Molecular Epidemiology of Isoniazid-resistant M tuberculosis in Port-au-Prince, Haiti.

Background: Isoniazid-resistant, rifampin-susceptible tuberculosis (Hr-TB) is associated with poor treatment outcomes and higher rates of acquisition of further drug resistance during treatment. Due to a lack of widespread diagnostics, Hr-TB is frequently undetected and its epidemiology is incompletely understood. Methods: We studied the molecular epidemiology of Hr-TB among all patients diagnosed with culture-positive pulmonary tuberculosis between January 1 and June 30, 2017, at an urban referral tuberculosis clinic in Port-au-Prince, Haiti. Demographic and clinical data were extracted from the electronic medical record. Archived diagnostic Mycobacterium tuberculosis isolates were tested for genotypic and phenotypic isoniazid resistance using the Genotype MTBDRplus assay (Hain, Nehren, Germany) and culture-based testing, respectively. All isoniazid-resistant isolates and a randomly selected subset of isoniazid-susceptible isolates underwent whole-genome sequencing to confirm the presence of mutations associated with isoniazid resistance, to validate use of Genotype MTBDRplus in this population, and to identify potential transmission links between isoniazid-resistant isolates. Results and Conclusions: Among 845 patients with culture-positive pulmonary tuberculosis in Haiti, 65 (7.7%) had Hr-TB based on the Genotype MTBDRplus molecular assay. Age < 20 years was significantly associated with Hr-TB (odds ratio, 2.39; 95% confidence interval, 1.14, 4.70; P = .015). Thirteen (20%) isoniazid-resistant isolates were found in 5 putative transmission clusters based on a single nucleotide polymorphism distance of ≤ 5. No patients in these transmission clusters were members of the same household. Adolescents are at higher risk for Hr-TB. Strains of isoniazid-resistant M tuberculosis are actively circulating in Haiti and transmission is likely occurring in community settings.

Mass incarceration as a driver of the tuberculosis epidemic in Latin America and projected impacts of policy alternatives: A mathematical modeling study.

Background: Tuberculosis incidence is increasing in Latin America, where the incarcerated population has nearly quadrupled since 1990. The full impact of incarceration on the tuberculosis epidemic, accounting for effects beyond prisons, has never been quantified. Methods: We calibrated dynamic compartmental transmission models to historical and contemporary data from Argentina, Brazil, Colombia, El Salvador, Mexico, and Peru, which comprise approximately 80% of the region's incarcerated population and tuberculosis burden. Using historical counterfactual scenarios, we estimated the transmission population attributable fraction (tPAF) for incarceration and the excess population-level burden attributable to increasing incarceration prevalence since 1990. We additionally projected the impact of alternative incarceration policies on future population tuberculosis incidence. Findings: Population tuberculosis incidence in 2019 was 29.4% (95% UI, 23.9-36.8) higher than expected without the rise in incarceration since 1990, corresponding to 34,393 (95% UI, 28,295-42,579) excess incident cases across countries. The incarceration tPAF in 2019 was 27.2% (95% UI, 20.9-35.8), exceeding estimates for other risk factors like HIV, alcohol use disorder, and undernutrition. Compared to a scenario where incarceration rates remain stable at current levels, a gradual 50% reduction in prison admissions and duration of incarceration by 2034 would reduce population tuberculosis incidence by over 10% in all countries except Mexico. Interpretation: The historical rise in incarceration in Latin America has resulted in a large excess tuberculosis burden that has been under-recognized to-date. International health agencies, ministries of justice, and national tuberculosis programs should collaborate to address this health crisis with comprehensive strategies, including decarceration. Funding: National Institutes of Health.

Risk factors underlying racial and ethnic disparities in tuberculosis diagnosis and treatment outcomes, 2011-19: a multiple mediation analysis of national surveillance data.

