Effect of Smoking on Longitudinal Interferon-ϒ Release Assay Results among Close Contacts of People with Pulmonary Tuberculosis.

Diagnosis of M. tuberculosis (Mtb) infection in close contacts is critical for TB control. Smoking is a risk factor for Mtb infection and TB disease but its effect on longitudinal interferon-gamma release assay (IGRA) results remains unknown. We conducted a multi-site prospective study in Brazil between 2015-2019, among close contacts of adults with culture-confirmed pulmonary TB. IGRA was performed at baseline, month 6 if negative at baseline, and month 24-30 after enrollment. IGRA results were categorized as IGRA-positive (maintained from baseline to last visit), IGRA-conversion (from negative to positive at any time), IGRA-reversion (from positive to negative at any time), and IGRA-negative (maintained from baseline to last visit). Associations between IGRA results and smoking status at baseline (current/former vs never) in contacts were evaluated using propensity score-adjusted logistic regression models. Estimated propensity score was used as a covariate in models, which regressed the outcome (IGRA-positive, IGRA-conversion, IGRA-reversion) on smoking status. Of 430 close contacts, 89 (21%) were IGRA-positive, 30 (7%) were converters, 30 (7%) were reverters and 22 were indeterminate. Smoking frequency was 26 (29%) among IGRA-positive contacts, 7 (23%) in converters, and 3 (10%) in reverters. Smoking in contacts was associated with lower odds of IGRA-reversion (adjusted odds ratio = 0.16; 95% confidence interval = [0.03-0.70]). We did not detect associations between smoking and IGRA-positive or IGRA-conversion. Our findings highlight the importance of smoking on longitudinal IGRA results. This has implications for clinical care and clinical trials in which IGRA status is monitored or used as an outcome.

Prediction Models for Adverse Drug Reactions During Tuberculosis Treatment in Brazil.

BACKGROUND: Tuberculosis (TB) treatment-related adverse drug reactions (TB-ADRs) can negatively affect adherence and treatment success rates. METHODS: We developed prediction models for TB-ADRs, considering participants with drug-susceptible pulmonary TB who initiated standard TB therapy. TB-ADRs were determined by the physician attending the participant, assessing causality to TB drugs, the affected organ system, and grade. Potential baseline predictors of TB-ADR included concomitant medication (CM) use, human immunodeficiency virus (HIV) status, glycated hemoglobin (HbA1c), age, body mass index (BMI), sex, substance use, and TB drug metabolism variables (NAT2 acetylator profiles). The models were developed through bootstrapped backward selection. Cox regression was used to evaluate TB-ADR risk. RESULTS: There were 156 TB-ADRs among 102 of the 945 (11%) participants included. Most TB-ADRs were hepatic (n = 82 [53%]), of moderate severity (grade 2; n = 121 [78%]), and occurred in NAT2 slow acetylators (n = 62 [61%]). The main prediction model included CM use, HbA1c, alcohol use, HIV seropositivity, BMI, and age, with robust performance (c-statistic = 0.79 [95% confidence interval {CI}, .74-.83) and fit (optimism-corrected slope and intercept of -0.09 and 0.94, respectively). An alternative model replacing BMI with NAT2 had similar performance. HIV seropositivity (hazard ratio [HR], 2.68 [95% CI, 1.75-4.09]) and CM use (HR, 5.26 [95% CI, 2.63-10.52]) increased TB-ADR risk. CONCLUSIONS: The models, with clinical variables and with NAT2, were highly predictive of TB-ADRs.

Transcriptomic signatures of progression to TB disease among close contacts in Brazil.

