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)
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
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.