brazil
research consortia
RePORT-BR (TB-SRN-CCASAnet-IeDEA) – NIH
background
The NIH-funded Caribbean, Central, and South America network for HIV epidemiology (CCASAnet) is the principal HIV epidemiology research network in Latin America and has an established 18-year track record of producing meaningful work.
aims
To identify and quantify the systemic and individual determinants of outcomes among PWH in Latin America using comprehensive retrospective data and novel data science methodologies to inform clinical practices and health policy in the region.
To characterize the contributions and consequences of psychosocial, behavioral, and non-communicable disease clinical outcomes in older adults, adolescents, and transgender persons with HIV through four nested prospective cohorts with enhanced data.
To establish a new collaborative platform and common data framework for global tuberculosis epidemiology in persons with and without HIV for public health, clinical, and translational science discovery.
This project provides support for cohort A infrastructure, including personnel, data management and quality. All RePORT-Brazil sites are involved.
status
Protocol has been approved at all RePORT Brazil sites and enrollment started on May 2022.
Pi
Timothy Sterling, M.D., Valeria Rolla, M.D., Ph.D., Bruno Bezerril Andrade, M.D., Ph.D, Afranio Kritski, M.D., Ph.D, Fernanda Mello M.D., Ph.D., Marcelo Cordeiro-Santos M.D., Ph.D.
RePORT-Brazil Phase 2 and Fellowship in TB Science
background
Brazil has the highest tuberculosis (TB) burden in the Western Hemisphere, and among the highest in the world. Advances in TB diagnosis, treatment, and prevention are necessary to improve the incidence, morbidity, and mortality of TB in Brazil, and globally. RePORT-Brazil Phase 1 enrolled 1,188 TB cases and 1,930 close-contacts. The plan for phase 2 is to double these cohorts.
aims
Enroll an additional 1,000 TB cases and 2,000 close-contacts; Gain insights that improve TB diagnosis, treatment, and outcomes; improve our understanding of TB transmission and infection, predictors of progression to TB, and protection against TB; support and develop the next generation of TB scientists, and enhance the scope and collaboration of RePORT-Brazil.
status
Participants are currently being recruited at all RePORT-Brazil sites; Fellowship Program has been launched in March 2023 under the name: RePORT Advanced Career Training Program (ReACT).
Pi
Timothy Sterling, M.D., Bruno Andrade, M.D., Ph.D., Valeria Rolla, M.D., Ph.D., Ph.D, Afranio Kritski, M.D., Ph.D, Fernanda Mello M.D., Ph.D., Marcelo Cordeiro-Santos M.D., Ph.D.
Predictors of mechanisms of emergence of drug resistance in MDR-TB (PREEMPT) – NIH
background
This study is evaluating predictors of the emergence of resistance to drugs such as the fluoroquinolones among persons treated for MDR-TB. This study included participants from INI (FIOCRUZ), Helio Fraga and the Federal University site, all in Rio de Janeiro.
aims
Determine whether low serum antimycobacterial drug concentrations are associated with the clinical emergence of drug resistance in MDR-TB patients; Determine whether HIV seropositivity is a risk factor for low serum drug concentrations; Determine the contribution of increased DNA mutation to clinical emergence of drug resistance in patient isolates; and to Determine the earliest time at which mutations responsible for drug resistance can be detected during treatment.
status
Both Brazil and India sites have completed enrollment. Data and laboratory analysis are ongoing.
pi
Robert Horsburgh, M.D., Timothy Sterling, M.D., Valeria Rolla, M.D., Ph.D., Afranio Kritski, M.D., Ph.D., Cristina Lourenço, Pharm.