BACKGROUND: Approximately 5% of people infected with Mycobacterium tuberculosis progress to tuberculosis (TB) disease without preventive therapy. There is a need for a prognostic test to identify those at highest risk of incident TB, so that therapy can be targeted. We evaluated host blood transcriptomic signatures for progression to TB disease. METHODS: Close contacts (≥4 hours exposure per week) of adult patients with culture-confirmed pulmonary TB were enrolled in Brazil. Investigation for incident, microbiologically-confirmed or clinically-diagnosed pulmonary or extra-pulmonary TB disease through 24 months of follow-up was symptom-triggered. Twenty previously validated blood TB transcriptomic signatures were measured at baseline by real-time quantitative PCR. Prognostic performance for incident TB was tested using receiver operating characteristic curve (ROC) analysis at 6, 9, 12, and 24 months of follow-up. RESULTS: Between June 2015 and June 2019, 1,854 close contacts were enrolled; Twenty-five progressed to incident TB, of whom 13 had microbiologically-confirmed disease. Baseline transcriptomic signature scores were measured in 1,789 close contacts. Prognostic performance for all signatures was best within 6 months of diagnosis. Seven signatures (Gliddon4, Suliman4, Roe3, Roe1, Penn-Nicholson6, Francisco2, and Rajan5) met the minimum World Health Organization target product profile (TPP) for a prognostic test through 6 months; three (Gliddon4, Rajan5, and Duffy9) through 9 months. None met the TPP threshold through 12 or more months of follow-up. CONCLUSIONS: Blood transcriptomic signatures may be useful for predicting TB risk within 9 months of measurement among TB-exposed contacts, to target preventive therapy administration.

The Xpert® MTB/RIF cycle threshold value predicts M. tuberculosis transmission to close contacts in a Brazilian prospective multicenter cohort.

BACKGROUND: The Xpert® MTB/RIF rapid molecular test provides a quantitative measure of Mycobacterium tuberculosis (Mtb) DNA in the form of cycle threshold (Ct) values. This information can be translated into mycobacterial load and used as a potential risk measure of bacterial spread for tuberculosis cases, which can impact infection control. However, the role of Ct values in assessing Mtb transmission to close contacts has not yet been demonstrated. METHODS: A prospective study was performed to investigate the association between Xpert® MTB/RIF Ct values and Mtb transmission to close contacts of patients with culture-confirmed pulmonary TB in a multi-center Brazilian cohort. We evaluated clinical and laboratory data, such as age, sex, race, smoking habits, drug use, alcohol use, chest radiograph, Xpert® MTB/RIF results among pulmonary tuberculosis cases, and QuantiFERON(QFT)-Plus results at baseline and after six months for close contacts who had a negative result at baseline. RESULTS: A total of 1,055 close contacts of 382 pulmonary tuberculosis cases were included in the study. The median Ct values from pulmonary tuberculosis cases of QFT-Plus positive (at baseline or six months) close contacts were lower compared with those who were QFT-Plus negative. An adjusted logistic regression demonstrated that reduced Ct values from the index cases were independently associated with QFT-Plus conversion from negative to positive (OR: 1.61, 95% CI: 1.12-2.32) after adjusting for clinical characteristics. CONCLUSION: Close contacts of pulmonary TB index cases exhibiting low Xpert MTB/RIF Ct values displayed higher rates of TB infection, reflecting Mtb transmission.

Tuberculosis Treatment Outcomes in Brazil: Different Predictors for Each Type of Unsuccessful Outcome.

BACKGROUND: Successful tuberculosis (TB) treatment is necessary for disease control. The World Health Organization (WHO) has a target TB treatment success rate of ≥90%. We assessed whether the different types of unfavorable TB treatment outcome had different predictors. METHODS: Using data from Regional Prospective Observational Research for Tuberculosis-Brazil, we evaluated biological and behavioral factors associated with each component of unsuccessful TB outcomes, recently updated by WHO (death, loss to follow-up [LTFU], and treatment failure). We included culture-confirmed, drug-susceptible, pulmonary TB participants receiving standard treatment in 2015-2019. Multinomial logistic regression models with inverse probability weighting were used to evaluate the distinct determinants of each unsuccessful outcome. RESULTS: Of 915 participants included, 727 (79%) were successfully treated, 118 (13%) were LTFU, 44 (5%) had treatment failure, and 26 (3%) died. LTFU was associated with current drug-use (adjusted odds ratio [aOR] = 5.3; 95% confidence interval [CI], 3.0-9.4), current tobacco use (aOR = 2.9; 95% CI, 1.7-4.9), and being a person with HIV (PWH) (aOR = 2.0; 95% CI, 1.1-3.5). Treatment failure was associated with PWH (aOR = 2.7; 95% CI, 1.2-6.2) and having diabetes (aOR = 2.2; 95% CI, 1.1-4.4). Death was associated with anemia (aOR = 5.3; 95% CI, 1.4-19.7), diabetes (aOR = 3.1; 95% CI, 1.4-6.7), and PWH (aOR = 3.9; 95% CI, 1.3-11.4). Direct observed therapy was protective for treatment failure (aOR = 0.5; 95% CI, .3-.9) and death (aOR = 0.5; 95% CI, .2-1.0). CONCLUSIONS: The treatment success rate was below the WHO target. Behavioral factors were most associated with LTFU, whereas clinical comorbidities were correlated with treatment failure and death. Because determinants of unsuccessful outcomes are distinct, different intervention strategies may be needed to improve TB outcomes.

