the cascade. CONCLUSION: There were losses at all LTBI cascade stages, but particularly at the initial screening and examination steps. Close contacts of low socioeconomic status and living with HIV were at heightened risk of not completing the LTBI cascade of care in Brazil.

Examination of respiratory specimens improves microbiological diagnosis of patients with presumptive extrapulmonary tuberculosis.

OBJECTIVES: Bacteriological confirmation of extrapulmonary tuberculosis (EPTB) is challenging for several reasons: the paucibacillary nature of the sample; scarce resources, mainly in middle and low-income countries; the need for hospitalization; and unfavorable outcomes. We evaluated the diagnostic role of respiratory specimen examination prospectively in a cohort of patients with presumptive EPTB. METHODS: From July 2018 to January 2019, in a tuberculosis (TB)/HIV reference hospital, a cohort of 157 patients with presumed EPTB was evaluated. Xpert® MTB/RIF Ultra or a culture-positive result was considered for bacteriologically confirmed TB. RESULTS: Out of 157 patients with presumptive EPTB, 97 (62%) provided extrapulmonary and respiratory specimens and 60 (38%) extrapulmonary specimens only. Of the 60 patients with extrapulmonary samples, 5 (8%) were positive. Of those with respiratory and extrapulmonary samples, 27 (28%) were positive: 10 in both the respiratory and extrapulmonary samples, 6 in the extrapulmonary sample only, and 11 in the respiratory sample only. A respiratory specimen examination increased by 6-fold the chance of bacteriological confirmation of TB (odds ratio = 5.97 [1.11-47.17]). CONCLUSION: We conclude that respiratory samples should be examined in patients with presumptive EPTB.

Novel stepwise approach to assess representativeness of a large multicenter observational cohort of tuberculosis patients: The example of RePORT Brazil.

BACKGROUND: A major goal of tuberculosis (TB) epidemiological studies is to obtain results that can be generalized to the larger population with TB. The ability to extrapolate findings on the determinants of TB treatment outcomes is also important. METHODS: We compared baseline clinical and demographic characteristics and determinants of anti-TB treatment outcomes between persons enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort between June 2015 and June 2019, and the registry of TB cases reported to the Brazilian National TB Program (Information System for Notifiable Diseases [SINAN]) during the same time period. Multivariable regression models adjusted for the study site were performed using second-generation p-values, a novel statistical approach. Associations with unfavorable treatment outcomes were tested for both RePORT-Brazil and SINAN cohorts. FINDINGS: A total of 1,060 culture-confirmed TB patients were enrolled in RePORT-Brazil and 455,873 TB cases were reported to SINAN. Second-generation p-value analyses revealed that the cohorts were strikingly similar with regard to sex, age, use of antiretroviral therapy and positive initial smear sputum microscopy. However, diabetes, HIV infection, and smoking were more frequently documented in RePORT-Brazil. Illicit drug use, the presence of diabetes, and history of prior TB were associated with unfavorable TB treatment outcomes; illicit drug use was associated with such outcomes in both cohorts. CONCLUSIONS: There were important similarities in demographic characteristics and determinants of clinical outcomes between the RePORT-Brazil cohort and the Brazilian National registry of TB cases.

Feasibility of GeneXpert® Edge for Tuberculosis Diagnosis in Difficult-to-Reach Populations: Preliminary Results of a Proof-of-Concept Study.

GeneXpert® Edge (GX-Edge) is a new point-of-care platform not yet tested in the field. In this proof-of-concept study conducted for the diagnosis of tuberculosis in communities living alongside two large rivers of the Brazilian Amazon, we demonstrate that GX-Edge implemented in boats to offer onsite testing is a feasible strategy to investigate potentially devastating diseases such as tuberculosis in difficult-to-reach populations, such as riverside communities.

Safety and efficacy of N-acetylcysteine in hospitalized patients with HIV-associated tuberculosis: An open-label, randomized, phase II trial (RIPENACTB Study).

Despite the availability of effective antimicrobials, tuberculosis (TB) is still a serious health threat. Mortality is even higher in people living with HIV who are diagnosed with TB. New therapies are needed to shorten the time required to cure TB and decrease fatality rates in this population. N-acetylcysteine (NAC) is a glutathione precursor and has shown recently in experimental setting to present in vitro and in vivo anti-mycobacterial activity. We test the hypothesis that NAC is safe, well tolerated and secondarily efficacious as adjunctive anti-TB therapy in hospitalized individuals with HIV-associated TB. Patients were enrolled sequentially in a tertiary care center, in the Brazilian Amazon. We performed a randomized, parallel group, single-center, open study trial of two arms, in hospitalized patients over 18 years of age, with microbiologically confirmed pulmonary TB in HIV: one with rifampicin, isoniazid, pyrazinamide and ethambutol at standard doses (Control Group), and a second in which NAC 600 mg bid for eight weeks was added (NAC Group). A total of 21 and 18 patients were enrolled to the Control Group and NAC Group, respectively. Adverse event rates were similar in the two arms. Our findings suggest that in the more critical population of hospitalized patients with HIV-associated TB, the use of NAC was not unsafe, despite the low sample size, and a potential impact on faster negative cultures needs to be further explored in larger studies.