Immunogenetic risk factors for Incipient and Active Tuberculosis – NIH
background
The mechanisms and contribution of host genetic, immunologic, and epidemiologic factors to protection and predisposition to TB are poorly understood. To address that, we are using data and specimens collected in RePORT-Brazil, from ~2,000 close contacts of TB cases (Phase 1). After 2 years of follow-up of all close contacts, we identified those who progressed to TB disease and those at risk for incipient TB. This prospective study design will enable us to examine our primary hypothesis that there are immunogenetic pathophysiologic underpinnings of progressing to active TB (1°endpoint) and incipient TB (2° endpoint), and these variables, together with epidemiologic factors such as HIV, will improve predicting progression to TB disease.
aims
To determine which macrophage genes and variants are associated with protection against and risk of TB disease and incipient TB, and regulate anti-microbial mechanisms; to identify the M. tuberculosis antigen-specific T-cell responses associated with protection against and risk of TB disease and incipient TB; and to develop predictive models that determine the relative contribution of genetic, immunologic, transcriptomic, and epidemiologic factors for protection against and risk of TB disease and incipient TB in a cohort of close contacts of culture-confirmed TB in Brazil.
status
An award was received mid-June 2019. Protocol was approved at all IRBs at Vanderbilt University Medical center, RePORT-Brazil sites, Washington University and University of Cape Town. Enrollment is complete and lab assays, as well as analysis are currently ongoing. There is a no-cost extension through May, 2026.
pi
Timothy Sterling, M.D., Thomas Hawn, Ph.D., Bruno Andrade, M.D., Ph.D., Thomas Scriba, Ph.D.
Characterization of Genomics and Metabolomics among Individuals Highly-Exposed, but Resistant to Mtb infection – NIH
background
We will carefully measure exposure among household and close contacts to identify a cohort of persons who remain uninfected despite a high degree of exposure. We will then characterize genetic and metabolic factors associated with resistance. These data will inform our understanding of host factors that confer resistance, which will, in turn, inform the development of preventive therapeutics such as a TB vaccine.
aims
To characterize a phenotype for resistance to Mtb infection using TST and IGRA results among household and close contacts recently exposed to TB; To determine genetic predictors for resistance to Mtb infection; and to identify metabolomic markers associated with resistance to Mtb infection.
status
RePORT-Brazil sites and Vanderbilt University Medical Center had their IRB approvals obtained in May 2020. Approximately 2,000 close contacts were re-consented so data and specimens could be used for this study. DNA extraction has been finalized and genetic material sent to Emory for the TB-GWAS portion of the work. Plasma samples were shipped later for the Metabolomics portion of the work. Preliminary results were presented at CROI 2025.
pi
Neel Gandhi, Ph.D., Yan Sun, Ph.D , Timothy Sterling, M.D., Bruno Andrade, M.D, Ph.D, Marcelo Cordeiro Santos, M.D, Ph.D, Amita Gupta, Ph.D.
Macrophage Immunogenetics and Incipient Tuberculosis in Brazil – CRDF Global
background
The mechanisms and relative contribution of host genetic, immunologic, and epidemiologic factors to protection and predisposition to TB are poorly understood. Recent studies reported a host peripheral blood correlate of risk (COR) transcriptional signature that identified individuals at risk for incipient TB (asymptomatic) who progress to develop active (symptomatic) TB disease within 12 months in the absence of treatment. Signatures such as COR are transforming our understanding of the progression from Mtb infection to TB disease.
aims
To utilize signatures such as COR to address current knowledge gaps in the immunogenetic basis of incipient TB and progression to disease.
status
An award was received in June 2019. Study protocol was submitted and approved at all IRBs in Brazil, UW and Vanderbilt. Participants were re-consented so that data and specimens could be used for this specific project. Lab assays and data analyses are ongoing.
pi
Thomas Hawn, Ph.D., Timothy Sterling, M.D., Bruno Andrade, M.D., Ph.D.
Innovative modelling for predicting TB treatment outcomes in global cohorts – CRDF Global
background
A subset of tuberculosis patients experience treatment failure, recurrence, or progress to death, either during treatment or in the months following its completion. Despite numerous studies describing clinical and laboratory risk factors associated with unfavorable outcomes, few have generated and validated clinically useful prognostic models.
aims
Our main aim is to develop and validate parsimonious models of baseline and longitudinal clinical data using traditional statistical methods, LASSO, and machine learning techniques. Using this methodology, we will assess the impact of co-conditions such as diabetes, alcohol use, HIV and malnutrition on adverse TB treatment outcomes. Our second aim will assess the additional contribution of molecular biomarkers such as inflammatory cytokines and gene signatures in predicting adverse outcomes, allowing us to identify critical biomarkers and remove low-performing markers.
status
This study was submitted and approved at all IRBs in Brazil, India and in the U.S. Data analysis is ongoing and study results should be submitted for publication soon.
pi
Bruno Andrade, M.D., Ph.D., Timothy Sterling, M.D., Matthew Robinson, M.D., Nikhil Gupte, Ph.D., Gustavo Amorim, Ph.D., Sonya Krishnan, MD.
