Research team

Global Health Institute (GHI)

Expertise

Epidemiology Public Health Implementation research Global Health Infectious disease epidemiology Tuberculosis HIV Whole genome sequencing

Identification of compensatory mutations in XDR-Mtb strains: understanding the dynamics and mechanisms of transmission. 01/11/2020 - 31/10/2021

Abstract

Tuberculosis (TB) continues to be a major global public health threat. The development of drug resistance, and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) especially, pose a major problem to TB control. Transmission of XDR-Mtb strains is in conflict with the dogma that XDR-Mtb strains are less transmissible due to a cumulative fitness costs of resistance conferring mutations. For rifampicin resistant strains for example, it has been shown that mycobacteria can acquire compensatory mutations in the rpoC gene to overcome the fitness cost of resistance conferring mutations. Due to the limited access to large sample sets of XDR-Mtb strains, the transmissibility of XDR-Mtb strains and the effect of compensatory mutations to reverse the fitness cost remain poorly studied. The FWO-funded TORCH consortium houses a whole genome sequence database of around 1000 XDR-Mtb strains collected in the Western Cape Province in South Africa over a 14-year period (2006 to 2019). This exceptional dataset of XDR strains allows an in-depth analysis of XDR-TB transmission dynamics and its evolutionary mechanisms. By combining bioinformatics analyses (identifying XDR-Mtb associated genomic convergence) with spatio-temporal analyses of the XDR-Mtb strains by transmission status we expect to identify novel compensatory mutations and their relative importance to the transmission of XDR-Mtb strains.

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Stratified host-directed therapy for drug-resistant tuberculosis: a randomized controlled multi-centre trial (DRTB-HDT). 01/01/2020 - 31/12/2023

Abstract

Tuberculosis is a leading cause of morbidity and mortality worldwide. Current TB treatments are inadequate, requiring patients closely adhere to multi-drug regimens that are long, complex, and often poorly tolerated. These concerns are greatly magnified in rifampicin-resistant (RIF-R) TB, an urgent global and EU public health priority. WHO estimates that only 54% of patients who began RIF-R TB treatment in 2016 were cured. In addition to these wellrecognized shortcomings, current TB treatments, particularly those for RIF-R TB, leave a majority of cured patients with permanent, clinically significant lung impairment and radiographic evidence of bronchiectasis and fibrosis. This project will determine if two adjunctive host-directed therapies (HDTs) can prevent these poor outcomes. 330 patients with RIF-R TB and baseline risk factors for poor outcome will be enrolled in a randomized, controlled, 3-armed multi-centre trial, with clinical sites in Germany, Romania, Moldova, Georgia, Mozambique, and South Africa. All patients will receive standard multidrug therapy according to national guidelines. Those patients randomized to the experimental arms will in addition receive either CC-11050 or metformin. These selected HDT candidates represent 2 complementary HDT strategies: reducing inflammation vs inducing host cell anti-microbial activity, respectively. Both candidates are supported by data from preclinical and clinical studies. Co-primary efficacy endpoints will examine effects on lung function (measured by spirometry) and infection (measured as time to stable sputum culture conversion). A sub-study will examine quantitative change in lung radiodensity by CT scan. If successful, this groundbreaking project will increase Europe's capacity to control RIF-R-TB by developing new treatments that increase the likelihood of cure and reduce the risk of life-long disability.

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Heteroresistance: an occult threat to the treatment success of resistant tuberculosis Acronym "DeepMTB". 01/01/2020 - 31/12/2023

Abstract

Rifampicin-resistant (RR) tuberculosis (TB) is an especially lethal form of TB, with less than 50% of over 0.5 million patients affected each year reaching successful treatment outcomes. Due to difficulties in defining the full drug resistance profile in each individual patient, there is a tremendous risk of losing key classic- (fluoroquinolones) and new drugs (bedaquiline (BDQ)) at a faster pace than novel drugs can be developed. The Mycobacteriology Unit at ITM is uniquely placed due to its key role as central microbiological laboratory for the largest RR-TB trials conducted to date. The two STREAM and two endTB trials, enrolling over 2000 patients, allow to robustly assess the impact of heteroresistance on treatment outcomes. In collaboration with the University of Antwe , we will use innovative, state-of-the-art methods to test the hypothesis that heteroresistance at RR-TB treatment initiation is associated with microbiological failure. We will be the first to apply targeted deep sequencing to clinical samples of RR-TB clinical trial participants and to quantify culture bias in the detection of heteroresistance. In addition, we aim to quantify the effect of treatment interruption on acquisition of resistance to BDQ, which poses a threat to the durability of new RR-TB regimens. The results will provide a leap forward in our knowledge and provide evidence required for defining the most appropriate diagnostic and management strategies for patients afflicted by RR-TB.

