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Updating the WHO target product profile for next-generation Mycobacterium tuberculosis drug susceptibility testing at peripheral centres.

ABSTRACT: There were approximately 10 million tuberculosis (TB) cases in 2020, of which 500,000 were drug-resistant. Only one third of drug-resistant TB cases were diagnosed and enrolled on appropriate treatment, an issue partly driven by a lack of rapid, accurate drug-susceptibility testing (DST) tools deployable in peripheral settings. In 2014, World Health Organization (WHO) published target product profiles (TPPs) which detailed minimal and optimal criteria to address high-priority TB diagnostic needs, including DST. Since then, the TB community's needs have evolved; new treatment regimens, changes in TB definitions, further emergence of drug resistance, technological advances, and changing end-users requirements have necessitated an update. The DST TPP's revision was therefore undertaken by WHO with the Stop TB Partnership New Diagnostics Working Group. We describe the process of updating the TPP for next-generation TB DST for use at peripheral centres, highlight key updates, and discuss guidance regarding technical and operational specifications.

SUBMITTER: MacLean EL

PROVIDER: S-EPMC10065236 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Updating the WHO target product profile for next-generation Mycobacterium tuberculosis drug susceptibility testing at peripheral centres.

MacLean Emily Lai-Ho EL Miotto Paolo P González Angulo Lice L Chiacchiaretta Matteo M Walker Timothy M TM Casenghi Martina M Rodrigues Camilla C Rodwell Timothy C TC Supply Philip P André Emmanuel E Kohli Mikashmi M Ruhwald Morten M Cirillo Daniela Maria DM Ismail Nazir N Zignol Matteo M

PLOS global public health 20230331 3

There were approximately 10 million tuberculosis (TB) cases in 2020, of which 500,000 were drug-resistant. Only one third of drug-resistant TB cases were diagnosed and enrolled on appropriate treatment, an issue partly driven by a lack of rapid, accurate drug-susceptibility testing (DST) tools deployable in peripheral settings. In 2014, World Health Organization (WHO) published target product profiles (TPPs) which detailed minimal and optimal criteria to address high-priority TB diagnostic needs ...[more]

PMID: 37000774

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Project description:BackgroundEfficient management of drug-resistant tuberculosis relies on fast diagnostics. To accelerate phenotypic drug susceptibility testing [pDST] for Mycobacterium tuberculosis [TB], we introduce TRACeR-TB, a test that infers drug resistance from antibiotic-specific mRNA biomarkers.MethodsTo develop TRACeR-TB, target genes were first identified through RNA sequencing experiments conducted on two drug-exposed, susceptible strains for four antitubercular drugs. Based on these findings, we designed drug-specific multiplex Quantigene panels to quantify mRNA levels of 8-9 biomarkers per drug (class), directly from crude cell lysates. The performance of TRACeR-TB was compared to the widely used Mycobacteria Growth Indicator Tube [MGIT] pDST by subjecting 238 strains with diverse drug resistance profiles to both methods, and aligning results to genotypic data. Furthermore, we explored TRACeR-TB's potential for evaluating molecules that enhance antibiotic efficacy, and investigated its applicability in macrophage models to assess Mtb's intracellular stress responses to drugs.FindingsAntituberculosis drugs trigger distinct transcriptional stress responses in susceptible, but not resistant bacilli, enabling a differentiation of the antibiotic phenotype in only 6 h. Validation on 238 strains showed TRACeR-TB had 100% (95% CI: 93·1-100%) sensitivity and 89·5% (95% CI: 74·7-97·2%) specificity compared to, respectively, 82·3% (95% CI: 69·2%-91·5%) and 94·8% (95% CI: 81·9%-99·4%) for MGIT pDST. TRACeR-TB specificity is likely underestimated due to the inclusion of isolates harbouring uncharacterised mutations. TRACeR-TB demonstrated 100% concordance with MGIT for drugs with reliable MGIT outcomes (moxifloxacin and isoniazid). Additionally, its sensitivity outperformed current rifampicin testing, detecting resistance in all borderline-resistant strains that MGIT missed, and bedaquiline testing. Furthermore, the assay detected the predicted effect of a novel drug booster and the intracellular drug-induced stress in macrophage models, highlighting its potential for drug optimisation.InterpretationTRACeR-TB is a complementary addition to current DSTs and can have a substantial impact on the TB diagnostics field. This tool can also play a vital role in identifying resistance mutations, thereby closing gaps in genotypic knowledge, and contribute to drug discovery and development.FundingInstitut Pasteur, Agence Nationale de la Recherche.

Dataset Information

Updating the WHO target product profile for next-generation Mycobacterium tuberculosis drug susceptibility testing at peripheral centres.

Publications

Updating the WHO target product profile for next-generation Mycobacterium tuberculosis drug susceptibility testing at peripheral centres.

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