Barriers and Facilitators to Integrating Depression Treatment Within a TB Program and Primary Care in Brazil.

Tuberculosis (TB) and depression is common and is associated with poor TB outcomes. The World Health Organization End TB Strategy explicitly calls for the integration of TB and mental health services. Interpersonal Counseling (IPC) is a brief evidence-based treatment for depression that can be delivered by non-mental health specialists with expert supervision. The goal of this study was to explore potential barriers and facilitators to training non-specialist providers to deliver IPC within the TB Control Program and primary care in Itaboraí, Rio de Janeiro state. Data collection consisted of six focus groups (n = 42) with health professionals (n = 29), program coordinators (n = 7), and persons with TB (n = 6). We used open coding to analyze the data, followed by deductive coding using the Chaudoir multi-level framework for implementation outcomes. The main structural barriers identified were poverty, limited access to treatment, political instability, violence, and social stigma. Organizational barriers included an overburdened and under-resourced health system with high staff turnover. Despite high levels of stress and burnout among health professionals, several provider-level facilitators emerged including a high receptivity to, and demand for, mental health training; strong community relationships through the community health workers; and overall acceptance of IPC delivered by any type of health provider. Patients were also receptive to IPC being delivered by any type of professional. No intervention-specific barriers or facilitators were identified. Despite many challenges, integrating depression treatment into primary care in Itaboraí using IPC was perceived as acceptable, feasible, and desirable.

The Effect of Diabetes and Prediabetes on Antituberculosis Treatment Outcomes: A Multicenter Prospective Cohort Study.

BACKGROUND: It is unclear whether diabetes or prediabetes affects unfavorable treatment outcomes and death in people with tuberculosis (PWTB). METHODS: Culture-confirmed, drug-susceptible PWTB, enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort between 2015 and 2019 (N = 643) were stratified based on glycemic status according to baseline glycated hemoglobin. Unfavorable tuberculosis (TB) outcome was defined as treatment failure or modification, recurrence, or death; favorable outcome was cure or treatment completion. We corroborated the findings using data from PWTB reported to the Brazilian National System of Diseases Notification (SINAN) during 2015-2019 (N = 20 989). Logistic regression models evaluated associations between glycemic status and outcomes. RESULTS: In both cohorts, in univariate analysis, unfavorable outcomes were more frequently associated with smoking, illicit drug use, and human immunodeficiency virus infection. Diabetes, but not prediabetes, was associated with unfavorable outcomes in the RePORT-Brazil (adjusted relative risk [aRR], 2.45; P < .001) and SINAN (aRR, 1.76; P < .001) cohorts. Furthermore, diabetes was associated with high risk of death (during TB treatment) in both RePORT-Brazil (aRR, 2.16; P = .040) and SINAN (aRR, 1.93; P = .001). CONCLUSIONS: Diabetes was associated with an increased risk of unfavorable outcomes and mortality in Brazilian PWTB. Interventions to improve TB treatment outcomes in persons with diabetes are needed.

A Clinical Prediction Model for Unsuccessful Pulmonary Tuberculosis Treatment Outcomes.

