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Background Adherence to anti-tuberculosis treatment (ATT) in Brazil remains a challenge in achieving the goals set by the World Health Organization (WHO). Patients who are lost to follow-up during treatment pose a significant public health problem. This study aimed to investigate the factors associated with unfavorable ATT outcomes among those undergoing retreatment in Brazil. Methods We conducted an observational study of patients aged ≥18 years with tuberculosis (TB) reported to the Brazilian National Notifiable Disease Information System between 2015 and 2022. Clinical and epidemiologic variables were compared between the study groups (new cases and retreatment). Regression models identified variables associated with unfavorable outcomes. Results Among 743 823 reported TB cases in the study period, 555 632 cases were eligible, consisting of 462 061 new cases and 93 571 undergoing retreatments (44 642 recurrent and 48 929 retreatments after loss to follow-up [RLTFU]). RLTFU (odds ratio [OR], 3.96 [95% confidence interval {CI}, 3.83–4.1]) was a significant risk factor for any type of unfavorable ATT. Furthermore, RLTFU (OR, 4.93 [95% CI, 4.76–5.11]) was the main risk factor for subsequent LTFU. For death, aside from advanced age, living with HIV (OR, 6.28 [95% CI, 6.03–6.54]) was the top risk factor. Conclusions Retreatment is a substantial risk factor for unfavorable ATT outcomes, especially after LTFU. The rates of treatment success in RLTFU are distant from the WHO End TB Strategy targets throughout Brazil. These findings underscore the need for targeted interventions to improve treatment adherence and outcomes in persons who experience RLTFU. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background The high burden of drug-resistant tuberculosis (TB) is a problem to achieve the goals of the End TB Strategy by 2035. Whether isoniazid monoresistance (Hr) affects anti-TB treatment (ATT) outcomes remains unknown in high-burden countries. Methods We evaluated determinants of ATT outcome among pulmonary TB cases reported to the National Notifiable Disease Information System (SINAN) between June 2015 and June 2019, according to drug sensitivity testing (DST) results. Binomial logistic regression models were employed to evaluate whether Hr was associated with an unfavorable ATT outcome: death or failure, compared to cure or treatment completion. Results Among 60 804 TB cases reported in SINAN, 21 197 (34.9%) were included in the study. In this database, the frequency of unfavorable outcomes was significantly higher in those with Hr in contrast to isoniazid-sensitive persons with pulmonary TB (9.1% vs 3.05%; P <.001). Using a binomial logistic regression model, Hr was independently associated with unfavorable outcomes (odds ratio, 3.34 [95% confidence interval, 2.06–5.40]; P <.001). Conclusions Hr detected prior to ATT was predictive of unfavorable outcomes at the national level in Brazil. Our data reinforce the need for high-TB-burden countries to prioritize DST to detect Hr. Effective treatment regimens for Hr-TB are needed to improve outcomes. [ABSTRACT FROM AUTHOR]

Background: Oxidized lipid mediators such as eicosanoids play a central role in the inflammatory response associated with tuberculosis (TB) pathogenesis. Diabetes mellitus (DM) leads to marked changes in lipid mediators in persons with TB. However, the associations between diabetes-related changes in lipid mediators and clearance of M. tuberculosis (Mtb) among persons on anti-TB treatment (ATT) are unknown. Quantification of urinary eicosanoid metabolites can provide insights into the circulating lipid mediators involved in Mtb immune responses. Methods: We conducted a multi-site prospective observational study among adults with drug-sensitive pulmonary TB and controls without active TB; both groups had subgroups with or without dysglycemia at baseline. Participants were enrolled from RePORTBrazil (Salvador site) and RePORT-South Africa (Durban site) and stratified according to TB status and baseline glycated hemoglobin levels: a) TB-dysglycemia (n=69); b) TBnormoglycemia (n=64); c) non-TB/dysglycemia (n=31); d) non-TB/non-dysglycemia (n=29). We evaluated the following urinary eicosanoid metabolites: 11α-hydroxy-9,15- dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (major urinary metabolite of prostaglandin E2, PGE-M), tetranor-PGE1 (metabolite of PGE2, TN-E), 9α-hydroxy11,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (metabolite of PGD2, PGD-M), 11-dehydro-thromboxane B2 (11dTxB2), 2,3-dinor-6-keto-PGF1α (prostaglandin I metabolite, PGI-M), and leukotriene E4 (LTE4). Comparisons between the study groups were performed at three time points: before ATT and 2 and 6 months after initiating therapy. Results: PGE-M and LTE4 values were consistently higher at all three time-points in the TB-dysglycemia group compared to the other groups (p<0.001). In addition, there was a significant decrease in PGI-M and LTE4 levels from baseline to month 6 in the TBdysglycemia and TB-normoglycemia groups. Finally, TB-dysglycemia was independently associated with increased concentrations of PGD-M, PGI-M, and LTE4 at baseline in a multivariable model adjusting for age, sex, BMI, and study site. These associations were not affected by HIV status. Conclusion: The urinary eicosanoid metabolite profile was associated with TBdysglycemia before and during ATT. These observations can help identify the mechanisms involved in the pathogenesis of TB-dysglycemia, and potential biomarkers of TB treatment outcomes, including among persons with dysglycemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Direct smear examination with Ziehl-Neelsen (ZN) staining for the diagnosis of pulmonary tuberculosis (PTB) is cheap and easy to use, but its low sensitivity is a major drawback, particularly in HIV seropositive patients. As such, new tools for laboratory diagnosis are urgently needed to improve the case detection rate, especially in regions with a high prevalence of TB and HIV. Objective To evaluate the performance of two in house PCR (Polymerase Chain Reaction): PCR dot-blot methodology (PCR dot-blot) and PCR agarose gel electrophoresis (PCR-AG) for the diagnosis of Pulmonary Tuberculosis (PTB) in HIV seropositive and HIV seronegative patients. Methods A prospective study was conducted (from May 2003 to May 2004) in a TB/HIV reference hospital. Sputum specimens from 277 PTB suspects were tested by Acid Fast Bacilli (AFB) smear, Culture and in house PCR assays (PCR dot-blot and PCR-AG) and their performances evaluated. Positive cultures combined with the definition of clinical pulmonary TB were employed as the gold standard. Results The overall prevalence of PTB was 46% (128/277); in HIV+, prevalence was 54.0% (40/74). The sensitivity and specificity of PCR dot-blot were 74% (CI 95%; 66.1%-81.2%) and 85% (CI 95%; 78.8%-90.3%); and of PCR-AG were 43% (CI 95%; 34.5%-51.6%) and 76% (CI 95%; 69.2%-82.8%), respectively. For HIV seropositive and HIV seronegative samples, sensitivities of PCR dot-blot (72% vs 75%; p = 0.46) and PCR-AG (42% vs 43%; p = 0.54) were similar. Among HIV seronegative patients and PTB suspects, ROC analysis presented the following values for the AFB smear (0.837), Culture (0.926), PCR dot-blot (0.801) and PCR-AG (0.599). In HIV seropositive patients, these area values were (0.713), (0.900), (0.789) and (0.595), respectively. Conclusion Results of this study demonstrate that the in house PCR dot blot may be an improvement for ruling out PTB diagnosis in PTB suspects assisted at hospitals with a high prevalence of TB/HIV.