Associative BRICS Research in COVID-19 and Tuberculosis (ABRICOT) – CRDF Global & CNPq
background
The COVID-19 pandemic has provided new challenges for TB control. However, there is limited information on the effect of severe COVID-19 on TB immunopathogenesis and how this affects, if at all, TB treatment outcomes.
aims
To investigate: a) the impact of COVID-19 lymphopenia or hyperinflammation on specific-TB immune responses; b) the impact of COVID-19 on complement system activation and consequent hyperinflammation; and c) the correlation of these immune responses with TB outcomes.
status
Study protocol has been developed and was approved at the INI IRB in Brazil and PHRU sites in South Africa. Enrollment has been finalized and data analysis is ongoing.
pi
Valeria Rolla, M.D., Ph.D., Timothy Sterling, M.D., Bavesh Kana, Ph.D.
Epidemiological factors associated with TB treatment outcomes across RePORT International consortia – CRDF Global
background
Several clinical factors have been associated with poor TB treatment outcomes. Key factors such as malnutrition, anemia, tobacco smoking, alcohol use, drug use, HIV infection, and previous TB infection may be independent predictors of poor TB treatment outcomes.
aims
To determine the impact of key non-communicable and communicable diseases on tuberculosis treatment outcomes and recurrence using data from multiple RePORT International consortia.
status
Study protocol has been developed and was approved at all RePORT sites. Data were harmonized across all countries and analysis is ongoing; the manuscript is in preparation.
pi
Valeria Rolla, M.D., Ph.D., Timothy Sterling, M.D., Bruno Andrade, Ph.D., Gustavo Amorim, Ph.D.
Analysis of Host Biomarkers Associated with Adverse TB treatment outcomes across RePORT International sites – CRDF Global
background
Diagnostic accuracy of biomarkers may be impacted by ethnicity and co-morbidities; therefore, the performance of these biomarkers should be evaluated across diverse populations.
aims
The overall goal is 1) to expand the validation studies of host biomarkers associated with TB treatment failure proposed at each RePORT site; 2) to cross validate the biomarkers in samples across RePORT International Consortia; and 3) to identify a biomarker of “cure” using a discovery-based approach.
status
Study protocol has been developed and was approved at all RePORT sites. Material Transfer Agreements were executed, and laboratory assays are ongoing.
pi
Timothy Sterling, M.D., Bruno Andrade, Ph.D., Mariana Pereira, Ph.D.
Functionally distinct human CD4 T cell responses to novel evolutionarily selected M. tuberculosis antigens – NIH
background
Combining principles of evolutionary biology and whole genome sequencing of phylogenetically diverse isolates, we discovered that the widely-studied antigens of M. tuberculosis are hyper conserved (that is, more conserved than other elements of the genome). This finding suggests that most human T cell recognition does not exert selection pressure on M. tuberculosis by being detrimental to the bacteria. We then used comparative genomics combined with studies of human immune responses to discover 7 new antigens of M. tuberculosis that do show evidence of evolutionary diversifying selection, implying that human T cell recognition of these antigens (which we term ‘rare variable antigens’ or RVA) is detrimental to the bacteria. This finding suggests that T cell responses to RVA contribute to protection and that including RVA would increase the efficacy of TB vaccines.
aims
We propose to determine whether protection from TB progression correlates more closely with the presence and magnitude of CD4 T cell responses to RVA than to classical Mtb antigens.
status
Eligible participants have been identified at all RePORT sites. Material Transfer Agreements have been executed, and samples shipped to UCSF for laboratory assays.
pi
Joel Ernst, M.D., Timothy Sterling, M.D., Bruno Andrade, Ph.D.