BACKGROUND: Despite widespread availability of curative therapy, tuberculosis (TB) treatment outcomes remain suboptimal. Clinical prediction models can inform treatment strategies to improve outcomes. Using baseline clinical data, we developed a prediction model for unsuccessful TB treatment outcome and evaluated the incremental value of human immunodeficiency virus (HIV)-related severity and isoniazid acetylator status. METHODS: Data originated from the Regional Prospective Observational Research for Tuberculosis Brazil cohort, which enrolled newly diagnosed TB patients in Brazil from 2015 through 2019. This analysis included participants with culture-confirmed, drug-susceptible pulmonary TB who started first-line anti-TB therapy and had ≥12 months of follow-up. The end point was unsuccessful TB treatment: composite of death, treatment failure, regimen switch, incomplete treatment, or not evaluated. Missing predictors were imputed. Predictors were chosen via bootstrapped backward selection. Discrimination and calibration were evaluated with c-statistics and calibration plots, respectively. Bootstrap internal validation estimated overfitting, and a shrinkage factor was applied to improve out-of-sample prediction. Incremental value was evaluated with likelihood ratio-based measures. RESULTS: Of 944 participants, 191 (20%) had unsuccessful treatment outcomes. The final model included 7 baseline predictors: hemoglobin, HIV infection, drug use, diabetes, age, education, and tobacco use. The model demonstrated good discrimination (c-statistic = 0.77; 95% confidence interval, .73-.80) and was well calibrated (optimism-corrected intercept and slope, -0.12 and 0.89, respectively). HIV-related factors and isoniazid acetylation status did not improve prediction of the final model. CONCLUSIONS: Using information readily available at treatment initiation, the prediction model performed well in this population. The findings may guide future work to allocate resources or inform targeted interventions for high-risk patients.

The Effect of Diabetes and Prediabetes on Mycobacterium tuberculosis Transmission to Close Contacts.

BACKGROUND: It is unknown whether dysglycemia is associated with Mycobacterium tuberculosis transmission. METHODS: We assessed epidemiological and clinical characteristics of patients with culture-confirmed pulmonary tuberculosis and their close contacts, enrolled in a multicenter prospective cohort in Brazil. Contacts were investigated at baseline and 6 months after enrollment. QuantiFERON positivity at baseline and conversion (from negative to positive at month 6) were compared between subgroups of contacts according to glycemic status of persons with tuberculosis (PWTB) as diabetes mellitus (DM) or prediabetes. Multivariable mixed-effects logistic regression models were performed to test independent associations with baseline QuantiFERON positive and QuantiFERON conversion. RESULTS: There were 592 PWTB (153 DM, 141 prediabetes, 211 normoglycemic) and 1784 contacts, of whom 658 were QuantiFERON-positive at baseline and 106 converters. Multivariable analyses demonstrated that tuberculosis-prediabetes cases, acid-fast bacilli-positive, pulmonary cavities, and living with someone who smoked were independently associated with QuantiFERON positive in contacts at baseline. DM, persistent cough, acid-fast bacilli-positive, and pulmonary cavities in tuberculosis source cases were associated with QuantiFERON conversion. CONCLUSIONS: Contacts of persons with pulmonary tuberculosis and dysglycemia were at increased risk of being QuantiFERON positive at baseline or month 6. Increased focus on such close contacts could improve tuberculosis control.

Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults.

