Dynamics of within-host<i>Mycobacterium tuberculosis</i>diversity and heteroresistance during treatment

Nimmo, Camus ORCID: 0000-0001-7355-4651, Brien, Kayleen, Millard, James ORCID: 0000-0001-6427-552X, Grant, Alison D ORCID: 0000-0002-2437-5195, Padayatchi, Nesri ORCID: 0000-0003-2543-9071, Pym, Alexander S ORCID: 0000-0002-6260-8180, O’Donnell, Max ORCID: 0000-0002-1232-3718, Goldstein, Richard ORCID: 0000-0001-5148-4672, Breuer, Judith ORCID: 0000-0001-8246-0534 and Balloux, François ORCID: 0000-0003-1978-7715
(2020) Dynamics of within-host<i>Mycobacterium tuberculosis</i>diversity and heteroresistance during treatment. 2020.02.03.20019786-.

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<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Studying within-host genetic diversity of<jats:italic>Mycobacterium tuberculosis</jats:italic>(<jats:italic>Mtb</jats:italic>) 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).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We analyse data from six studies in KwaZulu-Natal, South Africa. Most patients (&gt;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.</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>Baseline<jats:italic>Mtb</jats:italic>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 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.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>In this study of single-strain<jats:italic>Mtb</jats:italic>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.</jats:p></jats:sec><jats:sec><jats:title>Funding</jats:title><jats:p>Wellcome Trust, NIH/NIAID</jats:p></jats:sec>

Item Type: Article
Uncontrolled Keywords: 3207 Medical Microbiology, 32 Biomedical and Clinical Sciences, 3202 Clinical Sciences, 31 Biological Sciences, Sexually Transmitted Infections, Biodefense, Rare Diseases, Infectious Diseases, Emerging Infectious Diseases, Biotechnology, Genetics, HIV/AIDS, Antimicrobial Resistance, Orphan Drug, Tuberculosis, Clinical Research, Precision Medicine, 5 Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, 2 Aetiology, 2.2 Factors relating to the physical environment, Infection, 3 Good Health and Well Being
Depositing User: Symplectic Admin
Date Deposited: 16 Nov 2020 10:15
Last Modified: 22 Jun 2024 12:13
DOI: 10.1101/2020.02.03.20019786
Open Access URL: https://doi.org/10.1016/j.ebiom.2020.102747
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3106815