Current Projects



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.

Primary 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 also provides support for cohort A infrastructure, including personnel, data management and quality. All RePORT-Brazil sites are involved.

Current status: Protocol has been approved at all RePORT Brazil sites and Phase 2 enrollment started on May 2022.
Principal Investigators: Timothy Sterling, M.D., Valeria Rolla, M.D., Ph.D., Bruno Bezerril Andrade, 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.
Primary 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.
Current status: Participants are currently being recruited at all RePORT-Brazil sites; Fellowship Program has been launched in March 2023.
Principal Investigators: Timothy Sterling, M.D., Bruno Andrade, M.D., Ph.D.

Mapping M. tuberculosis transmission hotspots using patient location history

Background: Mapping hotspots for transmission of infectious diseases can offer great help in controlling outbreaks and eliminating reservoirs of infection. Usually, hospital staff in endemic areas try to determine such places by asking patients with transmissible infections, those places where they live/work (for diseases which require chronic exposure) or visited a few days prior going to the hospital (for acute diseases). However, information obtained through questionnaires are generally vague, inaccurate and not integrated into databases. This makes the process manual, slow, and of little value for large-scale epidemiologic studies. Since a significant portion of the population has mobile phones with GPS, the objective of this project is to improve the accuracy and organization of M. tuberculosis infection networks, and to study the temporal dynamics of geolocalization data collected from TB patients. We are developing an online tool in which patients who arrive at the referral centers can voluntarily provide GPS data of their mobile phones. User data will be anonymized, processed and sent to a secure server. By analyzing the location patterns of hundreds of patients during several months prior the clinical visit, we will be able to potentially map hotspots of M. tuberculosis transmission.
Primary aims:
To use location history data from TB patients and their close contacts to find regions with a high risk of disease transmission. And to develop a web application to collect location history data from those patients diagnosed with TB and their close contacts, and implement a data analysis pipeline for finding the disease hotspots
Current status: Participants are currently being recruited at all RePORT-Brazil sites.
Principal Investigators: Helder Nakaya, Ph.D., Bruno Andrade, M.D., Ph.D.

TB/HIV: Predictors of treatment toxicity, failure, and relapse in HIV related TB – NIH

Background: This study is evaluating pharmacogenomic predictors of TB/HIV treatment toxicity, and TB treatment outcomes (e.g., 2-month culture conversion and failure/relapse). All RePORT-Brazil study sites enrolled participants into this study and several manuscripts are under review.
Primary aims: To identify pharmacogenomic predictors of TB/HIV plasma drug exposure and increased risk for toxicity during TB therapy; and to determine the pharmacogenomic predictors of two month culture-positivity, and TB treatment failure and relapse, while accounting for host and M. tuberculosis pathogen factors.
Current status: All participants have been enrolled through RePORT-Brazil. An MTA was established so that the Biorepository in Brazil could ship the DNA and plasma samples to Vanderbilt (for genotyping and PK work, in which the assay to measure several TB and HIV drugs was developed). The ancestry informative markers (AIMs) evaluation was done in Brazil (Dr. Santos´ lab). A few papers have been published and there are several other manuscripts ongoing.
Principal Investigators: Timothy Sterling, M.D., Valeria Rolla, M.D., Ph.D, David Haas, M.D.

Predictors of mechanisms of emergence of drug resistance in MDR-TB (PREEMPT) – NIH

Background: This study will evaluate predictors of the emergence of resistance to drugs such as the fluoroquinolones among persons treated for MDR-TB. This study is currently enrolling participants from INI (FIOCRUZ), Helio Fraga and the Federal University site in Rio de Janeiro.
Primary 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.
Current status: Both Brazil and India sites are actively enrolling patients. Enrollment in Brazil started in July 2019, with a follow up time of 12 months after the last patient recruited completes his/her treatment.
Principal Investigators: 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.
Primary 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.
Current 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.
Principal Investigators: 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.
Primary 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.
Current status: RePORT-Brazil sites and Vanderbilt University Medical Center were added after the award was made. Protocol was submitted to the local IRBs in Brazil and has been approved 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.
Principal Investigators: 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.
Primary aims: To utilize signatures such as COR to address current knowledge gaps in the immunogenetic basis of incipient TB and progression to disease.
Current 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.
Principal Investigators: Thomas Hawn, Ph.D., Timothy Sterling, M.D., Bruno Andrade, M.D., Ph.D.