Abstract Background Tuberculosis is one of the most prominent health problems in the world, causing 1.75 million deaths each year. Rapid clinical diagnosis is important in patients who have co-morbidities such as Human Immunodeficiency Virus (HIV) infection. Direct microscopy has low sensitivity and culture takes 3 to 6 weeks 123. Therefore, new tools for TB diagnosis are necessary, especially in health settings with a high prevalence of HIV/TB co-infection. Methods In a public reference TB/HIV hospital in Brazil, we compared the cost-effectiveness of diagnostic strategies for diagnosis of pulmonary TB: Acid fast bacilli smear microscopy by Ziehl-Neelsen staining (AFB smear) plus culture and AFB smear plus colorimetric test (PCR dot-blot). From May 2003 to May 2004, sputum was collected consecutively from PTB suspects attending the Parthenon Reference Hospital. Sputum samples were examined by AFB smear, culture, and PCR dot-blot. The gold standard was a positive culture combined with the definition of clinical PTB. Cost analysis included health services and patient costs. Results The AFB smear plus PCR dot-blot require the lowest laboratory investment for equipment (US$ 20,000). The total screening costs are 3.8 times for AFB smear plus culture versus for AFB smear plus PCR dot blot costs (US$ 5,635,760 versus US$ 1,498, 660). Costs per correctly diagnosed case were US$ 50,773 and US$ 13,749 for AFB smear plus culture and AFB smear plus PCR dot-blot, respectively. AFB smear plus PCR dot-blot was more cost-effective than AFB smear plus culture, when the cost of treating all correctly diagnosed cases was considered. The cost of returning patients, which are not treated due to a negative result, to the health service, was higher in AFB smear plus culture than for AFB smear plus PCR dot-blot, US$ 374,778,045 and US$ 110,849,055, respectively. Conclusion AFB smear associated with PCR dot-blot associated has the potential to be a cost-effective tool in the fight against PTB for patients attended in the TB/HIV reference hospital.

Abstract Background Mutations associated with resistance to rifampin or streptomycin have been reported for W/Beijing and Latin American Mediterranean (LAM) strain families of Mycobacterium tuberculosis. A few studies with limited sample sizes have separately evaluated mutations in katG, ahpC and inhA genes that are associated with isoniazid (INH) resistance. Increasing prevalence of INH resistance, especially in high tuberculosis (TB) prevalent countries is worsening the burden of TB control programs, since similar transmission rates are noted for INH susceptible and resistant M. tuberculosis strains. Results We, therefore, conducted a comprehensive evaluation of INH resistant M. tuberculosis strains (n = 224) from three South American countries with high burden of drug resistant TB to characterize mutations in katG, ahpC and inhA gene loci and correlate with minimal inhibitory concentrations (MIC) levels and spoligotype strain family. Mutations in katG were observed in 181 (80.8%) of the isolates of which 178 (98.3%) was contributed by the katG S315T mutation. Additional mutations seen included oxyR-ahpC; inhA regulatory region and inhA structural gene. The S315T katG mutation was significantly more likely to be associated with MIC for INH ≥2 μg/mL. The S315T katG mutation was also more frequent in Haarlem family strains than LAM (n = 81) and T strain families. Conclusion Our data suggests that genetic screening for the S315T katG mutation may provide rapid information for anti-TB regimen selection, epidemiological monitoring of INH resistance and, possibly, to track transmission of INH resistant strains.

