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Population genomics of drug resistant tuberculosis

English title Population genomics of drug resistant tuberculosis
Applicant Egger Matthias
Number 153442
Funding scheme Project funding (Div. I-III)
Research institution Institut für Sozial- und Präventivmedizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Infectious Diseases
Start/End 01.06.2014 - 31.12.2017
Approved amount 526'000.00
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Keywords (19)

phylogeny; lineage; genomics; Tuberculosis; drug susceptibility; genetic diversity; evolution; treatment; Mycobacterium tuberculosis; compensatory mutations; phenotype; HIV; drug resistance; epistasis; epistasis; mutation; low-income countries; multidrug resistance; large nested project (SHCS)

Lay Summary (French)

Lead
Etude génomique de la tuberculose résistante aux médicaments sous l'influence de la coinfection avec le virus VIH
Lay summary

La tuberculose (TB) est causée par la bactérie Mycobacterium tuberculosis (Mtb). Elle représente aujourd’hui encore une menace majeure pour la santé publique, ceci d’autant plus qu’elle est souvent associée au VIH et que la bactérie est de plus en plus résistante aux médicaments antituberculeux. Des facteurs bactériens jouent un rôle important dans le développement des résistances. De récentes données indiquent l’existence d’interactions entre les mutations causant la résistance, des mutations compensatoires et les différentes lignées bactériennes. Cependant, peu de données sont disponibles sur ces mécanismes dans les cas de TB associée au VIH, notamment dans les pays à faibles revenus où les deux maladies coexistent.

Nous allons obtenir des isolats de Mtb et des données cliniques sur environ 500 patients co-infectés par le VIH et 500 patients VIH-négatifs. Les isolats viendront de huit pays à faible revenu représentatifs de la distribution géographique des différentes lignées de Mtb connues (Côte d’Ivoire, République Democratique du Congo, Kenya, Nigeria, Tanzanie, Afrique du Sud, Pérou, et Thaïlande). La moitié des isolats obtenus viendront de patients dont la TB est multirésistante, l’autre moitié de patients dont la TB est sensible aux médicaments. Le génome des souches sera séquencé en entier pour permettre l’identification de mutations associées à la résistance aux médicaments antituberculeux (y compris les mutations compensatoires) ainsi que la détermination des lignées bactériennes. En parallèle, des tests quantitatifs de résistance aux médicaments de première et seconde ligne seront effectués en culture. Les conséquences de la coinfection avec le VIH et des différentes lignées bactériennes sur les résistances aux médicaments seront étudiées au niveau moléculaire et phénotypique.

Cette étude apportera de nombreuses informations sur l’épidémiologie de la TB résistante aux médicaments dans les pays à faible revenu où la coinfection avec le VIH est fréquente.

Direct link to Lay Summary Last update: 05.12.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Drug susceptibility testing and mortality in patients treated for tuberculosis in high-burden countries
ZuercherKathrin, BallifMarie, FennerLukas, BorrellSonia, KellerPeter, GnokoroJoachim, MarcyOlivier, YotebiengMarcel, DieroLameck, CarterJane, RockwoodNeesha, WilkinsonRobert, CoxHelen, EzatiNicholas, AbimikuAlash'le, CollantesJimena, AvihingsanonAnchalee, KawkitinarongKamon, ReinhardMiriam, HoemkeRico, HuebnerRobin, GagneuxSébastien, BoettgerErik, EggerMatthias (2018), Drug susceptibility testing and mortality in patients treated for tuberculosis in high-burden countries, in bioRXiv, n/a.

Collaboration

Group / person Country
Types of collaboration
Khayelitsha ART programme, University of Cape Town South Africa (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
AID Autoimmun Diagnostika GmbH Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
National TB and Leprosy Training Center (NTBLTC) Saye Village Zaria Nigeria (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Cepref, Institut Pasteur, Abidjan Ivory Coast (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
ETH Zurich, Department of Biosystems Science and Engineering Switzerland (Europe)
- Research Infrastructure
Instituto de Medicina Tropical Alexander von Humboldt Universidad Peruana Cayetano Heredia Peru (South America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Ifakara Health Institute (Bagamoyo branch) Tanzania (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Kalembelembe Hospital, National TB Laboratory, Kinshasa Congo Democratic Republic (formerly Zaire) (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
HIV Netherlands Australia Thailand Research Collaboration Thai Red Cross AIDS Research Centre Thailand (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Broad Institute of MIT and Harvard University, Cambridge, MA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
AMPATH Eldoret, CDC Kisumu Kenya (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Stellenbosch University South Africa (Africa)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
22nd International AIDS Conference Talk given at a conference Drug susceptibility testing, HIV-coinfection and outcomes in patients treated for TB in low- and middle-income settings 22.07.2018 Amsterdam, Netherlands Egger Matthias; Böttger Erik Christian; Ballif Marie; Gagneux Sebastien; Zürcher Kathrin;
International Workshop on HIV and Hepatitis Observational Databases Poster Accuracy and clinical significance of TB drug resistance testing at TB clinics attached to antiretroviral therapy programs 22.03.2018 Fuengirola, Spain Böttger Erik Christian; Ballif Marie; Gagneux Sebastien; Egger Matthias; Zürcher Kathrin;
48th Union World Conference on Lung Health Poster Treatment outcome and mortality in pulmonary TB in lower income countries: impact of drug resistance and HIV co-infection 14.10.2017 Guadalajara, Mexico Gagneux Sebastien; Ballif Marie; Egger Matthias; Böttger Erik Christian; Zürcher Kathrin;