BACKGROUND: Despite an overall decline in tuberculosis incidence and mortality in the USA in the past two decades, racial and ethnic disparities in tuberculosis outcomes persist. We aimed to examine the extent to which inequalities in health and neighbourhood-level social vulnerability mediate these disparities. METHODS: We extracted data from the US National Tuberculosis Surveillance System on individuals with tuberculosis during 2011-19. Individuals with multidrug-resistant tuberculosis or missing data on race and ethnicity were excluded. We examined potential disparities in tuberculosis outcomes among US-born and non-US-born individuals and conducted a mediation analysis for groups with a higher risk of treatment incompletion (a summary outcome comprising diagnosis after death, treatment discontinuation, or death during treatment). We used sequential multiple mediation to evaluate eight potential mediators: three comorbid conditions (HIV, end-stage renal disease, and diabetes), homelessness, and four census tract-level measures (poverty, unemployment, insurance coverage, and racialised economic segregation [measured by Index of Concentration at the ExtremesRace-Income]). We estimated the marginal contribution of each mediator using Shapley values. FINDINGS: During 2011-19, 27 788 US-born individuals and 57 225 non-US-born individuals were diagnosed with active tuberculosis, of whom 27 605 and 56 253 individuals, respectively, met eligibility criteria for our analyses. We did not observe evidence of disparities in tuberculosis outcomes for non-US-born individuals by race and ethnicity. Therefore, subsequent analyses were restricted to US-born individuals. Relative to White individuals, Black and Hispanic individuals had a higher risk of not completing tuberculosis treatment (adjusted relative risk 1·27, 95% CI 1·19-1·35; 1·22, 1·11-1·33, respectively). In multiple mediator analysis, the eight measured mediators explained 67% of the disparity for Black individuals and 65% for Hispanic individuals. The biggest contributors to these disparities for Black individuals and Hispanic individuals were concomitant end-stage renal disease, concomitant HIV, census tract-level racialised economic segregation, and census tract-level poverty. INTERPRETATION: Our findings underscore the need for initiatives to reduce disparities in tuberculosis outcomes among US-born individuals, particularly in highly racially and economically polarised neighbourhoods. Mitigating the structural and environmental factors that lead to disparities in the prevalence of comorbidities and their case management should be a priority. FUNDING: US Centers for Disease Control and Prevention National Center for HIV, Viral Hepatitis, STD, and Tuberculosis Prevention Epidemiologic and Economic Modeling Agreement.

The long-term effects of domestic and international tuberculosis service improvements on tuberculosis trends within the USA: a mathematical modelling study.

BACKGROUND: For settings with low tuberculosis incidence, disease elimination is a long-term goal. We investigated pathways to tuberculosis pre-elimination (incidence <1·0 cases per 100 000 people) and elimination (incidence <0·1 cases per 100 000 people) in the USA, where incidence was estimated at 2·9 per 100 000 people in 2023. METHODS: Using a mathematical modelling framework, we simulated how US tuberculosis incidence could be affected by changes in tuberculosis services in the countries of origin for future migrants to the USA, as well as changes in tuberculosis services inside the USA. To do so, we used a linked set of transmission dynamic models, calibrated to demographic and epidemiological data for each setting. We constructed intervention scenarios representing improvements in tuberculosis services internationally and within the USA, individually and in combination, plus a base-case scenario representing continuation of current services. We simulated health and economic outcomes until 2100, using a Bayesian approach to quantify uncertainty in these outcomes. FINDINGS: Under the base-case scenario, US tuberculosis incidence was projected to decline to 1·8 cases per 100 000 (95% uncertainty interval [UI] 1·5-2·1) in the total population by 2050. Intervention scenarios produced substantial reductions in tuberculosis incidence, with the combination of all domestic and international interventions projected to achieve pre-elimination by 2033 (95% UI 2031-2037). Compared with the base-case scenario, this combination of interventions could avert 101 000 tuberculosis cases (95% UI 84 000-120 000) and 13 300 tuberculosis deaths (95% UI 10 500-16 300) in the USA from 2025 to 2050. Tuberculosis elimination was not projected before 2100. INTERPRETATION: Strengthening tuberculosis services domestically, promoting the development of more effective technologies and interventions, and supporting tuberculosis programmes in countries with a high tuberculosis burden are key strategies for accelerating progress towards tuberculosis elimination in the USA. FUNDING: US Centers for Disease Control and Prevention.

Cost-effectiveness and health impact of screening and treatment of Mycobacterium tuberculosis infection among formerly incarcerated individuals in Brazil: a Markov modelling study.

