Genetic ancestry proportion influences risk of adverse events from tuberculosis treatment in Brazil.

Tuberculosis (TB) treatment is highly effective, but response to therapy can vary by geography, race, and ethnicity. We assessed for differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry proportion according to major ancestry groups (African, European, and Amerindian ancestry) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. TB treatment outcomes that were attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Ancestry proportion was the main predictor in logistic regression for each outcome, with adjustments for candidate confounders. There were 941 pulmonary TB patients included in this study. We observed a decreased risk of Grade 2+ ADR when African ancestry proportion increased by 10% (Odds Ratio [OR] 0.41, 95% Confidence Interval [CI] 0.20 -0.85) and an increased risk for Grade 2+ ADR with increasing European ancestry (OR 2.84, 95% CI 1.47 - 5.48). We then performed the same analysis adding HIV status as an interaction term. The decreased risk for Grade 2+ ADR seen for African ancestry proportion did not hold for persons living with HIV; we observed increased risk for Grade 2+ ADR with increasing African ancestry proportion. There were no associations with Amerindian ancestry or for other treatment outcomes. In this Brazilian TB cohort, toxicity risk was associated with African and European ancestry, divergent, and affected by HIV. #RePORT-Brazil Consortium members include: Aline Benjamin and Flavia M. Sant'Anna Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, Brazil Jamile Garcia de Oliveira and João Marine Clínica de Saúde Rinaldo Delmare, Rio de Janeiro, Brazil Adriana Rezende and Anna Cristina Carvalho Secretaria de Saúde de Duque de Caxias, Rio de Janeiro, Brazil Michael Rocha and Betânia Nogueira Instituto Brasileiro para Investigação da Tuberculose, Fundação José Silveira, Salvador, Brazil Alexandra Brito and Renata Spener Fundação Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil Megan Turner Vanderbilt University Medical Center, Nashville, USA.

Retreatment and Anti-tuberculosis Therapy Outcomes in Brazil Between 2015 and 2022: A Nationwide Study.

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.

The effect of previous SARS-CoV-2 infection on systemic immune responses in individuals with tuberculosis.

Background: The impact of previous SARS-CoV-2 infection on the systemic immune response during tuberculosis (TB) disease has not been explored. Methods: An observational, cross-sectional cohort was established to evaluate the systemic immune response in persons with pulmonary tuberculosis with or without previous SARS-CoV-2 infection. Those participants were recruited in an outpatient referral clinic in Rio de Janeiro, Brazil. TB was defined as a positive Xpert-MTB/RIF Ultra and/or a positive culture of Mycobacterium tuberculosis from sputum. Stored plasma was used to perform specific serology to identify previous SARS-CoV-2 infection (TB/Prex-SCoV-2 group) and confirm the non- infection of the tuberculosis group (TB group). Plasmatic cytokine/chemokine/growth factor profiling was performed using Luminex technology. Tuberculosis severity was assessed by clinical and laboratory parameters. Participants from TB group (4.55%) and TB/Prex-SCoV-2 (0.00%) received the complete COVID-19 vaccination. Results: Among 35 participants with pulmonary TB, 22 were classified as TB/Prex-SCoV-2. The parameters associated with TB severity, together with hematologic and biochemical data were similar between the TB and TB/Prex-SCoV-2 groups. Among the signs and symptoms, fever and dyspnea were significantly more frequent in the TB group than the TB/Prex-SCoV-2 group (p < 0,05). A signature based on lower amount of plasma EGF, G-CSF, GM-CSF, IFN-α2, IL-12(p70), IL-13, IL-15, IL-17, IL-1ß, IL-5, IL-7, and TNF-ß was observed in the TB/Prex-SCoV-2 group. In contrast, MIP-1ß was significantly higher in the TB/Prex-SCoV-2 group than the TB group. Conclusion: TB patients previously infected with SARS-CoV-2 had an immunomodulation that was associated with lower plasma concentrations of soluble factors associated with systemic inflammation. This signature was associated with a lower frequency of symptoms such as fever and dyspnea but did not reflect significant differences in TB severity parameters observed at baseline.