Validation of T-SPOT.TB test in participants of RePORT Brazil – Oxford Immunotech
background
Tuberculosis (TB) is still an important plague for humanity, and Brazil has a high disease burden. TB infection (formerly called latent TB) is a critical component of the TB control strategy, and interferon-gamma release assays (IGRAs) are a commonly used test for TB infection diagnosis. However, the sensitivity and specificity of IGRA may vary depending on the population being tested.
aims
To evaluate a new IGRA test for the diagnosis of TB infection in Brazil and to compare its sensitivity and specificity with the currently used standard IGRA test (QTF-plus).
status
Protocol has been approved at all RePORT-Brazil sites as well as at Vanderbilt University Medical Center. Enrollment is ongoing and expected to be completed by January 2026.
pi
Timothy Sterling, M.D., Bruno Andrade, Ph.D., Valeria Rolla, M.D., Ph.D., Ph.D, Afranio Kritski, M.D., Ph.D, Marcelo Cordeiro-Santos M.D., Ph.D., Marina Figueiredo, M.S., Cody Staats, M.S., Mariana Araujo, Ph.D.
Prevalence, Incidence, and Biomarkers of Subclinical Tuberculosis (TB) in Close TB Contacts in the RePORT International Consortium – CRDF Global
background
The overarching goal of this proposal is to determine the prevalence and incidence of subclinical tuberculosis (TB) in close TB contacts, and evaluate novel biomarkers and diagnostic tests for subclinical TB. Subclinical TB is defined as active, microbiologically confirmed TB in persons without TB symptoms, such as cough, hemoptysis, fever, night sweats, weight loss, or chest pain. It has been reported to occur in 50% or more of TB patients identified in community-wide prevalence surveys in high-burden settings such as South Africa.1,2 The prevalence of clinical (i.e., symptomatic) TB in close contacts is approximately 5%.3 The risk of incident clinical TB over the next two years is also ~5%.4–6 The true prevalence and incidence of subclinical TB in close TB contacts is unclear, particularly in settings outside of sub-Saharan Africa.
aims
We will evaluate the prevalence, incidence, and biomarkers of subclinical TB in close TB contacts in RePORT-Brazil, RePORT-Uganda and RePORT-India through the following specific aims: to determine the prevalence of subclinical TB among close contacts of culture-confirmed pulmonary TB at the time of contact investigation; to determine the incidence of subclinical TB during the first 6 months after exposure to TB; and to compare novel diagnostic tests for the diagnosis of subclinical TB.
status
Study protocol has been developed and was approved at all RePORT sites and VUMC. Enrollment started in January 2025 and is expected to be completed by August 2026.
pi
Timothy Sterling, M.D., Bruno Andrade, M.D., Ph.D., Valeria Rolla, M.D., Ph.D., Afranio Kritski, M.D., Ph.D, Fernanda Mello M.D., Ph.D, Marcelo Cordeiro-Santos M.D., Ph.D.
RePORT IeDEA TB-SRN Collaboration – CRDF Global
background
aims
This project encompasses three specific aims: one informatics aim and two TB epidemiology analyses.
- To develop a replicable data harmonization pipeline that aligns the data models for RePORT International and IeDEA TB-SRN for sustained collaborative research;
- Assess the representativeness of the RePORT and IeDEA TB-SRN cohorts in relation to the countries from which they derive; and
- Assess country-level differences in the clinical characteristics of TB patients and clinical outcomes across cohorts.
status
IRB approvals were obtained at all RePORT sites and VUMC. Data sharing agreements are being executed, and data harmonization is ongoing between the two consortia.
pi
Timothy Sterling, M.D., Stephany Duda, Ph.D., Felipe Ridolfi M.D., Ph.D., Bruno Andrade, M.D., Ph.D.
Genetic alterations associated with iron homeostasis and their impact on predicting tuberculosis treatment outcomes – CNPq/DECIT
background
Iron homeostasis plays a key role in host-pathogen interactions during Mycobacterium tuberculosis infection. Genetic variants affecting iron metabolism may influence the immune response and treatment efficacy. Understanding these associations could help identify patients at higher risk of poor outcomes and guide precision medicine strategies in TB care.
aims
To investigate genetic variants involved in iron metabolism pathways and their association with clinical outcomes of tuberculosis treatment in a Brazilian cohort.
status
IRB approvals were obtained and recruitment started in September 2024.
pi
Mariana Araújo-Pereira, Ph.D.,Timothy Sterling, M.D., Bruno Andrade, M.D., Ph.D., Valeria Rolla, M.D., Ph.D., Afranio Kritski, M.D., Ph.D, Marcelo Cordeiro-Santos, M.D., Ph.D.