BACKGROUND: Individuals who were formerly incarcerated have high tuberculosis incidence, but are generally not considered among the risk groups eligible for tuberculosis prevention. We investigated the potential health impact and cost-effectiveness of Mycobacterium tuberculosis infection screening and tuberculosis preventive treatment (TPT) for individuals who were formerly incarcerated in Brazil. METHODS: Using published evidence for Brazil, we constructed a Markov state transition model estimating tuberculosis-related health outcomes and costs among individuals who were formerly incarcerated, by simulating transitions between health states over time. The analysis compared tuberculosis infection screening and TPT, to no screening, considering a combination of M tuberculosis infection tests and TPT regimens. We quantified health effects as reductions in tuberculosis cases, tuberculosis deaths, and disability-adjusted life-years (DALYs). We assessed costs from a tuberculosis programme perspective. We report intervention cost-effectiveness as the incremental costs per DALY averted, and tested how results changed across subgroups of the target population. FINDINGS: Compared with no intervention, an intervention incorporating tuberculin skin testing and treatment with 3 months of isoniazid and rifapentine would avert 31 (95% uncertainty interval 14-56) lifetime tuberculosis cases and 4·1 (1·4-5·8) lifetime tuberculosis deaths per 1000 individuals, and cost US$242 per DALY averted. All test and regimen combinations were cost-effective compared with no screening. Younger age, longer incarceration, and more recent prison release were each associated with significantly greater health benefits and more favourable cost-effectiveness ratios, although the intervention was cost-effective for all subgroups examined. INTERPRETATION: M tuberculosis infection screening and TPT for individuals who were formerly incarcerated appears cost-effective, and would provide valuable health gains. FUNDING: National Institutes of Health. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

e3SIM: epidemiological-ecological-evolutionary simulation framework for genomic epidemiology.

Infectious disease dynamics are driven by the complex interplay of epidemiological, ecological, and evolutionary processes. Accurately modeling these interactions is crucial for understanding pathogen spread and informing public health strategies. However, existing simulators often fail to capture the dynamic interplay between these processes, resulting in oversimplified models that do not fully reflect real-world complexities in which the pathogen's genetic evolution dynamically influences disease transmission. We introduce the epidemiological-ecological-evolutionary simulator (e3SIM), an open-source framework that concurrently models the transmission dynamics and molecular evolution of pathogens within a host population while integrating environmental factors. Using an agent-based, discrete-generation, forward-in-time approach, e3SIM incorporates compartmental models, host-population contact networks, and quantitative-trait models for pathogens. This integration allows for realistic simulations of disease spread and pathogen evolution. Key features include a modular and scalable design, flexibility in modeling various epidemiological and population-genetic complexities, incorporation of time-varying environmental factors, and a user-friendly graphical interface. We demonstrate e3SIM's capabilities through simulations of realistic outbreak scenarios with SARS-CoV-2 and Mycobacterium tuberculosis, illustrating its flexibility for studying the genomic epidemiology of diverse pathogen types.

Potential of Pan-Tuberculosis Treatment to Drive Emergence of Novel Resistance.

New tuberculosis (TB) drugs with little existing antimicrobial resistance enable a pan-TB treatment regimen, intended for universal use without prior drug-susceptibility testing. However, widespread use of such a regimen could contribute to an increasing prevalence of antimicrobial resistance, potentially rendering the pan-TB regimen ineffective or driving clinically problematic patterns of resistance. We developed a model of multiple sequential TB patient cohorts to compare treatment outcomes between continued use of current standards of care (guided by rifampin-susceptibility testing) and a hypothetical pan-TB approach. A pan-TB regimen that met current target profiles was likely to initially outperform the standard of care; however, a rising prevalence of transmitted resistance to component drugs could make underperformance likely among subsequent cohorts. Although the pan-TB approach led to an increased prevalence of resistance to novel drugs, it was unlikely to cause accumulation of concurrent resistance to novel drugs and current first-line drugs.

Phylogeographic Analysis of Mycobacterium kansasii Isolates from Patients with M. kansasii Lung Disease in Industrialized City, Taiwan.