Predictors of mortality among intensive care unit patients coinfected with tuberculosis and HIV.

OBJECTIVE: To identify factors predictive of mortality in patients admitted to the ICU with tuberculosis (TB)/HIV coinfection in the Manaus, Amazon Region. METHODS: This was a retrospective cohort study of TB/HIV coinfected patients over 18 years of age who were admitted to an ICU in the city of Manaus, Brazil, between January of 2011 and December of 2014. Sociodemographic, clinical, and laboratory variables were assessed. To identify factors predictive of mortality, we employed a Cox proportional hazards model. RESULTS: During the study period, 120 patients with TB/HIV coinfection were admitted to the ICU. The mean age was 37.0 ± 11.7 years. Of the 120 patients evaluated, 94 (78.3%) died and 62 (66.0%) of those deaths having occurred within the first week after admission. Data on invasive mechanical ventilation (IMV) and ARDS were available for 86 and 67 patients, respectively Of those 86, 75 (87.2%) underwent IMV, and, of those 67, 48 (71.6%) presented with ARDS. The factors found to be independently associated with mortality were IMV (p = 0.002), hypoalbuminemia (p = 0.013), and CD4 count < 200 cells/mm3 (p = 0.002). CONCLUSIONS: A high early mortality rate was observed among TB/HIV coinfected ICU patients. The factors predictive of mortality in this population were IMV, hypoalbuminemia, and severe immunosuppression.

Predictors of mortality among intensive care unit patients coinfected with tuberculosis and HIV / Preditores de mortalidade em pacientes da unidade de terapia intensiva coinfectados por tuberculose e HIV

ABSTRACT Objective: To identify factors predictive of mortality in patients admitted to the ICU with tuberculosis (TB)/HIV coinfection in the Manaus, Amazon Region. Methods: This was a retrospective cohort study of TB/HIV coinfected patients over 18 years of age who were admitted to an ICU in the city of Manaus, Brazil, between January of 2011 and December of 2014. Sociodemographic, clinical, and laboratory variables were assessed. To identify factors predictive of mortality, we employed a Cox proportional hazards model. Results: During the study period, 120 patients with TB/HIV coinfection were admitted to the ICU. The mean age was 37.0 ± 11.7 years. Of the 120 patients evaluated, 94 (78.3%) died and 62 (66.0%) of those deaths having occurred within the first week after admission. Data on invasive mechanical ventilation (IMV) and ARDS were available for 86 and 67 patients, respectively Of those 86, 75 (87.2%) underwent IMV, and, of those 67, 48 (71.6%) presented with ARDS. The factors found to be independently associated with mortality were IMV (p = 0.002), hypoalbuminemia (p = 0.013), and CD4 count < 200 cells/mm3 (p = 0.002). Conclusions: A high early mortality rate was observed among TB/HIV coinfected ICU patients. The factors predictive of mortality in this population were IMV, hypoalbuminemia, and severe immunosuppression.

RESUMO Objetivo: Identificar fatores preditores de mortalidade em pacientes da UTI coinfectados por tuberculose (TB)/HIV em Manaus (AM). Métodos: Estudo retrospectivo de coorte com pacientes coinfectados por TB/HIV, com mais de 18 anos de idade e admitidos na UTI entre janeiro de 2011 e dezembro de 2014. Foram avaliadas variáveis sociodemográficas, clínicas e laboratoriais. Para identificar fatores preditores de mortalidade, foi empregado um modelo de riscos proporcionais de Cox. Resultados: Durante o período estudado, 120 pacientes com coinfecção por TB/HIV foram admitidos na UTI. A média de idade foi de 37,0 ± 11,7 anos. Dos 120 pacientes avaliados, 94 (78,3%) morreram; dos 94 óbitos, 62 (66,0%) ocorreram na primeira semana após a admissão. Havia dados sobre ventilação mecânica invasiva (VMI) e SARA referentes a 86 e 67 pacientes, respectivamente. Dos 86, 75 (87,2%) foram submetidos a VMI, e, dos 67, 48 (71,6%) apresentaram SARA. Os fatores que se relacionaram independentemente com a mortalidade foram VMI (p = 0,002), hipoalbuminemia (p = 0,013) e contagem de CD4 < 200 células/mm3 (p = 0,002). Conclusões: Elevada mortalidade precoce foi observada em pacientes com coinfecção por TB/HIV admitidos na UTI. Os fatores preditores de mortalidade nessa população foram VMI, hipoalbuminemia e imunodepressão grave.