Self-organised

Title Date Place
Swiss Epidemiology Winter School 2016: Course on Sequence Analysis in Molecular Epidemiology of Pathogens 17.01.2016 Wengen, Switzerland
Swiss Epidemiology Winter School 2015: Course on Sequence Analysis in Molecular Epidemiology of Pathogens 18.01.2015 Wengen, Switzerland

Associated projects

Number Title Start Funding scheme
163452 Socio-Economic Position, Pregnancy Outcomes and Infant Mortality: The Swiss National Cohort 01.07.2016 Project funding (special)
125441 Molecular and clinical epidemiology of tuberculosis in Switzerland: Studies of populations infected and not infected with HIV 01.04.2009 Project funding (special)
119205 Integrating Genomic and Ecologic Approaches to Understand the Nature and Consequence of Genetic Diversity in Mycobacterium tuberculosis 01.03.2010 SNSF Professorships
125441 Molecular and clinical epidemiology of tuberculosis in Switzerland: Studies of populations infected and not infected with HIV 01.04.2009 Project funding (special)
170834 Evolution and epidemiology of rifampicin-resistant tuberculosis in Khayelitsha, Cape Town: implications for biology and disease control 01.06.2017 Bilateral programmes

Abstract

Background - Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a major global public-health problem, particularly in the context of HIV and the emergence of multidrug resistance and extensive drug resistance. Strategies for controlling drug resistance in Mtb include drug susceptibility testing, surveillance, as well as ensuring completion of an adequate treatment regimen and patient follow-up. Bacterial factors may also contribute to the global emergence and spread of drug-resistant TB. In particular, there is growing evidence that interactions between drug resistance mutations, compensatory mutations and different strain lineages could play a role in this context. Little is known about these mechanisms in HIV-associated TB, particularly in low- and middle-income countries, where both diseases co-exist. Hypotheses - We hypothesize that i) drug-resistance-associated mutations in Mtb (including compensatory mutations) differ in HIV-positive compared to HIV-negative patients, ii) levels of phenotypic drug resistance resulting from particular resistance-associated mutations differ between isolates collected from HIV-positive versus HIV-negative patients, iii) levels of phenotypic drug resistance are a function of both drug-resistance-associated mutations and Mtb lineages.Objectives - To study drug resistance-associated mutations (including compensatory mutations) in HIV-positive and HIV-negative patients, and to determine the levels of phenotypic drug resistance associated with particular mutations in HIV-infected versus non-infected patients and across different genetic backgrounds (i.e. phylogenetic lineages) of Mtb.Methods - We will collect Mtb isolates and clinical data of 500 HIV-infected and 500 HIV-negative TB patients from eight low- and middle-income countries. Participating countries reflect Mtb’s global phylogenetic diversity and are part of the International epidemiologic Databases to Evaluate AIDS (IeDEA) network: Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, Peru, South Africa, Thailand, Tanzania. Overall, half of the Mtb isolates will be MDR and half pansusceptible. These 1,000 Mtb isolates will undergo whole genome sequencing at the Broad Institute in Cambridge, USA. Quantitative phenotypic drug susceptibly testing will be done for 12 anti-TB drugs at the National Center for Mycobacteria in Zurich. Genome sequences will be analysed to identify different drug-resistance-associated-mutations (including compensatory mutations) and Mtb lineages. These will then be correlated to quantitative levels of drug resistance. The impact of HIV infection and Mtb lineage on drug resistance at the molecular and phenotypic level will be elucidated.Relevance of study - The proposed study is unique and will contribute important information on the epidemiology of drug-resistant TB in the context of HIV in low- and middle-income countries, and provide insight into the bacterial factors contributing to the global spread of drug resistance. It adds substantial value to the TB genomics project funded by NIAID and other work of the applicants and is good value for money as the field work and whole genome sequencing is funded by NIAID.
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