Little is known about environmental transmission of Mycobacterium kansasii. We retrospectively investigated potential environmental acquisition, primarily water sources, of M. kansasii among 216 patients with pulmonary disease from an industrial city in Taiwan during 2015-2017. We analyzed sputum mycobacterial cultures using whole-genome sequencing and used hierarchical Bayesian spatial network methods to evaluate risk factors for genetic relatedness of M. kansasii strains. The mean age of participants was 67 years; 24.1% had previously had tuberculosis. We found that persons from districts served by 2 water purification plants were at higher risk of being infected with genetically related M. kansasii isolates. The adjusted odds ratios were 1.81 (1.25-2.60) for the Weng Park plant and 1.39 (1.12-1.71) for the Fongshan plant. Those findings unveiled the association between water purification plants and M. kansasii pulmonary disease, highlighting the need for further environmental investigations to evaluate the risk for M. kansasii transmission.

Uncertainty in tuberculosis clinical decision-making: An umbrella review with systematic methods and thematic analysis.

Tuberculosis is a major infectious disease worldwide, but currently available diagnostics have suboptimal accuracy, particularly in patients unable to expectorate, and are often unavailable at the point-of-care in resource-limited settings. Test/treatment decision are, therefore, often made on clinical grounds. We hypothesized that contextual factors beyond disease probability may influence clinical decisions about when to test and when to treat for tuberculosis. This umbrella review aimed to identify such factors, and to develop a framework for uncertainty in tuberculosis clinical decision-making. Systematic reviews were searched in seven databases (MEDLINE, CINAHL Complete, Embase, Scopus, Cochrane, PROSPERO, Epistemonikos) using predetermined search criteria. Findings were classified as barriers and facilitators for testing or treatment decisions, and thematically analysed based on a multi-level model of uncertainty in health care. We included 27 reviews. Study designs and primary aims were heterogeneous, with seven meta-analyses and three qualitative evidence syntheses. Facilitators for decisions to test included providers' advanced professional qualification and confidence in tests results, availability of automated diagnostics with quick turnaround times. Common barriers for requesting a diagnostic test included: poor provider tuberculosis knowledge, fear of acquiring tuberculosis through respiratory sampling, scarcity of healthcare resources, and complexity of specimen collection. Facilitators for empiric treatment included patients' young age, severe sickness, and test inaccessibility. Main barriers to treatment included communication obstacles, providers' high confidence in negative test results (irrespective of negative predictive value). Multiple sources of uncertainty were identified at the patient, provider, diagnostic test, and healthcare system levels. Complex determinants of uncertainty influenced decision-making. This could result in delayed or missed diagnosis and treatment opportunities. It is important to understand the variability associated with patient-provider clinical encounters and healthcare settings, clinicians' attitudes, and experiences, as well as diagnostic test characteristics, to improve clinical practices, and allow an impactful introduction of novel diagnostics.

Combining genomic data and infection estimates to characterize the complex dynamics of SARS-CoV-2 Omicron variants in the US.

Omicron surged as a variant of concern in late 2021. Several distinct Omicron variants appeared and overtook each other. We combined variant frequencies and infection estimates from a nowcasting model for each US state to estimate variant-specific infections, attack rates, and effective reproduction numbers (Rt). BA.1 rapidly emerged, and we estimate that it infected 47.7% of the US population before it was replaced by BA.2. We estimate that BA.5 infected 35.7% of the US population, persisting in circulation for nearly 6 months. Other variants-BA.2, BA.4, and XBB-together infected 30.7% of the US population. We found a positive correlation between the state-level BA.1 attack rate and social vulnerability and a negative correlation between the BA.1 and BA.2 attack rates. Our findings illustrate the complex interplay between viral evolution, population susceptibility, and social factors during the Omicron emergence in the US.

The impact of COVID-19 national lockdowns on drug-resistant tuberculosis in KwaZulu-Natal, South Africa: A spatial analysis.

PURPOSE: We sought to understand the impact of the initial COVID-19 mitigation strategies in 2020 on drug-resistant (DR) TB diagnoses in KwaZulu-Natal province (KZN), South Africa. METHODS: We compared the number, spatial distribution, and characteristics of DR TB diagnoses before and after the initial COVID-19 lockdown on March 26th, 2020. Information on DR TB diagnoses was collected from the CONTEXT prospective cohort study and municipality characteristics were collected from Statistics South Africa. We used Bayesian conditional autoregressive models and relative-risk surface maps to examine spatial correlates and patterns of DR TB notifications. RESULTS: Between October 2018 and February 2022, there were 693 individuals diagnosed with DR TB in KZN, South Africa. The rate of diagnoses per year was 274 and 155 prior and after to the initial lockdowns, respectively, corresponding to a 43 % decrease in the notification rate of cases. Compared to cases diagnosed before the lockdown, cases diagnosed after were less likely to have a fuel source for heating, piped water, a flush toilet, or own a phone (p-values≤0.02). Changes in notifications were not homogenously distributed, with predominantly rural northeastern and southwestern municipalities having significantly greater relative-risks after the lockdown. CONCLUSIONS: We found a reduction in the rate of DR TB diagnoses after the COVID-19 pandemic lockdowns and observed that individuals diagnosed after the lockdowns had worse living conditions, fewer household resources, and more adults living in their household compared to before the pandemic.

Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

BACKGROUND: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). METHODS AND FINDINGS: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. CONCLUSIONS: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

Predictors of unsuccessful tuberculosis treatment outcomes in Brazil: an analysis of 259,484 patient records.

INTRODUCTION: Tuberculosis (TB) causes over 1 million deaths annually. Providing effective treatment is a key strategy for reducing TB deaths. In this study, we identified factors associated with unsuccessful treatment outcomes among individuals treated for TB in Brazil. METHODS: We obtained data on individuals treated for TB between 2015 and 2018 from Brazil's National Disease Notification System (SINAN). We excluded patients with a history of prior TB disease or with diagnosed TB drug resistance. We extracted information on patient-level factors potentially associated with unsuccessful treatment, including demographic and social factors, comorbid health conditions, health-related behaviors, health system level at which care was provided, use of directly observed therapy (DOT), and clinical examination results. We categorized treatment outcomes as successful (cure, completed) or unsuccessful (death, regimen failure, loss to follow-up). We fit multivariate logistic regression models to identify factors associated with unsuccessful treatment. RESULTS: Among 259,484 individuals treated for drug susceptible TB, 19.7% experienced an unsuccessful treatment outcome (death during treatment 7.8%, regimen failure 0.1%, loss to follow-up 11.9%). The odds of unsuccessful treatment were higher with older age (adjusted odds ratio (aOR) 2.90 [95% confidence interval: 2.62-3.21] for 85-100-year-olds vs. 25-34-year-olds), male sex (aOR 1.28 [1.25-1.32], vs. female sex), Black race (aOR 1.23 [1.19-1.28], vs. White race), no education (aOR 2.03 [1.91-2.17], vs. complete high school education), HIV infection (aOR 2.72 [2.63-2.81], vs. no HIV infection), illicit drug use (aOR 1.95 [1.88-2.01], vs. no illicit drug use), alcohol consumption (aOR 1.46 [1.41-1.50], vs. no alcohol consumption), smoking (aOR 1.20 [1.16-1.23], vs. non-smoking), homelessness (aOR 3.12 [2.95-3.31], vs. no homelessness), and immigrant status (aOR 1.27 [1.11-1.45], vs. non-immigrants). Treatment was more likely to be unsuccessful for individuals treated in tertiary care (aOR 2.20 [2.14-2.27], vs. primary care), and for patients not receiving DOT (aOR 2.35 [2.29-2.41], vs. receiving DOT). CONCLUSION: The risk of unsuccessful TB treatment varied systematically according to individual and service-related factors. Concentrating clinical attention on individuals with a high risk of poor treatment outcomes could improve the overall effectiveness of TB treatment in Brazil.

Factors associated with tuberculosis treatment initiation among bacteriologically negative individuals evaluated for tuberculosis: an individual patient data meta-analysis.

Background: Globally, over one-third of pulmonary tuberculosis (TB) disease diagnoses are made based on clinical criteria after a negative diagnostic test result. Understanding factors associated with clinicians' decisions to initiate treatment for individuals with negative test results is critical for predicting the potential impact of new diagnostics. Methods: We performed a systematic review and individual patient data meta-analysis using studies conducted between January/2010 and December/2022 (PROSPERO: CRD42022287613). We included trials or cohort studies that enrolled individuals evaluated for TB in routine settings. In these studies participants were evaluated based on clinical examination and routinely-used diagnostics, and were followed for ≥1 week after the initial test result. We used hierarchical Bayesian logistic regression to identify factors associated with treatment initiation following a negative result on an initial bacteriological test (e.g., sputum smear microscopy, Xpert MTB/RIF). Findings: Multiple factors were positively associated with treatment initiation: male sex [adjusted Odds Ratio (aOR) 1.61 (1.31-1.95)], history of prior TB [aOR 1.36 (1.06-1.73)], reported cough [aOR 4.62 (3.42-6.27)], reported night sweats [aOR 1.50 (1.21-1.90)], and having HIV infection but not on ART [aOR 1.68 (1.23-2.32)]. Treatment initiation was substantially less likely for individuals testing negative with Xpert [aOR 0.77 (0.62-0.96)] compared to smear microscopy and declined in more recent years. Interpretation: Multiple factors influenced decisions to initiate TB treatment despite negative test results. Clinicians were substantially less likely to treat in the absence of a positive test result when using more sensitive, PCR-based diagnostics.