Genomic and inflammatory mechanisms underlying tuberculosis treatment failure in a Brazilian multicenter cohort – CNPq/DECIT
background
Despite standardized treatment protocols, a subset of TB patients experiences treatment failure, and the underlying biological mechanisms remain poorly understood. Inflammatory dysregulation and host genetic factors may contribute to these unfavorable outcomes. Integrating genomic and immunological data can uncover predictive signatures and improve treatment stratification.
aims
To explore genomic and immunological signatures associated with treatment failure in tuberculosis patients using a multi-omics approach.
status
We are currently selecting samples for the laboratory assays.
pi
Mariana Araújo-Pereira, Ph.D., Timothy Sterling, M.D., Bruno Andrade, M.D., Ph.D., Valeria Rolla, M.D., Ph.D., Afranio Kritski, M.D., Ph.D., Fernanda Mello M.D., Ph.D, Marcelo Cordeiro-Santos, M.D., Ph.D.
Impact of Diabetes Mellitus on tuberculosis treatment outcomes in Brazil: A systems biology and multi-omics approach – FAPESB
background
Diabetes mellitus is a known risk factor for TB, but the molecular basis of its impact on treatment outcomes is not fully elucidated. This study leverages multi-omics approaches to understand how diabetes alters immune responses and disease progression. The findings may support targeted interventions for comorbid TB-DM patients.
aims
To evaluate how diabetes mellitus impacts the immune response and treatment outcomes in TB patients using transcriptomic and proteomic profiling.
status
All lab experiments have been performed. Data are being analyzed.
pi
Bruno Andrade, M.D., Ph.D., Artur Queiroz, M.D., Ph.D., Mariana Araújo-Pereira, Ph.D., Timothy Sterling, M.D., Valeria Rolla, M.D., Ph.D., Afranio Kritski, M.D., Ph.D., Marcelo Cordeiro-Santos, M.D., Ph.D.
Use of non-respiratory samples to diagnose incipient/subclinical tuberculosis in contacts of smear-positive patients – applicability of findings from the ABRICOT study – Inova Fiocruz
background
Diagnosing TB in asymptomatic or subclinical individuals remains a major challenge, particularly when sputum samples are unavailable. The ABRICOT study identified promising biomarkers in non-respiratory fluids. This project aims to validate their utility among close contacts of TB patients, advancing early detection strategies.
aims
To evaluate the diagnostic potential of non-respiratory biological samples to detect incipient or subclinical TB in contacts of TB patients.
status
Enrollment started in April 2025.
pi
Valeria Rolla, M.D., Ph.D., Adriano Gomes, M.D., Afranio Kritski, M.D., Ph.D., Fernanda Mello M.D., Ph.D, Bruno Andrade, M.D., Ph.D., Marcelo Cordeiro-Santos, M.D., Ph.D., Timothy Sterling, M.D.
Clinical impact of NAT2 polymorphism on treatment outcomes of latent tuberculosis infection in close contacts of pulmonary TB cases in Brazil – CNPq/DECIT
background
Isoniazid metabolism is influenced by NAT2 genetic polymorphisms, affecting both drug efficacy and toxicity. Incorporating pharmacogenetic insights into LTBI treatment could improve outcomes and adherence. This study investigates NAT2 variants as predictors of treatment response in TB contacts, with implications for personalized therapy.
aims
To assess the role of NAT2 polymorphisms in shaping treatment outcomes among individuals receiving therapy for latent TB infection.
status
Sample selection in progress.
pi
Marcelo Cordeiro-Santos, M.D., Ph.D., Renata Spener-Gomes, M.D., Allyson Guimarães, M.D., Valeria Rolla, M.D., Ph.D., Afranio Kritski, M.D., Ph.D., Bruno Andrade, M.D., Ph.D., Timothy Sterling, M.D.
