Keertan Dheda1, Jason D Limberis2, Elize Pietersen2, Jody Phelan3, Aliasgar Esmail4, Maia Lesosky5, Kevin P Fennelly6, Julian Te Riele7, Barbara Mastrapa8, Elizabeth M Streicher9, Tania Dolby10, Abdallah M Abdallah11, Fathia Ben-Rached11, John Simpson10, Liezel Smith4, Tawanda Gumbo12, Paul van Helden9, Frederick A Sirgel9, Ruth McNerney2, Grant Theron13, Arnab Pain11, Taane G Clark14, Robin M Warren9. 1. Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa. Electronic address: keertan.dheda@uct.ac.za. 2. Department of Medicine, University of Cape Town, Cape Town, South Africa. 3. Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK. 4. Division of Pulmonology and UCT Lung Institute, University of Cape Town, Cape Town, South Africa. 5. Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa. 6. 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. 7. Brooklyn Chest Hospital, Cape Town, South Africa. 8. Harry Surtie Hospital, Upington, South Africa. 9. 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. 10. National Health Laboratory Services, Green Point, Cape Town, South Africa. 11. Pathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia. 12. Center for Infectious Diseases Research and Experimental Therapeutics, Baylor University Medical Center, Dallas, TX, USA. 13. 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. 14. 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.
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.
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.
Authors: Grant Theron; Jason Limberis; Rouxjeane Venter; Liezel Smith; Elize Pietersen; Aliasgar Esmail; Greg Calligaro; Julian Te Riele; Marianna de Kock; Paul van Helden; Tawanda Gumbo; Taane G Clark; Kevin Fennelly; Robin Warren; Keertan Dheda Journal: Nat Med Date: 2020-06-29 Impact factor: 53.440
Authors: Sara C Auld; N Sarita Shah; Barun Mathema; Tyler S Brown; Nazir Ismail; Shaheed Vally Omar; James C M Brust; Kristin N Nelson; Salim Allana; Angela Campbell; Koleka Mlisana; Pravi Moodley; Neel R Gandhi Journal: Eur Respir J Date: 2018-10-18 Impact factor: 16.671
Authors: Julian S Peters; Jason R Andrews; Mark Hatherill; Sabine Hermans; Leonardo Martinez; Erwin Schurr; Yuri van der Heijden; Robin Wood; Roxana Rustomjee; Bavesh D Kana Journal: Lancet Infect Dis Date: 2018-12-13 Impact factor: 25.071
Authors: Palwasha Y Khan; Tom A Yates; Muhammad Osman; Robin M Warren; Yuri van der Heijden; Nesri Padayatchi; Edward A Nardell; David Moore; Barun Mathema; Neel Gandhi; Vegard Eldholm; Keertan Dheda; Anneke C Hesseling; Valerie Mizrahi; Roxana Rustomjee; Alexander Pym Journal: Lancet Infect Dis Date: 2018-12-13 Impact factor: 25.071
Authors: Michael G Whitfield; Robin M Warren; Vanessa Mathys; Lesley Scott; Elise De Vos; Wendy Stevens; Elizabeth M Streicher; Guido Groenen; Frederick A Sirgel; Annelies Van Rie Journal: J Antimicrob Chemother Date: 2018-10-01 Impact factor: 5.790
Authors: Keertan Dheda; Laura Lenders; Gesham Magombedze; Shashikant Srivastava; Prithvi Raj; Erland Arning; Paula Ashcraft; Teodoro Bottiglieri; Helen Wainwright; Timothy Pennel; Anthony Linegar; Loven Moodley; Anil Pooran; Jotam G Pasipanodya; Frederick A Sirgel; Paul D van Helden; Edward Wakeland; Robin M Warren; Tawanda Gumbo Journal: Am J Respir Crit Care Med Date: 2018-11-01 Impact factor: 21.405
Authors: Maha R Farhat; Jaimie Sixsmith; Roger Calderon; Nathan D Hicks; Sarah M Fortune; Megan Murray Journal: J Antimicrob Chemother Date: 2019-06-01 Impact factor: 5.790
Authors: Samuel Agyei Nyantakyi; Ming Li; Pooja Gopal; Matthew Zimmerman; Véronique Dartois; Martin Gengenbacher; Thomas Dick; Mei-Lin Go Journal: J Med Chem Date: 2018-06-25 Impact factor: 7.446
Authors: Kevin P Fennelly; Carlos Acuna-Villaorduna; Edward Jones-Lopez; William G Lindsley; Donald K Milton Journal: Chest Date: 2019-10-31 Impact factor: 9.410