BACKGROUND: A 9-month regimen of isoniazid can prevent active tuberculosis in persons with latent tuberculosis infection. However, the regimen has been associated with poor adherence rates and with toxic effects. METHODS: In an open-label trial conducted in nine countries, we randomly assigned adults with latent tuberculosis infection to receive treatment with a 4-month regimen of rifampin or a 9-month regimen of isoniazid for the prevention of confirmed active tuberculosis within 28 months after randomization. Noninferiority and potential superiority were assessed. Secondary outcomes included clinically diagnosed active tuberculosis, adverse events of grades 3 to 5, and completion of the treatment regimen. Outcomes were adjudicated by independent review panels. RESULTS: Among the 3443 patients in the rifampin group, confirmed active tuberculosis developed in 4 and clinically diagnosed active tuberculosis developed in 4 during 7732 person-years of follow-up, as compared with 4 and 5 patients, respectively, among 3416 patients in the isoniazid group during 7652 person-years of follow-up. The rate differences (rifampin minus isoniazid) were less than 0.01 cases per 100 person-years (95% confidence interval [CI], -0.14 to 0.16) for confirmed active tuberculosis and less than 0.01 cases per 100 person-years (95% CI, -0.23 to 0.22) for confirmed or clinically diagnosed tuberculosis. The upper boundaries of the 95% confidence interval for the rate differences of the confirmed cases and for the confirmed or clinically diagnosed cases of tuberculosis were less than the prespecified noninferiority margin of 0.75 percentage points in cumulative incidence; the rifampin regimen was not superior to the isoniazid regimen. The difference in the treatment-completion rates was 15.1 percentage points (95% CI, 12.7 to 17.4). The rate differences for adverse events of grade 3 to 5 occurring within 146 days (120% of the 4-month planned duration of the rifampin regimen) were -1.1 percentage points (95% CI, -1.9 to -0.4) for all events and -1.2 percentage points (95% CI, -1.7 to -0.7) for hepatotoxic events. CONCLUSIONS: The 4-month regimen of rifampin was not inferior to the 9-month regimen of isoniazid for the prevention of active tuberculosis and was associated with a higher rate of treatment completion and better safety. (Funded by the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council; ClinicalTrials.gov number, NCT00931736 .).

Lack of Weight Gain During the First 2 Months of Treatment and Human Immunodeficiency Virus Independently Predict Unsuccessful Treatment Outcomes in Tuberculosis.

BACKGROUND: Weight change may inform tuberculosis treatment response, but its predictive power may be confounded by human immunodeficiency virus (HIV). METHODS: We prospectively followed up adults with culture-confirmed, drug-susceptible, pulmonary tuberculosis receiving standard 4-drug therapy (isoniazid, rifampin, pyrazinamide, and ethambutol) in Brazil. We examined median weight change 2 months after treatment initiation by HIV status, using quantile regression, and unsuccessful tuberculosis treatment outcome (treatment failure, tuberculosis recurrence, or death) by HIV and weight change status, using Cox regression. RESULTS: Among 547 participants, 102 (19%) were HIV positive, and 35 (6%) had an unsuccessful outcome. After adjustment for confounders, persons living with HIV (PLWH) gained a median of 1.3 kg (95% confidence interval [CI], -2.8 to .1) less than HIV-negative individuals during the first 2 months of tuberculosis treatment. PLWH were at increased risk of an unsuccessful outcome (adjusted hazard ratio, 4.8; 95% CI, 2.1-10.9). Weight change was independently associated with outcome, with risk of unsuccessful outcome decreasing by 12% (95% CI, .81%-.95%) per 1-kg increase. CONCLUSIONS: PLWH gained less weight during the first 2 months of tuberculosis treatment, and lack of weight gain and HIV independently predicted unsuccessful tuberculosis treatment outcomes. Weight, an easily collected biomarker, may identify patients who would benefit from alternative treatment strategies.

The role of mini-bronchoalveolar lavage fluid in the diagnosis of pulmonary tuberculosis in critically ill patients.

BACKGROUND: The detection of Mycobacterium tuberculosis (MTB) in the intensive care unit (ICU) presents several challenges, mainly associated to the clinical state of the patient. The presence of HIV infection further aggravates this scenario, requiring a reliable collection method, with better performance in the microbiological/molecular techniques to be used. We evaluated the performance of two methods for sample collection, mini bronchoalveolar lavage (Mini-BAL) and endotracheal aspirate (ETA), for diagnosis of pulmonary tuberculosis (PTB) in critically ill patients. METHODS: This prospective study involved 26 HIV positive ICU internalized patients, with presumptive PTB who required mechanical ventilation. Two samples were obtained prospectively from 26 HIV ICU patients with presumptive PTB by Mini-BAL and ETA. The samples were processed for smear microscopy, Löwenstein-Jensen medium and the BACTEC Mycobacteria Growth Indicator Tube 960 system®. We define as confirmed PTB patients with positive MTB culture. Furthermore, all samples obtained through the Mini-BAL were analyzed by Xpert® MTB/RIF. RESULTS: Our results demonstrated that the respiratory samples obtained by Mini-BAL were able to increase MTB detection in critically ill patients with presumptive PTB. The Mini-BAL allowed 30% increased recovery and guaranteed enough sample volume for processing in all methods. In addition, the larger volume of the samples obtained with this technique enabled the Xpert® MTB/RIF molecular test for diagnosis of TB. CONCLUSIONS: The Mini-BAL showed be an acceptable alternative to ETA in this population, since these critically ill and often-immunocompromised patients are more likely to develop complications related to invasive procedures.