Impact of Xpert MTB/RIF implementation in tuberculosis case detection and control in Brazil: a nationwide intervention time-series analysis (2011-2022).

Background: Since 2014, Brazil has gradually implemented the Xpert MTB/RIF (Xpert) test to enhance early tuberculosis (TB) and drug-resistant (DR-TB) detection and control, yet its nationwide impact remains underexplored. Our study conducts an intervention time-series analysis (ITSA) to evaluate how the Xpert's implementation has improved TB and DR-TB detection nationwide. Methods: 1,061,776 cases from Brazil's National TB Registry (2011-2022) were reviewed and ITSA (2011-2019) was used to gauge the impact of the Xpert's adoption on TB and DR-TB notification. Granger Causality and dynamic regression modelling determined if incorporating Xpert testing as an external regressor enhanced forecasting accuracy for Brazil's future TB trends. Findings: Xpert implementation resulted in a 9.7% increase in TB notification and substantial improvements in DR-TB (63.6%) and drug-susceptible TB (92.1%) detection compared to expected notifications if it had not been implemented. Xpert testing counts also presented a time-dependent relationship with DR-TB detection post-implementation, and improved predictions in forecasting models, which depicted a potential increase in TB and DR-TB detection in the next six years. Interpretation: This study underscores the critical role of Xpert's adoption in boosting TB and DR-TB detection in Brazil, reinforcing the case for its widespread use in disease control. Improvements in prediction accuracy resulting from integrating Xpert data are crucial for allocating resources and reducing the incidence of TB. By acknowledging Xpert's role in both disease control and improving predictions, we advocate for its expanded use and further research into advanced molecular diagnostics for effective TB and DR-TB control. Funding: FIOCRUZ.

Machine learning algorithms using national registry data to predict loss to follow-up during tuberculosis treatment.

BACKGROUND: Identifying patients at increased risk of loss to follow-up (LTFU) is key to developing strategies to optimize the clinical management of tuberculosis (TB). The use of national registry data in prediction models may be a useful tool to inform healthcare workers about risk of LTFU. Here we developed a score to predict the risk of LTFU during anti-TB treatment (ATT) in a nationwide cohort of cases using clinical data reported to the Brazilian Notifiable Disease Information System (SINAN). METHODS: We performed a retrospective study of all TB cases reported to SINAN between 2015 and 2022; excluding children (< 18 years-old), vulnerable groups or drug-resistant TB. For the score, data before treatment initiation were used. We trained and internally validated three different prediction scoring systems, based on Logistic Regression, Random Forest, and Light Gradient Boosting. Before applying our models we splitted our data into training (~ 80% data) and test (~ 20%) sets, and then compared the model metrics using the test data set. RESULTS: Of the 243,726 cases included, 41,373 experienced LTFU whereas 202,353 were successfully treated. The groups were different with regards to several clinical and sociodemographic characteristics. The directly observed treatment (DOT) was unbalanced between the groups with lower prevalence in those who were LTFU. Three models were developed to predict LTFU using 8 features (prior TB, drug use, age, sex, HIV infection and schooling level) with different score composition approaches. Those prediction scoring systems exhibited an area under the curve (AUC) ranging between 0.71 and 0.72. The Light Gradient Boosting technique resulted in the best prediction performance, weighting specificity and sensitivity. A user-friendly web calculator app was developed ( https://tbprediction.herokuapp.com/ ) to facilitate implementation. CONCLUSIONS: Our nationwide risk score predicts the risk of LTFU during ATT in Brazilian adults prior to treatment commencement utilizing schooling level, sex, age, prior TB status, and substance use (drug, alcohol, and/or tobacco). This is a potential tool to assist in decision-making strategies to guide resource allocation, DOT indications, and improve TB treatment adherence.

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.

An integrative multi-omics approach to characterize interactions between tuberculosis and diabetes mellitus.