Disparities in Tuberculosis Incidence by Race and Ethnicity Among the U.S.-Born Population in the United States, 2011 to 2021 : An Analysis of National Disease Registry Data.

BACKGROUND: Elevated tuberculosis (TB) incidence rates have recently been reported for racial/ethnic minority populations in the United States. Tracking such disparities is important for assessing progress toward national health equity goals and implementing change. OBJECTIVE: To quantify trends in racial/ethnic disparities in TB incidence among U.S.-born persons. DESIGN: Time-series analysis of national TB registry data for 2011 to 2021. SETTING: United States. PARTICIPANTS: U.S.-born persons stratified by race/ethnicity. MEASUREMENTS: TB incidence rates, incidence rate differences, and incidence rate ratios compared with non-Hispanic White persons; excess TB cases (calculated from incidence rate differences); and the index of disparity. Analyses were stratified by sex and by attribution of TB disease to recent transmission and were adjusted for age, year, and state of residence. RESULTS: In analyses of TB incidence rates for each racial/ethnic population compared with non-Hispanic White persons, incidence rate ratios were as high as 14.2 (95% CI, 13.0 to 15.5) among American Indian or Alaska Native (AI/AN) females. Relative disparities were greater for females, younger persons, and TB attributed to recent transmission. Absolute disparities were greater for males. Excess TB cases in 2011 to 2021 represented 69% (CI, 66% to 71%) and 62% (CI, 60% to 64%) of total cases for females and males, respectively. No evidence was found to indicate that incidence rate ratios decreased over time, and most relative disparity measures showed small, statistically nonsignificant increases. LIMITATION: Analyses assumed complete TB case diagnosis and self-report of race/ethnicity and were not adjusted for medical comorbidities or social determinants of health. CONCLUSION: There are persistent disparities in TB incidence by race/ethnicity. Relative disparities were greater for AI/AN persons, females, and younger persons, and absolute disparities were greater for males. Eliminating these disparities could reduce overall TB incidence by more than 60% among the U.S.-born population. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

The recent rapid expansion of multidrug resistant Ural lineage Mycobacterium tuberculosis in Moldova.

The projected trajectory of multidrug resistant tuberculosis (MDR-TB) epidemics depends on the reproductive fitness of circulating strains of MDR M. tuberculosis (Mtb). Previous efforts to characterize the fitness of MDR Mtb have found that Mtb strains of the Beijing sublineage (Lineage 2.2.1) may be more prone to develop resistance and retain fitness in the presence of resistance-conferring mutations than other lineages. Using Mtb genome sequences from all culture-positive cases collected over two years in Moldova, we estimate the fitness of Ural (Lineage 4.2) and Beijing strains, the two lineages in which MDR is concentrated in the country. We estimate that the fitness of MDR Ural strains substantially exceeds that of other susceptible and MDR strains, and we identify several mutations specific to these MDR Ural strains. Our findings suggest that MDR Ural Mtb has been transmitting efficiently in Moldova and poses a substantial risk of spreading further in the region.

Identifying local foci of tuberculosis transmission in Moldova using a spatial multinomial logistic regression model.