Mapping the tuberculosis scientific landscape among BRICS countries: a bibliometric and network analysis.

BACKGROUND: The five BRICS (Brazil, Russian, Indian, China, and South Africa) countries bear 49% of the world's tuberculosis (TB) burden and they are committed to ending tuberculosis. OBJECTIVES: The aim of this paper is to map the scientific landscape related to TB research in BRICS countries. METHODS: Were combined bibliometrics and social network analysis techniques to map the scientific publications related to TB produced by the BRICS. Was made a descriptive statistical data covering the full period of analysis (1993-2016) and the research networks were made for 2007-2016 (8,366 records). The bubble charts were generated by VantagePoint and the networks by the Gephi 0.9.1 software (Gephi Consortium 2010) from co-occurrence matrices produced in VantagePoint. The Fruchterman-Reingold algorithm provided the networks' layout. FINDINGS: During the period 1993-2016, there were 38,315 peer-reviewed, among them, there were 11,018 (28.7%) articles related by one or more authors in a BRICS: India 38.7%; China 23.8%; South Africa 21.1%; Brazil 13.0%; and Russia 4.5% (The total was greater than 100% because our criterion was all papers with at least one author in a BRICS). Among the BRICS, there was greater interaction between India and South Africa and organisations in India and China had the highest productivity; however, South African organisations had more interaction with countries outside the BRICS. Publications by and about BRICS generally covered all research areas, especially those in India and China covered all research areas, although Brazil and South Africa prioritised infectious diseases, microbiology, and the respiratory system. MAIN CONCLUSIONS: An overview of BRICS scientific publications and interactions highlighted the necessity to develop a BRICS TB research plan to increase efforts and funding to ensure that basic science research successfully translates into products and policies to help end the TB epidemic.

Primary and acquired multidrug-resistant tuberculosis: Predictive factors for unfavorable treatment outcomes in Rio de Janeiro, 2000-2016.

OBJECTIVE: To identify clinical and demographic factors associated with unfavorable treatment outcomes in patients with primary and acquired multidrug-resistant tuberculosis (MDR-TB) in Rio de Janeiro State. METHODS: Retrospective cohort study using data on 2 269 MDR-TB cases in 2000-2016. Factors associated with unsuccessful, loss to follow-up, and death outcomes in patients with primary and acquired resistance were investigated with bivariate and multivariate regression. RESULTS: Primary resistance was 14.7% among MDR-TB cases. The unfavorable outcomes proportion was 30.3% in the primary resistance group and 46.7% in the acquired resistance group. There were significant differences in demographic and clinical characteristics between the two groups. Proportionally, the group with primary resistance had more cases among women (46.4% vs. 33.5% in the acquired resistance group), Caucasians (47.3% and 34%), and those with ≥8 years of schooling (37.7% and 27.4%). Extensively drug-resistant TB patients had 12.2-fold higher odds of unsuccessful outcome than MDR-TB patients, and comorbidities had 2-fold higher odds in the primary resistance group. Extensively drug-resistant TB had 5.43-fold higher odds in the acquired MDR-TB group. Bilateral disease and <8 years of schooling were associated with unsuccessful outcome in both groups. Being an inmate had 8-fold higher odds of loss to follow-up in the primary resistance group. Culture conversion by the sixth month was a protective factor for all outcomes. CONCLUSIONS: Primary resistance cases of MDR-TB constitute a different transmission reservoir, which is related to other chronic diseases associated with higher acquisition of TB. The poor results observed in Rio de Janeiro State can contribute to increasing the transmission of primary MDR-TB, thus favoring drug resistance.