Tuberculosis-diabetes mellitus (TB-DM) is linked to a distinct inflammatory profile, which can be assessed using multi-omics analyses. Here, a machine learning algorithm was applied to multi-platform data, including cytokines and gene expression in peripheral blood and eicosanoids in urine, in a Brazilian multi-center TB cohort. There were four clinical groups: TB-DM(n = 24), TB only(n = 28), DM(HbA1c ≥ 6.5%) only(n = 11), and a control group of close TB contacts who did not have TB or DM(n = 13). After cross-validation, baseline expression or abundance of MMP-28, LTE-4, 11-dTxB2, PGDM, FBXO6, SECTM1, and LINCO2009 differentiated the four patient groups. A distinct multi-omic-derived, dimensionally reduced, signature was associated with TB, regardless of glycemic status. SECTM1 and FBXO6 mRNA levels were positively correlated with sputum acid-fast bacilli grade in TB-DM. Values of the biomarkers decreased during the course of anti-TB therapy. Our study identified several markers associated with the pathophysiology of TB-DM that could be evaluated in future mechanistic investigations.

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.

Isoniazid Monoresistance and Antituberculosis Treatment Outcome in Persons With Pulmonary Tuberculosis in Brazil.

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.

The sound of silent RNA in tuberculosis and the lncRNA role on infection.

Tuberculosis (TB) is one of the leading causes of death worldwide, and Diabetes Mellitus is one of the major comorbidities (TB/DM) associated with the disease. A total of 103 differentially expressed ncRNAs have been identified in the TB and TB/DM comparisons. A machine learning algorithm was employed to identify the most informative lncRNAs: ADM-DT, LINC02009, LINC02471, SOX2-OT, and GK-AS1. These lncRNAs presented substantial accuracy in classifying TB from HC (AUCs >0.85) and TB/DM from HC (AUCs >0.90) in the other three countries. Genes with significant correlations with the five lncRNAs enriched common pathways in Brazil and India for both TB and TB/DM. This suggests that lncRNAs play an important role in the regulation of genes related to the TB immune response.

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.

Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort.

Background: Genetic polymorphisms have been associated with risk of anti-tuberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil. Methods: Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015-2019, and who were evaluable for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24 month follow-up. Analyses included 43 polymorphisms in 20 genes related to anti-tuberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset. Results: Among 903 participants in multivariable genetic association analyses, NAT2 slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely among NAT2 rapid acetylators, but not statistically significant at the 5% level. A GSTM1 polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. SLCO1B1 polymorphisms were associated with increased risk of treatment- related hepatoxicity and treatment failure/recurrence. Polymorphisms in NR1/2 were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism in VTI1A , and the genes METTL17 and PRSS57 , but none achieved genome-wide significance. Conclusions: In a clinical cohort representing three regions of Brazil, NAT2 acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations.

A multi-center, prospective cohort study of whole blood gene expression in the tuberculosis-diabetes interaction.

Diabetes mellitus (DM) increases tuberculosis (TB) severity. We compared blood gene expression in adults with pulmonary TB, with or without diabetes mellitus (DM) from sites in Brazil and India. RNA sequencing (RNAseq) performed at baseline and during TB treatment. Publicly available baseline RNAseq data from South Africa and Romania reported by the TANDEM Consortium were also analyzed. Across the sites, differentially expressed genes varied for each condition (DM, TB, and TBDM) and no pattern classified any one group across all sites. A concise signature of TB disease was identified but this was expressed equally in TB and TBDM. Pathway enrichment analysis failed to distinguish TB from TBDM, although there was a trend for greater neutrophil and innate immune pathway activation in TBDM participants. Pathways associated with insulin resistance, metabolic dysfunction, diabetic complications, and chromosomal instability were positively correlated with glycohemoglobin. The immune response to pulmonary TB as reflected by whole blood gene expression is substantially similar with or without comorbid DM. Gene expression pathways associated with the microvascular and macrovascular complications of DM are upregulated during TB, supporting a syndemic interaction between these coprevalent diseases.

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.

Determinants of losses in the tuberculosis infection cascade of care among children and adolescent contacts of pulmonary tuberculosis cases: A Brazilian multi-centre longitudinal study.

