Dynamics of within-host Mycobacterium tuberculosis diversity and heteroresistance during treatment

EBioMedicine

James Millard¹  Alison D. Grant²  Richard Goldstein³  François Balloux⁴  Kayleen Brien⁵  Max O'Donnell⁶  Judith Breuer⁷  Nesri Padayatchi⁷  Alexander S. Pym⁷  Camus Nimmo⁸ 

[1] Africa Health Research Institute, Durban, South Africa;Corresponding author at: Division of Infection and Immunity, University College London, London, UK.;Institute of Infection and Global Health, University of Liverpool, Liverpool, UK;;London School of Hygiene &UCL Genetics Institute, University College London, London, UK;Wellcome Trust Liverpool Glasgow Centre for Global Health Research, Liverpool, UK;Africa Health Research Institute, Durban, South Africa;Division of Infection and Immunity, University College London, London, UK;

关键词: Mycobacterium tuberculosis;    TB;    Heteroresistance;    Genetic diversity;    Bedaquiline;    Whole genome sequencing;   

DOI  :  

来源: DOAJ

【 摘 要 】

Background: Studying within-host genetic diversity of Mycobacterium tuberculosis (Mtb) in patients during treatment may identify adaptations to antibiotic and immune pressure. Understanding the significance of genetic heteroresistance, and more specifically heterozygous resistance-associated variants (RAVs), is clinically important given increasing use of rapid molecular tests and whole genome sequencing (WGS). Methods: We analyse data from six studies in KwaZulu-Natal, South Africa. Most patients (>75%) had baseline rifampicin resistance. Sputum was collected for culture at baseline and at between two and nine intervals until month six. Positive cultures underwent WGS. Mixed infections and reinfections were excluded from analysis. Findings: Baseline Mtb overall genetic diversity (at treatment initiation or major change to regimen) was associated with cavitary disease, not taking antiretroviral therapy if HIV infected, infection with lineage 2 strains and absence of second-line drug resistance on univariate analyses. Baseline genetic diversity was not associated with six-month outcome. Genetic diversity increased from baseline to weeks one and two before returning to previous levels. Baseline genetic heteroresistance was most common for bedaquiline (6/10 [60%] of isolates with RAVs) and fluoroquinolones (9/62 [13%]). Most patients with heterozygous RAVs on WGS with sequential isolates available demonstrated RAV persistence or fixation (17/20, 85%). New RAVs emerged in 9/286 (3%) patients during treatment. We could detect low-frequency RAVs preceding emergent resistance in only one case, although validation of deep sequencing to detect rare variants is required. Interpretation: In this study of single-strain Mtb infections, baseline within-host bacterial genetic diversity did not predict outcome but may reveal adaptations to host and drug pressures. Predicting emergent resistance from low-frequency RAVs requires further work to separate transient from consequential mutations. Funding: Wellcome Trust, NIH/NIAID

【 授权许可】

Unknown