Polymorphisms in TLR4 and TNFA and Risk of Mycobacterium tuberculosis Infection and Development of Active Disease in Contacts of Tuberculosis Cases in Brazil: A Prospective Cohort Study.

BACKGROUND: The role of genetic polymorphisms in latent tuberculosis (TB) infection and progression to active TB is not fully understood. METHODS: We tested the single-nucleotide polymorphisms (SNPs) rs5743708 (TLR2), rs4986791 (TLR4), rs361525 (TNFA), rs2430561 (IFNG) rs1143627 (IL1B) as risk factors for tuberculin skin test (TST) conversion or development of active TB in contacts of active TB cases. Contacts of microbiologically confirmed pulmonary TB cases were initially screened for longitudinal evaluation up to 24 months, with clinical examination and serial TST, between 1998 and 2004 at a referral center in Brazil. Data and biospecimens were collected from 526 individuals who were contacts of 177 active TB index cases. TST conversion was defined as induration ≥5 mm after a negative TST result (0 mm) at baseline or month 4 visit. Independent associations were tested using logistic regression models. RESULTS: Among the 526 contacts, 60 had TST conversion and 44 developed active TB during follow-up. Multivariable regression analysis demonstrated that male sex (odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.1-4.6), as well as SNPs in TLR4 genes (OR: 62.8, 95% CI: 7.5-525.3) and TNFA (OR: 4.2, 95% CI: 1.9-9.5) were independently associated with TST conversion. Moreover, a positive TST at baseline (OR: 4.7, 95% CI: 2.3-9.7) and SNPs in TLR4 (OR: 6.5, 95% CI: 1.1-36.7) and TNFA (OR: 12.4, 95% CI:5.1-30.1) were independently associated with incident TB. CONCLUSIONS: SNPs in TLR4 and TNFA predicted both TST conversion and active TB among contacts of TB cases in Brazil.

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Modelling the impact of chest X-ray and alternative triage approaches prior to seeking a tuberculosis diagnosis.

BACKGROUND: Tuberculosis is a major challenge to health in the developing world. Triage prior to diagnostic testing could potentially reduce the volume of tests and costs associated with using the more accurate, but costly, Xpert MTB/RIF assay. An effective methodology to predict the impact of introducing triage prior to tuberculosis diagnostic testing could be useful in helping to guide policy. METHODS: The development and use of operational modelling to project the impact on case detection and health system costs of alternative triage approaches for tuberculosis, with or without X-ray, based on data from Porto Alegre City, Brazil. RESULTS: Most of the triage approaches modelled without X-ray were predicted to provide no significant benefit. One approach based on an artificial neural network applied to patient and symptom characteristics was projected to increase case detection (82% vs. 75%) compared to microscopy, and reduce costs compared to Xpert without triage. In addition, use of X-ray before diagnostic testing for HIV-negative patients could maintain diagnostic yield of using Xpert without triage, and reduce costs. CONCLUSION: A model for the impact assessment of alternative triage approaches has been tested. The results from using the approach demonstrate its usefulness in informing policy in a typical high burden setting for tuberculosis.

Multicenter evaluation of TB-SPRINT 59-Plex Beamedex®: accuracy and cost analysis.

BACKGROUND: Molecular tests can allow the rapid detection of tuberculosis (TB) and multidrug-resistant TB (MDR-TB). TB-SPRINT 59-Plex Beamedex® is a microbead-based assay developed for the simultaneous spoligotyping and detection of MDR-TB. The accuracy and cost evaluation of new assays and technologies are of great importance for their routine use in clinics and in research laboratories. The aim of this study was to evaluate the performance of TB-SPRINT at three laboratory research centers in Brazil and calculate its mean cost (MC) and activity-based costing (ABC). METHODS: TB-SPRINT data were compared with the phenotypic and genotypic profiles obtained using Bactec™ MGIT™ 960 system and Genotype® MTBDRplus, respectively. RESULTS: Compared with MGIT, the accuracies of TB-SPRINT for the detection of rifampicin and isoniazid resistance ranged from 81 to 92% and 91.3 to 93.9%, respectively. Compared with MTBDRplus, the accuracies of TB-SPRINT for rifampicin and isoniazid were 99 and 94.2%, respectively. Moreover, the MC and ABC of TB-SPRINT were USD 127.78 and USD 109.94, respectively. CONCLUSION: TB-SPRINT showed good results for isoniazid and rifampicin resistance detection, but still needs improvement to achieve In Vitro Diagnostics standards.

