title: High rates of multidrug-resistant and rifampicin-resistant tuberculosis among re-treatment cases: where do they come from?
abstract: Globally 3.9% of new and 21% of re-treatment tuberculosis (TB) cases are multidrug-resistant or rifampicin-resistant (MDR/RR), which is often interpreted as evidence that drug resistance results mainly from poor treatment adherence. This study aims to assess the respective contributions of the different causal pathways leading to MDR/RR-TB at re-treatment.
  
  
  
  We use a simple mathematical model to simulate progression between the different stages of disease and treatment for patients diagnosed with TB. The model is parameterised using region and country-specific TB disease burden data reported by the World Health Organization (WHO). The contributions of four separate causal pathways to MDR/RR-TB among re-treatment cases are estimated: I) initial drug-susceptible TB with resistance amplification during treatment; II) initial MDR/RR-TB inappropriately treated as drug-susceptible TB; III) MDR/RR-TB relapse despite appropriate treatment; and IV) re-infection with MDR/RR-TB.
  
  
  
  At the global level, Pathways I, II, III and IV contribute 38% (28-49, 95% Simulation Interval), 44% (36-52, 95% SI), 6% (5-7, 95% SI) and 12% (7-19, 95% SI) respectively to the burden of MDR/RR-TB among re-treatment cases. Pathway II is dominant in the Western Pacific (74%; 67-80 95% SI), Eastern Mediterranean (68%; 60-74 95% SI) and European (53%; 48-59 95% SI) regions, while Pathway I makes the greatest contribution in the American (53%; 40-66 95% SI), African (43%; 28-61 95% SI) and South-East Asian (50%; 40-59 95% SI) regions.
  
  
  
  Globally, failure to diagnose MDR/RR-TB at first presentation is the leading cause of the high proportion of MDR/RR-TB among re-treatment cases. These findings highlight the need for contextualised solutions to limit the impact and spread of MDR/RR-TB.
authors.affiliation: Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia. romain.ragonnet@burnet.edu.au.|Centre for Population Health, Burnet Institute, 85 Commercial Road, Melbourne, 3141, VIC, Australia. romain.ragonnet@burnet.edu.au.
authors.forename: Romain
authors.initials: R
authors.lastname: Ragonnet
authors.affiliation: Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia.|Centre for Population Health, Burnet Institute, 85 Commercial Road, Melbourne, 3141, VIC, Australia.|Victorian Tuberculosis Program, Melbourne Health, Melbourne, Australia.|School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
authors.forename: James M
authors.initials: JM
authors.lastname: Trauer
authors.affiliation: Victorian Tuberculosis Program, Melbourne Health, Melbourne, Australia.|Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute, Melbourne, Australia.|Victorian Infectious Diseases Service, Royal Melbourne Hospital, Parkville, VIC, Australia.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Denholm
authors.affiliation: Marie Bashir Institute and the Centre for Research Excellence in Tuberculosis, University of Sydney, Sydney, Australia.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Marais
authors.affiliation: Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia.|Centre for Population Health, Burnet Institute, 85 Commercial Road, Melbourne, 3141, VIC, Australia.|Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Australia.
authors.forename: Emma S
authors.initials: ES
authors.lastname: McBryde
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use*; D006801:Humans; D015233:Models, Statistical; D019233:Retreatment; D012293:Rifampin / Q000627:therapeutic use*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology; D014944:World Health Organization
chemical_list: D000995:Antitubercular Agents; D012293:Rifampin
keywords: Causal pathway; Drug resistance amplification; Inappropriate therapy; Misdiagnosis; Multidrug-resistant tuberculosis; Re-treatment; Tuberculosis