Prospective, Multicentre Trial to Assess the Diagnostic Accuracy of the Truenat Assays at Intended Settings of Use – CNPq

Background: The Truenat MTB (including both MTB and MTB plus) and the MTB-RIF Dx reflex assays (Molbio Diagnostics; Bangalore, India) utilize chip-based real-time micro PCR for detection of tuberculosis (TB) and rifampicin (RIF) resistance from DNA extracted from sputum samples in about 25 minutes. A pilot trial conducted in India of the Truenat MTB assay found the assay to achieve high clinical performance. However, further evidence of the Truenat MTB as well as the Truenat MTB-RIF Dx assay, is needed prior to recommending the clinical use of the assays.
Primary aims: To determine the diagnostic accuracy of the Truenat MTB assays and MTB-RIF Dx assay using culture and phenotypic/genotypic drug susceptibility test (DST) as gold standard in the intended setting of use.
Current status: The study protocol has been approved by the IRBs in Brazil. Equipment was imported with the support of the Brazilian government from Molbio. Enrollment and analysis will be completed in 2023.
Principal Investigators: Adam Penn-Nicholson (FIND, Switzerland), Afranio Kritski, M.D., Ph.D.; Sites in RePORT-India; Other sites in Peru, Ethiopia and Papua New Guinea.

Evaluation of microvirin-based point-of-care diagnostic tests for tuberculosis

Background: Biomarker detection tests, such as enzyme-linked immunosorbent assays (ELISAs) and lateral flow assays (LFAs), are inexpensive and can be performed with minimal equipment. LFAs are particularly advantageous as they can provide results rapidly at the point-of-care (POC). The most commonly detected biomarker for TB is lipoarabinomannan (LAM). Currently, the only commercially-available LFA for LAM is the Alere LFA, which detects LAM in urine – a noninvasive, low biohazard risk sample method.  However, due to low sensitivity, the Alere LFA is only approved for use in HIV-positive individuals as immunocompromised individuals have higher concentrations of LAM in urine. With increased sensitivity, an LFA could detect LAM in all individuals, regardless of immune status. Such an LFA would be an important advance in TB diagnostic tests, given its rapid turn-around-time and low-cost.
Microvirin (MVN) is a lectin with a high affinity for alpha-1,2-mannose linkages, which are present in the endcaps of M.tb LAM. Using bio-layer interferometry, we have studied the binding of MVN to LAM and found the interaction to be of equivalent strength or stronger than the binding of LAM to anti-LAM antibodies. Furthermore, MVN has enhanced specificity for M. tb. Anti-LAM antibodies bind to the LAM backbone, which is common to LAM from all species of mycobacteria. In contrast, MVN binds to the endcaps of LAM, which vary according to the species of Mycobacterium. Thus, using MVN as a molecular recognition element to detect LAM in an LFA for diagnosis of TB would potentially result in a more sensitive and specific test compared to traditional LAM biomarker detection tests that utilize antibodies, while maintaining the speed and low cost that make LFAs so promising.
Primary aim: The purpose of this study is to evaluate the clinical performance of two diagnostic tests for TB: an on-bead ELISA and a lateral flow assay. Both tests use MVN to capture and detect LAM, a biomarker for TB, in urine.
Current status: The study protocol has been approved by the IRBs in Brazil and participants were re-consented, so that data and specimens could be used for this specific project. Lab assays are ongoing, lead by Dr. Adriano Gomes in Brazil.
Principal Investigators: David Wright, Ph.D., Megan van der Horst, Micaella Jorge, Valeria Rolla, M.D., Ph.D, Adriano Gomes, Ph.D, Timothy Sterling, M.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.
Primary 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.
Current status: This study will be part of RePORT-Brazil Phase II and protocol amendments were submitted and approved at all IRBs in Brazil, India and in the U.S.
Principal Investigators: Bruno Andrade, M.D., Ph.D., Timothy Sterling, M.D., Matthew Robinson, M.D., Nikhil Gupte, Ph.D., Gustavo Amorim, Ph.D., Moreno Rodrigues, 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.
Primary 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.
Current status: Study protocol has been developed and was approved at the INI IRB in Brazil, as well as NIRT in India, and PHRU sites in South Africa. Enrollment is ongoing in all countries.
Principal Investigators: Valeria Rolla, M.D., Ph.D., Timothy Sterling, M.D., Bavesh Kana, Ph.D., Subash Babu, 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.
Primary 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.
Current status: Study protocol has been developed and was approved at all RePORT sites. Data is being merged and analysis is ongoing.
Principal Investigators (Brazil): Valeria Rolla, M.D., Ph.D., Timothy Sterling, M.D., Bruno Andrade, 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 performance of these biomarkers should be evaluated across diverse populations.
Primary 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.
Current status: Study protocol has been developed and was approved at all RePORT sites. Material Transfer Agreements are being executed, so samples can be shipped across countries.
Principal Investigators (Brazil): Timothy Sterling, M.D., Bruno Andrade, Ph.D.