title: Outcomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and home-discharged patients with programmatically incurable tuberculosis: a prospective cohort study.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa. Electronic address: keertan.dheda@uct.ac.za.
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
authors.affiliation: Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Limberis
authors.affiliation: Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Elize
authors.initials: E
authors.lastname: Pietersen
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Jody
authors.initials: J
authors.lastname: Phelan
authors.affiliation: Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa.
authors.forename: Aliasgar
authors.initials: A
authors.lastname: Esmail
authors.affiliation: Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Maia
authors.initials: M
authors.lastname: Lesosky
authors.affiliation: Pulmonary Clinical Medicine Section, Cardiovascular and Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Fennelly
authors.affiliation: Brooklyn Chest Hospital, Cape Town, South Africa.
authors.forename: Julian
authors.initials: J
authors.lastname: Te Riele
authors.affiliation: Harry Surtie Hospital, Upington, South Africa.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mastrapa
authors.affiliation: DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Streicher
authors.affiliation: National Health Laboratory Services, Green Point, Cape Town, South Africa.
authors.forename: Tania
authors.initials: T
authors.lastname: Dolby
authors.affiliation: Pathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
authors.forename: Abdallah M
authors.initials: AM
authors.lastname: Abdallah
authors.affiliation: Pathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
authors.forename: Fathia
authors.initials: F
authors.lastname: Ben-Rached
authors.affiliation: National Health Laboratory Services, Green Point, Cape Town, South Africa.
authors.forename: John
authors.initials: J
authors.lastname: Simpson
authors.affiliation: Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa.
authors.forename: Liezel
authors.initials: L
authors.lastname: Smith
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor University Medical Center, Dallas, TX, USA.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
authors.affiliation: DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Paul
authors.initials: P
authors.lastname: van Helden
authors.affiliation: DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Sirgel
authors.affiliation: Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Ruth
authors.initials: R
authors.lastname: McNerney
authors.affiliation: Department of Medicine, University of Cape Town, Cape Town, South Africa; DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Grant
authors.initials: G
authors.lastname: Theron
authors.affiliation: Pathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
authors.forename: Arnab
authors.initials: A
authors.lastname: Pain
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK; Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.affiliation: DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, SAMRC Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Warren
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy / Q000401:mortality* / Q000635:transmission*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D010351:Patient Discharge / Q000706:statistics & numerical data*; D010641:Phenotype; D011446:Prospective Studies; D013019:South Africa; D013183:Sputum; D017211:Treatment Failure
chemical_list: D000995:Antitubercular Agents