[Factors associated with TB/HIV coinfection: evidence from notification data in the State of Amazonas, Brazil, 2001-2012]. / Fatores associados à coinfecção tuberculose e HIV: o que apontam os dados de notificação do Estado do Amazonas, Brasil, 2001-2012.

Tuberculosis (TB) in persons living with HIV (PLHIV) is the leading infectious cause of AIDS-related death. The aim of this study was to estimate the prevalence of TB/HIV coinfection, evaluate notification of the two diseases over time by probabilistic database linkage, and identify factors associated with AIDS and TB notifications. Prevalence of TB/HIV coinfection was 7.7%. The group of PLHIV with subsequent TB diagnosis was the most representative, despite available preventive measures. Underreporting of TB among AIDS cases was 35%, and 19.6% of TB cases could have been reported as AIDS. For AIDS cases with mention of TB, living in the state capital showed 75% greater odds of being reported to the Tuberculosis Notification System (SINAN-TB), and having died increased the odds of reporting by 40%. Of TB cases with mention of HIV, brown skin color, age 25 to 39 years, living in the state capital, and having evolved to death were associated with higher odds of reporting to the AIDS Notification System. Periodic linkage of these databases can be a powerful tool for programs to decrease underreporting.

Fatores associados à coinfecção tuberculose e HIV: o que apontam os dados de notificação do Estado do Amazonas, Brasil, 2001-2012 / Factors associated with TB/HIV coinfection: evidence from notification data in the State of Amazonas, Brazil, 2001-2012 / Factores asociados a la coinfección de la tuberculosis y VIH: lo que apuntan los datos de notificación del estado de Amazonas, Brasil, 2001-2012

A tuberculose (TB) em pessoas vivendo com HIV (PVHIV) é a maior causa infecciosa de morte relacionada à AIDS. O objetivo deste trabalho foi estimar a prevalência da coinfecção TB/HIV, avaliar a notificação dos dois agravos de maneira temporal, por meio de relacionamento de bases de dados, e buscar fatores associados às notificações de AIDS e TB. A prevalência de coinfecção TB/HIV foi de 7,7%. O grupo de PVHIV com posterior diagnóstico de TB foi o mais representativo, apesar de medidas preventivas disponíveis. A subnotificação de TB entre os casos de AIDS foi de 35%, e 19,6% dos casos de TB poderiam ser notificados como AIDS. Para os casos de AIDS com menção de TB, residir na capital apresentou uma chance 75% maior de ser notificado no Sistema de Informação de Agravos de Notificação/Tuberculose (SINAN TB), e ter falecido aumentou em 40% a chance de registro. Dos casos de TB com menção de HIV, ser de cor parda, ter entre 25 e 39 anos, residir na capital e ter evoluído para o óbito estiveram associados à maior chance de notificação na AIDS. O linkage periódico dessas bases pode ser uma ferramenta programática poderosa para diminuir a subnotificação.

Tuberculosis (TB) in persons living with HIV (PLHIV) is the leading infectious cause of AIDS-related death. The aim of this study was to estimate the prevalence of TB/HIV coinfection, evaluate notification of the two diseases over time by probabilistic database linkage, and identify factors associated with AIDS and TB notifications. Prevalence of TB/HIV coinfection was 7.7%. The group of PLHIV with subsequent TB diagnosis was the most representative, despite available preventive measures. Underreporting of TB among AIDS cases was 35%, and 19.6% of TB cases could have been reported as AIDS. For AIDS cases with mention of TB, living in the state capital showed 75% greater odds of being reported to the Tuberculosis Notification System (SINAN-TB), and having died increased the odds of reporting by 40%. Of TB cases with mention of HIV, brown skin color, age 25 to 39 years, living in the state capital, and having evolved to death were associated with higher odds of reporting to the AIDS Notification System. Periodic linkage of these databases can be a powerful tool for programs to decrease underreporting.

La tuberculosis (TB) en personas viviendo con VIH (PVVIH) es la mayor causa infecciosa de muerte relacionada con el SIDA. El objetivo de este trabajo fue estimar la prevalencia de la coinfección TB/VIH, evaluar la notificación de las dos enfermedades de manera temporal, relación de bases de datos, y buscar factores asociados a las notificaciones de SIDA y TB. La prevalencia de coinfección TB/VIH fue de un 7,7%. El grupo de PVVIH, con posterior diagnóstico de TB, fue el más representativo, a pesar de las medidas preventivas disponibles. La subnotificación de TB entre los casos de SIDA fue de un 35%, y un 19,6% de los casos de TB podrían ser notificados como SIDA. Para los casos de SIDA con mención de TB, residir en la capital presentó una oportunidad un 75% mayor de ser notificada en el Sistema de Notificación de Tuberculosis (SINAN TB), y haber fallecido aumentó en un 40% la oportunidad de registro. De los casos de TB con mención de VIH, ser mestizo, tener entre 25 y 39 años, residir en la capital y haber evolucionado hacia el óbito estuvieron asociados a una mayor oportunidad de notificación en el SIDA. La vinculación periódica de estas bases puede ser una herramienta programática poderosa para disminuir la subnotificación.