Background: Approximately 10% of the global tuberculosis (TB) burden is in children. Identification, diagnosis, and early treatment of Mycobacterium tuberculosis infection (TBI) is critical to prevent progression to TB in children. The risk of TB, including severe disease, is highest in children <5 years old. We evaluated the cascade of TBI care among child and adolescent TB contacts to identify factors associated with losses in the cascade. Methods: Close contacts ≤ 18 years old of pulmonary TB patients enrolled between 2015 and 2019 in a multi-centre Brazilian cohort were followed for up to 24 months and classified according to age groups: <5 years, 5-9 years, 10-14 years and 15-18 years. Data on clinical investigation, radiographic examination, IGRA testing at baseline and 6 months, initiation and completion of TB preventive treatment (TPT) were collected. Multivariable regression analyses identified factors associated with TBI and losses in the cascade of care in children and adolescents. Findings: Among 1795 TB contacts initially identified, 530 (29·5%) were ≤18 years old. Losses for all steps in the cascade were especially high in children <5 years old (88%) because at this age all contacts are recommended to initiate TPT. As a proportion of all children, completion of TPT was low (between 10% and 13%) in all age-groups. Furthermore, multivariable regression revealed that younger age of contacts and TB index cases who were female, had pulmonary cavities, and persistent cough were independently associated with losses in the cascade of care among persons ≤18 years old. Interpretation: Losses in the TBI cascade were the highest among children <5 years, which was the group at highest risk for TB among the four age groups. The findings highlight the need to improve screening, initiation, and completion of TPT of young children who are close contacts of people with TB in Brazil. Funding: National Institutes of Allergy and Infectious Diseases.

Diagnostic biomarkers for active tuberculosis: progress and challenges.

Tuberculosis (TB) is a leading cause of morbidity and mortality from a single infectious agent, despite being preventable and curable. Early and accurate diagnosis of active TB is critical to both enhance patient care, improve patient outcomes, and break Mycobacterium tuberculosis (Mtb) transmission cycles. In 2020 an estimated 9.9 million people fell ill from Mtb, but only a little over half (5.8 million) received an active TB diagnosis and treatment. The World Health Organization has proposed target product profiles for biomarker- or biosignature-based diagnostics using point-of-care tests from easily accessible specimens such as urine or blood. Here we review and summarize progress made in the development of pathogen- and host-based biomarkers for active TB diagnosis. We describe several unique patient populations that have posed challenges to development of a universal diagnostic TB biomarker, such as people living with HIV, extrapulmonary TB, and children. We also review additional limitations to widespread validation and utilization of published biomarkers. We conclude with proposed solutions to enhance TB diagnostic biomarker validation and uptake.

Tuberculosis treatment outcomes of diabetic and non-diabetic TB/HIV co-infected patients: A nationwide observational study in Brazil.

Background: Tuberculosis (TB) is a worldwide public health problem, especially in countries that also report high numbers of people living with HIV (PLWH) and/or diabetes mellitus (DM). However, the unique features of persons with TB-HIV-DM are incompletely understood. This study compared anti-TB treatment (ATT) outcomes of diabetic and non-diabetic TB/HIV co-infected patients. Methods: A nationwide retrospective observational investigation was performed with data from the Brazilian Tuberculosis Database System among patients reported to have TB-HIV co-infection between 2014 and 2019. This database includes all reported TB cases in Brazil. Exploratory and association analyses compared TB treatment outcomes in DM and non-DM patients. Unfavorable outcomes were defined as death, treatment failure, loss to follow-up or recurrence. Multivariable stepwise logistic regressions were used to identify the variables associated with unfavorable ATT outcomes in the TB-HIV population. Results: Of the 31,070 TB-HIV patients analyzed, 999 (3.2%) reported having DM. However, in these TB-HIV patients, DM was not associated with any unfavorable treatment outcome [adjusted Odds Ratio (aOR): 0.97, 95% CI: 0.83-1.12, p = 0.781]. Furthermore, DM was also not associated with any specific type of unfavorable outcome in this study. In both the TB-HIV group and the TB-HIV-DM subpopulation, use of alcohol, illicit drugs and tobacco, as well as non-white ethnicity and prior TB were all characteristics more frequently observed in persons who experienced an unfavorable ATT outcome. Conclusion: DM is not associated with unfavorable TB treatment outcomes in persons with TB-HIV, including death, treatment failure, recurrence and loss to follow up. However, consumption habits, non-white ethnicity and prior TB are all more frequently detected in those with unfavorable outcomes in both TB-HIV and TB-HIV-DM patients.

