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    Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study

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    Type
    Article
    Authors
    Dheda, Keertan
    Limberis, Jason D
    Pietersen, Elize
    Phelan, Jody
    Esmail, Aliasgar
    Lesosky, Maia
    Fennelly, Kevin P
    te Riele, Julian
    Mastrapa, Barbara
    Streicher, Elizabeth M
    Dolby, Tania
    Abdallah, Abdallah
    Ben Rached, Fathia
    Simpson, John
    Smith, Liezel
    Gumbo, Tawanda
    van Helden, Paul
    Sirgel, Frederick A
    McNerney, Ruth cc
    Theron, Grant
    Pain, Arnab cc
    Clark, Taane G. cc
    Warren, Robin M
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Bioscience Program
    NGS, qPCR and Single Cell Genomics
    Pathogen Genomics Laboratory
    Date
    2017-01-19
    Online Publication Date
    2017-01-19
    Print Publication Date
    2017-04
    Permanent link to this record
    http://hdl.handle.net/10754/622901
    
    Metadata
    Show full item record
    Abstract
    Background: The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and containment strategies. Methods: In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179). Findings: Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20·3 months (IQR 9·6-27·8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) home-discharged patients had failed treatment, with a median time to death after discharge of 9·9 months (IQR 4·2-17·4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (<5 μm), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid. Interpretation: More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing. Funding: UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology.
    Citation
    Dheda K, Limberis JD, Pietersen E, Phelan J, Esmail A, et al. (2017) Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study. The Lancet Respiratory Medicine. Available: http://dx.doi.org/10.1016/S2213-2600(16)30433-7.
    Sponsors
    Medical Research Council[grant no MR/K000551/1, MR/M01360X/1, MR/N010469/1]
    Publisher
    Elsevier BV
    Journal
    The Lancet Respiratory Medicine
    DOI
    10.1016/S2213-2600(16)30433-7
    Additional Links
    http://www.sciencedirect.com/science/article/pii/S2213260016304337
    ae974a485f413a2113503eed53cd6c53
    10.1016/S2213-2600(16)30433-7
    Scopus Count
    Collections
    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program

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