Temporal distribution of tuberculosis in the State of Amazonas, Brazil.

Tuberculosis (TB) is one of the infectious diseases that contributes most to the morbidity and mortality of millions of people worldwide. Brazil is one of 22 countries that accounts for 80% of the tuberculosis global burden. The highest incidence rates in Brazil occur in the States of Amazonas and Rio de Janeiro. The aim of this study was to describe the temporal distribution of TB in the State of Amazonas. Between 2001 and 2011, 28,198 cases of tuberculosis were reported in Amazonas, distributed among 62 municipalities, with the capital Manaus reporting the highest (68.7%) concentration of cases. Tuberculosis was more prevalent among males (59.3%) aged 15 to 34 years old (45.5%), whose race/color was predominantly pardo (64.7%) and who had pulmonary TB (84.3%). During this period, 81 cases of multidrug-resistant TB were registered, of which the highest concentration was reported from 2008 onward (p = 0.002). The municipalities with the largest numbers of indigenous individuals affected were São Gabriel da Cachoeira (93%), Itamarati (78.1%), and Santa Isabel do Rio Negro (70.1%). The future outlook for this region includes strengthening the TB control at the primary care level, by expanding diagnostic capabilities, access to treatment, research projects developed in collaboration with the Dr. Heitor Vieira Dourado Tropical Medicine Foundation .;Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD).; and financing institutions, such as the project for the expansion of the Clinical Research Center and the creation of a hospital ward for individuals with transmissible respiratory diseases, including TB.

Temporal distribution of tuberculosis in the State of Amazonas, Brazil

Tuberculosis (TB) is one of the infectious diseases that contributes most to the morbidity and mortality of millions of people worldwide. Brazil is one of 22 countries that accounts for 80% of the tuberculosis global burden. The highest incidence rates in Brazil occur in the States of Amazonas and Rio de Janeiro. The aim of this study was to describe the temporal distribution of TB in the State of Amazonas. Between 2001 and 2011, 28,198 cases of tuberculosis were reported in Amazonas, distributed among 62 municipalities, with the capital Manaus reporting the highest (68.7%) concentration of cases. Tuberculosis was more prevalent among males (59.3%) aged 15 to 34 years old (45.5%), whose race/color was predominantly pardo (64.7%) and who had pulmonary TB (84.3%). During this period, 81 cases of multidrug-resistant TB were registered, of which the highest concentration was reported from 2008 onward (p = 0.002). The municipalities with the largest numbers of indigenous individuals affected were São Gabriel da Cachoeira (93%), Itamarati (78.1%), and Santa Isabel do Rio Negro (70.1%). The future outlook for this region includes strengthening the TB control at the primary care level, by expanding diagnostic capabilities, access to treatment, research projects developed in collaboration with the Dr. Heitor Vieira Dourado Tropical Medicine Foundation .;Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD).; and financing institutions, such as the project for the expansion of the Clinical Research Center and the creation of a hospital ward for individuals with transmissible respiratory diseases, including TB.

Factors associated with tuberculosis treatment default in an endemic area of the Brazilian Amazon: a case control-study.

SETTING: Treatment default is a serious problem in tuberculosis control because it implies persistence of infection source, increased mortality, increased relapse rates and facilitates the development of resistant strains. OBJECTIVE: This study analyzed tuberculosis treatment default determinants in the Amazonas State to contribute in planning appropriate control interventions. DESIGN: Observational study with a retrospective cohort using Brazilian Disease Notification System data from 2005 to 2010. A nested case control study design was used. Patients defaulting from treatment were considered as 'cases' and those completing treatment as 'controls'. In the analysis, 11,312 tuberculosis patients were included, 1,584 cases and 9,728 controls. RESULTS: Treatment default was observed to be associated to previous default (aOR 3.20; p<0.001), HIV positivity (aOR 1.62; p<0.001), alcoholism (aOR 1.51; p<0.001), low education level (aOR 1.35; p<0.001) and other co-morbidities (aOR 1.31; p = 0.05). Older patients (aOR 0.98; p = 0.001) and DOT (aOR 0,72; p<0.01) were considered as protective factor for default. CONCLUSIONS: Associated factors should be considered in addressing care and policy actions to tuberculosis control. Information on disease and treatment should be intensified and appropriate to the level of education of the population, in order to promote adherence to treatment and counter the spread of multidrug resistance to anti-TB drugs.