Background: Neutrophils have been associated with lung tissue damage in many diseases, including tuberculosis (TB). Whether neutrophil count can serve as a predictor of adverse treatment outcomes is unknown. Methods: We prospectively assessed 936 patients (172 HIV-seropositive) with culture-confirmed pulmonary TB, enrolled in a multicenter prospective cohort study from different regions in Brazil, from June 2015 to June 2019, and were followed up to two years. TB patients had a baseline visit before treatment (month 0) and visits at month 2 and 6 (or at the end of TB treatment). Smear microscopy, and culture for Mycobacterium tuberculosis (MTB) were performed at TB diagnosis and during follow-up. Complete blood counts were measured at baseline. Treatment outcome was defined as either unfavorable (death, treatment failure or TB recurrence) or favorable (cure or treatment completion). We performed multivariable logistic regression, with propensity score regression adjustment, to estimate the association between neutrophil count with MTB culture result at month 2 and unfavorable treatment outcome. We used a propensity score adjustment instead of a fully adjusted regression model due to the relatively low number of outcomes. Results: Among 682 patients who had MTB culture results at month 2, 40 (5.9%) had a positive result. After regression with propensity score adjustment, no significant association between baseline neutrophil count (103/mm3) and positive MTB culture at month 2 was found among either HIV-seronegative (OR = 1.06, 95% CI = [0.95;1.19] or HIV-seropositive patients (OR = 0.77, 95% CI = [0.51; 1.20]). Of 691 TB patients followed up for at least 18 months and up to 24 months, 635 (91.9%) were either cured or completed treatment, and 56 (8.1%) had an unfavorable treatment outcome. A multivariable regression with propensity score adjustment found an association between higher neutrophil count (103/mm3) at baseline and unfavorable outcome among HIV-seronegative patients [OR= 1.17 (95% CI= [1.06;1.30]). In addition, adjusted Cox regression found that higher baseline neutrophil count (103/mm3) was associated with unfavorable treatment outcomes overall and among HIV-seronegative patients (HR= 1.16 (95% CI = [1.05;1.27]). Conclusion: Increased neutrophil count prior to anti-TB treatment initiation was associated with unfavorable treatment outcomes, particularly among HIV-seronegative patients. Further prospective studies evaluating neutrophil count in response to drug treatment and association with TB treatment outcomes are warranted. [ABSTRACT FROM AUTHOR]

Abstract Background Smear-negative pulmonary tuberculosis (SNPTB) accounts for 30% of Pulmonary Tuberculosis (PTB) cases reported annually in developing nations. Polymerase chain reaction (PCR) may provide an alternative for the rapid detection of Mycobacterium tuberculosis (MTB); however little data are available regarding the clinical utility of PCR in SNPTB, in a setting with a high burden of TB/HIV co-infection. Methods To evaluate the performance of the PCR dot-blot in parallel with pretest probability (Clinical Suspicion) in patients suspected of having SNPTB, a prospective study of 213 individuals with clinical and radiological suspicion of SNPTB was carried out from May 2003 to May 2004, in a TB/HIV reference hospital. Respiratory specialists estimated the pretest probability of active disease into high, intermediate, low categories. Expectorated sputum was examined by direct microscopy (Ziehl-Neelsen staining), culture (Lowenstein Jensen) and PCR dot-blot. Gold standard was based on culture positivity combined with the clinical definition of PTB. Results In smear-negative and HIV subjects, active PTB was diagnosed in 28.4% (43/151) and 42.2% (19/45), respectively. In the high, intermediate and low pretest probability categories active PTB was diagnosed in 67.4% (31/46), 24% (6/25), 7.5% (6/80), respectively. PCR had sensitivity of 65% (CI 95%: 50%–78%) and specificity of 83% (CI 95%: 75%–89%). There was no difference in the sensitivity of PCR in relation to HIV status. PCR sensitivity and specificity among non-previously TB treated and those treated in the past were, respectively: 69%, 43%, 85% and 80%. The high pretest probability, when used as a diagnostic test, had sensitivity of 72% (CI 95%:57%–84%) and specificity of 86% (CI 95%:78%–92%). Using the PCR dot-blot in parallel with high pretest probability as a diagnostic test, sensitivity, specificity, positive and negative predictive values were: 90%, 71%, 75%, and 88%, respectively. Among non-previously TB treated and HIV subjects, this approach had sensitivity, specificity, positive and negative predictive values of 91%, 79%, 81%, 90%, and 90%, 65%, 72%, 88%, respectively. Conclusion PCR dot-blot associated with a high clinical suspicion may provide an important contribution to the diagnosis of SNPTB mainly in patients that have not been previously treated attended at a TB/HIV reference hospital.