Treatment outcomes of MDR-tuberculosis patients in Brazil: a retrospective cohort analysis.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a threat for the global TB epidemic control. Despite existing evidence that individualized treatment of MDR-TB is superior to standardized regimens, the latter are recommended in Brazil, mainly because drug-susceptibility tests (DST) are often restricted to first-line drugs in public laboratories. We compared treatment outcomes of MDR-TB patients using standardized versus individualized regimens in Brazil, a high TB-burden, low resistance setting. METHODS: The 2007-2013 cohort of the national electronic database (SITE-TB), which records all special treatments including drug-resistance, was analysed. Patients classified as MDR-TB in SITE-TB were eligible. Treatment outcomes were classified as successful (cure/treatment completed) or unsuccessful (failure/relapse/death/loss to follow-up). The odds for successful treatment according to type of regimen were controlled for demographic and clinical variables. RESULTS: Out of 4029 registered patients, we included 1972 recorded from 2010 to 2012, who had more complete outcome data. The overall success proportion was 60%. Success was more likely in non-HIV patients, sputum-negative at baseline, with unilateral disease and without prior DR-TB. Adjusted for these variables, those receiving standardized regimens had 2.7-fold odds of success compared to those receiving individualized treatments when failure/relapse were considered, and 1.4-fold odds of success when death was included as an unsuccessful outcome. When loss to follow-up was added, no difference between types of treatment was observed. Patients who used levofloxacin instead of ofloxacin had 1.5-fold odds of success. CONCLUSION: In this large cohort of MDR-TB patients with a low proportion of successful outcomes, standardized regimens had superior efficacy than individualized regimens, when adjusted for relevant variables. In addition to the limitations of any retrospective observational study, database quality hampered the analyses. Also, decision on the use of standard or individualized regimens was possibly not random, and may have introduced bias. Efforts were made to reduce classification bias and confounding. Until higher-quality evidence is produced, and DST becomes widely available in the country, our findings support the Brazilian recommendation for the use of standardized instead of individualized regimens for MDR-TB, preferably containing levofloxacin. Better quality surveillance data and DST availability across the country are necessary to improve MDR-TB control in Brazil.

Performance of a molecular assay to detect Mycobacterium tuberculosis complex DNA in clinical specimens: multicenter study in Brazil.

BACKGROUND: In high tuberculosis (TB) burden countries, there are few data on the performance of new molecular commercialised assays developed locally. OBJECTIVE: To evaluate the performance of a new molecular commercialised assay for TB diagnosis (Detect-TB) in three laboratories. METHODS: A total of 302 sputum samples from an equal number of patients with presumptive diagnosis of pulmonary tuberculosis (PTB) were submitted for routine smear microscopy, culture, and Detect-TB assay at three different sites in Brazil (the cities of Caxias do Sul, São Paulo and Canoas). FINDINGS: Seventy four (24.7%) TB cases were diagnosed (65 bacteriologically confirmed). When compared to smear microscopy/culture results, the overall sensitivity and specificity of Detect-TB assay was 84.6% (CI 95%; 73.7-91.6) and 93.1% (CI 95%; 89.1-95.8), respectively. When compared to bacteriological and clinical diagnostic criteria, the sensitivity and specificity of Detect-TB assay was 74.3% (CI 95%; 63.3-82.9) and 92.9% (CI 95%; 88.7-95.6), respectively. Among the three sites - Caxias do Sul, São Paulo and Canoas - the sensitivity and specificity were respectively 94.7% and 97.8%; 71.4% and 93.9%, 82.1% and 88.9%. MAIN CONCLUSIONS: These findings suggest that the Detect-TB assay could be applied routinely in reference laboratories across different regions in Brazil.