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Development of novel methods to predict the drug resistance phenotype of Mycobacterium tuberculosis variants. 01/01/2019 - 31/12/2022

Abstract

Every year, ten million people develop tuberculosis (TB) and 1,7 million people die from TB. About 600,000 people are diagnosed with TB resistant to rifampicin, a key first-line TB drug. Drug resistant TB thus poses a global public health problem and threatens global TB control. Whole Genome Sequencing (WGS) is an innovative method to detect drug resistance, but current drug resistance tools can only predict the resistance profile for a small proportion of the over 2000 genetic variants that may be associated with resistance. Furthermore, in late 2018, the WHO will prioritize fluoroquinolones (FQ) and bedaquiline (BDQ) as two of the three core drugs for treatment of rifampicin resistant TB. While FQs are a well-studied class of antibiotics, BDQ is a new drug. Consequently, genotype-phenotype data is limited, and no mutations have been statistically associated with BDQ resistance. New tools to predict resistance are needed to make optimal clinical use of WGS. In this project, I will develop two different methods for prediction of drug resistance in Mycobacterium tuberculosis. In the first method, I will apply pattern mining methods to assess alteration of the drug binding site as a resistance mechanism, by modelling the drug-drug target interaction. In the second method, I will assess regulatory resistance mechanisms, such as upregulation of efflux pumps, by modelling transcriptional changes caused by genetic mutations.

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A personalized recommendation system for whole genome sequencing based and individualized tuberculosis treatment. 01/01/2019 - 31/12/2022

Abstract

Tuberculosis (TB) continues to be a global public health problem with 10.4 million new cases and 1.4 million TB deaths annually. About 600 000 of these new TB cases are resistant to rifampicin, the most important first line drug. In this PhD project I aim to bring Whole Genome Sequencing (WGS) as a diagnostic method, currently mostly used in research, to the patient. Interpretation of WGS data requires expertise which is unavailable in high burden countries, I will bridge this gap by developing a software suite which automatically interprets the WGS data and recommends the optimal individualized treatment regimen for each patient, also taking clinical patient information into account. Additionally, the software will also be able to, dependent on the region and based on the prevalence of drug resistance in that region, detect unexpected drug resistance patterns in patients. For these patients, additional drug susceptibility tests (DSTs) will be recommended. The software will have an easy to use interface where health care workers can enter the clinical patient data. The WGS results will be combined with the clinical information and the results will be made available to the health care worker. Depending on the expertise of the health care worker, additional details describing the decision process towards the optimal regimen and DST recommendation can be made available. This all-inclusive software suite will allow for easier diagnosis and treatment of drug resistant TB.

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Improved infectious diseases control in Peru through sustainable capacity building for bioinformatics and genome sequencing. 01/01/2019 - 31/12/2021

Abstract

The Peruvian population is adversly affected by infectious diseases and current govermental efforts are not sufficient to reduce the burden. While bioinformatics and genomics are relatively new approaches in molecular epidemiology, they have already made important contributions to the health of patients and populations. Bioinformatics and genome sequencing capacity in Peru is still extremely limited. Public universities like UNSA in Arequipa and UNAP in Loreto could play a major role in regional and national level infectious disease control by providing further insights in the molecular epidemiology of the infectious diseases in Peru. We propose to develop sustainable capacity in bioinformatics and sequencing through the development of a academic network between 3 universities in Peru and 2 institutions in Belgium. We selected topics of local public health importance: malaria, tuberculosis and antibiotic resistance. For these diseases, next generation sequencing can significantly improve diagnostics, surveillance and control, thus contributing to better health of the population of Peru.

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Improved infectious diseases research and surveillance in Ethiopia through capacity building in bioinformatics and sequencing. 01/01/2018 - 31/12/2021

Abstract

Even though bioinformatics and genomics are relatively new biomedical disciplines, they have already made important contributions to the health of patients and populations. Bioinformatics and genome sequencing ca-pacity in Ethiopia is however extremely limited. African scientists are well positioned to play an important role in sequencing-based surveillance and research because the cost of sequencing technologies has dropped dra-matically, internet connectivity is constantly improving, and bioinformatics software tools are often freely availa-ble. We propose to develop sustainable capacity in bioinformatics and sequencing surveillance and research through an academic collaboration between Ethiopia, South Africa and Belgium. We selected topics of local public health importance: hospital acquired infections, vector borne diseases and tuberculosis. For these dis-eases, sequencing can significantly improve diagnostics, surveillance and control, thus contributing to better health of the population of Ethiopia.