BACKGROUND: Multidrug resistant tuberculosis (MDR-TB) represents a major public health concern in the Republic of Moldova, with an estimated 31% of new and 56% of previously treated TB cases having MDR disease in 2022. A recent genomic epidemiology study of incident TB occurring in 2018 and 2019 found that 92% of MDR-TB was the result of transmission. The MDR phenotype was concentrated among two M. tuberculosis (Mtb) lineages: L2.2.1 (Beijing) and L4.2.1 (Ural). METHODS: We developed and applied a hierarchical Bayesian multinominal logistic regression model to Mtb genomic, spatial, and epidemiological data collected from all individuals with diagnosed TB in Moldova in 2018 and 2019 to identify locations in which specific Mtb strains are being transmitted. We then used a logistic regression model to estimate locality-level factors associated with local transmission. FINDINGS: We found differences in the spatial distribution and degree of local concentration of disease due to specific strains of Beijing and Ural lineage Mtb. Foci of transmission for four strains of Beijing lineage Mtb, predominantly of the MDR-TB phenotype, were located in several regions, but largely concentrated in Transnistria. In contrast, transmission of Ural lineage Mtb had less marked patterns of spatial aggregation, with a single strain (also of the MDR phenotype) spatially clustered in southern Transnistria. We found a 30% (95% credible interval 2%-80%) increase in odds of a locality being a transmission cluster for each increase of 100 persons per square kilometer, while higher local tuberculosis incidence and poverty were not associated with a locality being a transmission focus. INTERPRETATION: Our results identified localities where specific Mtb transmission networks were concentrated and quantified the association between locality-level factors and focal transmission. This analysis revealed Transnistria as the primary area where specific Mtb strains (predominantly of the MDR-TB phenotype) were locally transmitted and suggests that targeted intensified case finding in this region may be an attractive policy option. FUNDING: Funding for this work was provided by the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health.

Quantifying gaps in the tuberculosis care cascade in Brazil: A mathematical model study using national program data.

BACKGROUND: In Brazil, many individuals with tuberculosis (TB) do not receive appropriate care due to delayed or missed diagnosis, ineffective treatment regimens, or loss-to-follow-up. This study aimed to estimate the health losses and TB program costs attributable to each gap in the care cascade for TB disease in Brazil. METHODS AND FINDINGS: We constructed a Markov model simulating the TB care cascade and lifetime health outcomes (e.g., death, cure, postinfectious sequelae) for individuals developing TB disease in Brazil. We stratified the model by age, human immunodeficiency virus (HIV) status, drug resistance, state of residence, and disease severity, and developed a parallel model for individuals without TB that receive a false-positive TB diagnosis. Models were fit to data (adult and pediatric) from Brazil's Notifiable Diseases Information System (SINAN) and Mortality Information System (SIM) for 2018. Using these models, we assessed current program performance and simulated hypothetical scenarios that eliminated specific gaps in the care cascade, in order to quantify incremental health losses and TB diagnosis and treatment costs along the care cascade. TB-attributable disability-adjusted life years (DALYs) were calculated by comparing changes in survival and nonfatal disability to a no-TB counterfactual scenario. We estimated that 90.0% (95% uncertainty interval [UI]: 85.2 to 93.4) of individuals with TB disease initiated treatment and 10.0% (95% UI: 7.6 to 12.5) died with TB. The average number of TB-attributable DALYs per incident TB case varied across Brazil, ranging from 2.9 (95% UI: 2.3 to 3.6) DALYs in Acre to 4.0 (95% UI: 3.3 to 4.7) DALYs in Rio Grande do Sul (national average 3.5 [95% UI: 2.8 to 4.1]). Delayed diagnosis contributed the largest health losses along the care cascade, followed by post-TB sequelae and loss to follow up from TB treatment, with TB DALYs reduced by 71% (95% UI: 65 to 76), 41% (95% UI: 36 to 49), and 10% (95% UI: 7 to 16), respectively, when these factors were eliminated. Total health system costs were largely unaffected by improvements in the care cascade, with elimination of treatment failure reducing attributable costs by 3.1% (95% UI: 1.5 to 5.4). TB diagnosis and treatment of false-positive individuals accounted for 10.2% (95% UI: 3.9 to 21.7) of total programmatic costs but contributed minimally to health losses. Several assumptions were required to interpret programmatic data for the analysis, and we were unable to estimate the contribution of social factors to care cascade outcomes. CONCLUSIONS: In this study, we observed that delays to diagnosis, post-disease sequelae and treatment loss to follow-up were primary contributors to the TB burden of disease in Brazil. Reducing delays to diagnosis, improving healthcare after TB cure, and reducing treatment loss to follow-up should be prioritized to improve the burden of TB disease in Brazil.