Effect of Dysglycemia on Urinary Lipid Mediator Profiles in Persons With Pulmonary Tuberculosis.

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 sub-groups with or without dysglycemia at baseline. Participants were enrolled from RePORT-Brazil (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) TB-normoglycemia (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-hydroxy-11,15-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 TB-dysglycemia 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 TB-dysglycemia 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.

Late-onset opportunistic infections while receiving anti-retroviral therapy in Latin America: burden and risk factors.

OBJECTIVES: The aim of this study was to describe the incidence, clinical characteristics, and risk factors of late-onset opportunistic infections (LOI) in people who live with HIV (PWLHA) within the Caribbean, Central and South America network for HIV epidemiology. METHODS: We performed a retrospective cohort study including treatment-naive PWLHA enrolled at seven sites (Argentina, Brazil, Chile, Peru, Mexico, and two sites in Honduras). Follow-up began at 6 months after treatment started. Outcomes were LOI, loss to follow-up, and death. We used a Cox proportional hazards model and a competing risks model to evaluate risk factors. RESULTS: A total of 10,583 patients were included. Median follow up was at 5.4 years. LOI occurred in 895 (8.4%) patients. Median time to opportunistic infection was 2.1 years. The most common infections were tuberculosis (39%), esophageal candidiasis (10%), and Pneumocystis jirovecii (P. jirovecii) pneumonia (10%). Death occurred in 576 (5.4%) patients, and 3021 (28.5%) patients were lost to follow-up. A protease inhibitor-based regimen (hazard ratio 1.25), AIDS-defining events during the first 6 months of antiretroviral-treatment (hazard ratio 2.12), starting antiretroviral-treatment in earlier years (hazard ratio 1.52 for 2005 vs 2010), and treatment switch (hazard ratio 1.31) were associated with a higher risk of LOI. CONCLUSION: LOI occurred in nearly one in 10 patients. People with risk factors could benefit from closer follow-up.

Immunologic Biomarkers in Peripheral Blood of Persons With Tuberculosis and Advanced HIV.

Introduction: Tuberculosis (TB) is a common opportunistic infection among people living with HIV. Diagnostic tests such as culture, Xpert-MTB-RIF, and ULTRA have low sensitivity in paucibacillary TB disease; a blood biomarker could improve TB diagnostic capabilities. We assessed soluble factors to identify biomarkers associated with TB among persons with advanced HIV. Methods: A case-control (1:1) study was conducted, with participants from Rio de Janeiro and Manaus, Brazil. People living with HIV presenting with CD4 count ≤100 cells/mm3 were eligible to participate. Cases had culture-confirmed TB (N=15) (positive for Mycobacterium tuberculosis [Mtb]); controls had HIV-infection only (N=15). Study visits included baseline, month 2 and end of TB therapy, during which samples of peripheral blood were obtained. A panel containing 29 biomarkers including cytokines, chemokines and growth factors was utilized to assess candidate biomarkers using Luminex technology in cryopreserved EDTA plasma samples. We used neural network analysis, based on machine learning, to identify biomarkers (single or in combination) that best distinguished cases from controls. Additional multi-dimensional analyses provided detailed profiling of the systemic inflammatory environment in cases and controls. Results: Median CD4 count and HIV-1 RNA load values were similar between groups at all timepoints. Persons with TB had lower body mass index (BMI) (median=19.6, Interquartile Range [IQR]=18.6-22.3) than controls (23.7; IQR: 21.8 = 25.5, p=0.004). TB coinfection was also associated with increased frequency of other comorbidities. The overall profile of plasma cytokines, chemokines and growth factors were distinct between the study groups at all timepoints. Plasma concentrations of IL-15 and IL-10 were on average lower in TB cases than in controls. When used in combination, such markers were able to discriminate between TB cases and controls with the highest degree of accuracy at each study timepoint. Conclusion: Among persons with advanced HIV, plasma concentrations of IL-15 and IL-10 can be used in combination to identify TB disease regardless of time on anti-TB treatment.