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Research on European children and adults born preterm (RECAP preterm). 01/01/2017 - 30/09/2021

Abstract

The project's overall aim is to improve the health, development and quality of life of children and adults born very preterm (VPT, < 32 weeks of gestation) or very low birth weight (VLBW, < 1500g) – approximately 50 000 births each year in Europe – by establishing an ICT platform to integrate, harmonise and exploit the wealth of data from 20 European cohorts of VPT/VLBW children and adults and their families constituted from the early 1980s to the present, together with data from national registries.

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Development of a Centre for Whole Genome Sequencing studies of Mycobacterium. 01/10/2016 - 30/09/2021

Abstract

Tuberculosis (TB) is a global problem, with > 9 million cases annually and rising numbers of multi-drug resistant TB (MDR-TB). In the 1990's, IS6110 DNA fingerprinting revolutionized the study of Mycobacterium tuberculosis (MTB). Using this technique, I performed groundbreaking studies that proved exogenous reinfection, challenged the dogma that most TB cases are due to re-activation of latent infection, opposed the belief that most MDR-TB is acquired, and demonstrated mixed infection (NEJM 1999, JID 1999, Lancet 2000, AJCCRM 2005). The recent development of high-throughput, relatively low-cost whole genome sequencing (WGS) raises again the promise of significant gains in molecular epidemiology of MTB. Arriving at new paradigms however demands that inferences of WGS data on phylogeny, transmissibility, virulence and resistance are contextualized and integrated with clinical and demographic meta-data in large-scale studies to test the hypotheses generated by small-scale studies on isolates collected in low TB burden countries. As a clinical and molecular epidemiologist, I propose to establish and direct a multidisciplinary Centre for WGS studies of MTB at the University of Antwerp. The Centre will embed itself in the molecular microbiology laboratory of Prof Herman Goossens, who has substantial expertise in WGS research of pathogens other than MTB. The Centre will work in close collaboration with Prof Robin Warren of the South African Centre of Excellence for Biomedical Tuberculosis Research (CEBTR), Stellenbosch University. Access to the ~50,000 MTB strains in the CEBTR biobank will provide a unique opportunity for the Centre to perform molecular epidemiological MTB studies that address ground-breaking basic science and molecular epidemiological questions. To maximize the public health gains of WGS, we will focus on studies of MTB transmission dynamics in a high TB burden setting, the role of epistatis in emergence of drug resistance, MTB adaptation to drug pressure, and within-host MTB diversity.

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Perform a systematic review of the published literature and unpublished data from ongoing clinical trial on diagnostic accuracy on commercially available hybridization-based technology for pyrazinamide resistance detection. 01/10/2020 - 31/12/2020

Abstract

The goal of the systematic literature review and meta-analysis is to estimate the diagnostic accuracy of the PZA LPA assay for detection of PZA resistance in cultured MTB isolates and sputum samples from patients diagnosed with pulmonary TB with or without rifampicin resistance using three different reference standards: phenotypic DST (pDST), genotypic DST (gDST) and a composite reference standard (CRS). The goal is to, if the data allows, to estimate the diagnostic accuracy of the PZA LPA overall and stratified by sputum smear microscopy status, rifampicin resistance status and treatment outcome.

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Whole Genome Sequencing to streamline TB diagnosis, improve TB surveillance and optimize individualized TB treatment: a pragmatic trial. 01/10/2018 - 30/09/2020

Abstract

Tuberculosis (TB) continues to be an important public health problem with more than 10 million new cases and over 1 million deaths annually. In low burden regions such as Flanders, immigration and drug resistance pose important hurdles to TB control efforts. Due to the challenges in the current diagnostic pathway, patients suffering from drug resistant TB often receive suboptimal treatment in the first months following their diagnosis, which can amplify drug resistance and lead to transmission of drug resistant strains in the community. Whole genome sequencing (WGS) of Mycobacterium tuberculosis as part of routine TB diagnosis is an attractive prospect as WGS rapidly interrogates the entire 4.4 Mbp M. tuberculosis genome. This information would generate the most comprehensive resistance profile for each patient and allow rapid initiation of the most effective and patient-friendly individualized treatment for each person diagnosed with active TB. Furthermore, WGS would not only contribute to diagnostics but also to public health surveillance, as the results of the WGS assay performed for diagnostic purposes will generate phylogenetic data for routine surveillance of transmission events and outbreak detection. Coupling genomic diagnostics and epidemiology would transform the approach to TB control in Flanders towards a 21st century innovative digital disease detection platform and surveillance system. WGS thus has great potential to become the future cornerstone of routine TB diagnosis, care and surveillance in Flanders. We propose to perform a pragmatic multicenter theragnostic trial of WGS of M. tuberculosis to streamline TB diagnosis, improve TB surveillance and optimize individualized treatment of drug resistant TB to improve treatment outcomes. A pragmatic trial undertaken in real-life conditions will generate the data required for policy development, facilitate the translation of results into routine practice and thus contribute to TB control in Flanders.

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  • Social Epidemiology & Health Policy (SEHPO)

Single molecule long-read sequencing technology: beyond state-of-the-art in biological and medical research. 01/05/2018 - 30/04/2021

Abstract

This project aims to advance the currently available sequencing technologies at the University of Antwerp (UA) by acquiring a third generation sequencing (3GS) platform. The flagship of the third generation, single-molecule longread sequencers, PacBio Sequel, harnesses the natural process of DNA replication and enables real-time observation of DNA synthesis. 3GS promises to open new avenues for sequencing-based research beyond the current state-of-the-art for this consortium, which consists of more than 14 UA research groups in various disciplines of medicine, biology and bioinformatics. Furthermore, several third parties have also committed to utilize this technology for their ongoing and future research studies. 3GS will be utilized by this consortium to (i) sequence prokaryotic and eukaryotic genomes, and difficult-to-sequence genome regions, (ii) identify new genes and mutations in various rare Mendelian disorders, (iii) identify epigenetic modifications to better understand biological processes like gene expression and host-pathogen interactions, (iv) precisely profile the human, murine, and environmental microbiome in disease and under various environmental stressors, and (v) develop novel preventive therapies for infection-prone disorders for better drug targeting. The analysis of the large amount of genomic and transcriptomic data generated by the various research groups will be coordinated by the UZA/UA bioinformatics group Biomina.

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Hyperendemic M. tuberculosis from a hypertemporal genomic perspective (HyperMTB). 01/05/2018 - 30/04/2019

Abstract

The Karonga Prevention Study has collected, cultured and genome sequenced more than 2000 sputum samples from 1995 to 2014. We will apply a range of phylodynamic methods to investigate the evolution of Mycobacterium tuberculosis over this period. This study will investigate factors involved in strain success, outbreak likelihood of strains and the impact of interventions on strain diversity.

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Project website

Multi-level determinants of uptake and adherence to a novel women-empowered HIV Prevention Strategy. 08/04/2017 - 31/07/2019

Abstract

Due to their biological, social and economic vulnerabilities, adolescent girls and young women (AGYW) continue to be at increased risk for HIV acquisition. We propose an implementation research study to optimize woman-empowered HIV prevention strategies for AGYW. Key to optimizing HIV prevention strategies is an improved understanding of the multilevel determinants (individual, familial, relationship and community-level) of uptake and adherence to HIV prevention strategies targeting AGYW. Funded through a DREAMS Innovation grant, Witkoppen Health and Welfare Centre, a primary health clinic in Johannesburg, South Africa, will enroll HIV-negative AGYW unaware of the HIV status of their sexual partner(s) in an implementation research study. AGYW will be offered free home-based HIV self-testing for their male partners. Interested AGYW will be given HIV test kits and AGYW whose partners test HIV-positive or AGYW who remain unaware of their partner(s) HIV status will be offered pre-exposure prophylaxis (PrEP). The proposed work will build upon the DREAMS Innovation study described above. Using mixed methods, we will evaluate multilevel determinants of uptake and adherence to the novel AGYW-empowered HIV prevention strategy. Quantitative secondary data collected by the DREAMS Innovation study will be complemented with qualitative interviews with AGYW and their male partners at each of the steps of the proposed HIV prevention cascade: AGYW acceptance of self-testing kits for partners; AGYW delivery of self-testing kits to their male partner(s); male partner acceptance of HIV self-testing; disclosure of HIV test results to AGYW; linkage to care of HIV positive male partners; PrEP uptake among eligible AGYW; and PrEP adherence. Our specific aims are as follows: Aim 1: Perform a mixed methods study of multi-level (individual, relationship and community) determinants of uptake of and adherence to each of the steps of the novel AGYW-empowered HIV prevention strategy. Analyses of the DREAMS Innovation cohort data will quantify uptake and adherence to each step, and multi-level modeling will allow for assessment of key determinants of engagement at each step of the prevention cascade. At each step, we will identify 6-8 AGYW and male partners who failed to complete the cascade step and perform in-depth interviews to explore reasons for not completing engagement in HIV prevention activities as well as facilitators of successful engagement in previous steps. Aim 2: Evaluate the impact of engagement in the HIV care cascade on changes in risk profiles among AGYW. Longitudinal changes in AGYW risk profiles will be described and the impact of engagement across the HIV prevention cascade on changes in AGYW risk profiles before and at the end of program participation evaluated.

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Research team(s)

  • Social Epidemiology & Health Policy (SEHPO)