title: Tuberculosis--advances in development of new drugs, treatment regimens, host-directed therapies, and biomarkers.
abstract: Tuberculosis is the leading infectious cause of death worldwide, with 9·6 million cases and 1·5 million deaths reported in 2014. WHO estimates 480,000 cases of these were multidrug resistant (MDR). Less than half of patients who entered into treatment for MDR tuberculosis successfully completed that treatment, mainly due to high mortality and loss to follow-up. These in turn illustrate weaknesses in current treatment regimens and national tuberculosis programmes, coupled with operational treatment challenges. In this Review we provide an update on recent developments in the tuberculosis drug-development pipeline (including new and repurposed antimicrobials and host-directed drugs) as they are applied to new regimens to shorten and improve outcomes of tuberculosis treatment. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR tuberculosis, and two new antimicrobial drug candidates are in early-stage trials. Several trials to reduce the duration of therapy in MDR and drug-susceptible tuberculosis are ongoing. A wide range of candidate host-directed therapies are being developed to accelerate eradication of infection, prevent new drug resistance, and prevent permanent lung injury. As these drugs have been approved for other clinical indications, they are now ready for repurposing for tuberculosis in phase 2 clinical trials. We assess risks associated with evaluation of new treatment regimens, and highlight opportunities to advance tuberculosis research generally through regulatory innovation in MDR tuberculosis. Progress in tuberculosis-specific biomarkers (including culture conversion, PET and CT imaging, and gene expression profiles) can support this innovation. Several global initiatives now provide unique opportunities to tackle the tuberculosis epidemic through collaborative partnerships between high-income countries and middle-income and low-income countries for clinical trials training and research, allowing funders to coordinate several national and regional programmes for greatest overall effect.
authors.affiliation: Aurum Institute, Johannesburg, South Africa; Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Advancing Care for TB/HIV, Cape Town, South Africa.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wallis
authors.affiliation: Therapeutic Immunology, Departments of Laboratory Medicine and Microbiology, Tumour and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Maeurer
authors.affiliation: UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia.
authors.forename: Peter
authors.initials: P
authors.lastname: Mwaba
authors.affiliation: Kenya Medical Research Institute, Nairobi, Kenya.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Chakaya
authors.affiliation: South African Medical Research Council, Cape Town, South Africa.
authors.forename: Roxana
authors.initials: R
authors.lastname: Rustomjee
authors.affiliation: WHO Collaborating Centre for TB and Lung Diseases, Fondazione S Maugeri Care and Research Institute, Tradate, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Migliori
authors.affiliation: Children's Hospital at Westmead and the Centre for Research Excellence in Tuberculosis, University of Sydney, Sydney, NSW, Australia.
authors.forename: Ben
authors.initials: B
authors.lastname: Marais
authors.affiliation: Critical Path to TB Drug Regimens, Critical Path Institute, Tucson, AZ, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Schito
authors.affiliation: Aurum Institute, Johannesburg, South Africa; Department of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; School of Public Health, University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Gavin
authors.initials: G
authors.lastname: Churchyard
authors.affiliation: National Institute for Research on Tuberculosis, Chennai, India.
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich, Munich, Germany; DZIF German Centre for Infection Research, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.affiliation: UNZA-UCLMS Research and Training Project, University Teaching Hospital, Lusaka, Zambia; Centre for Clinical Microbiology, Division of Infection and Immunity, University College London (UCL), London, UK; National Institute for Health Research Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK. Electronic address: a.i.zumla@gmail.com.
authors.forename: Alimuddin
authors.initials: A
authors.lastname: Zumla
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis; D055808:Drug Discovery; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014376:Tuberculosis / Q000188:drug therapy*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*
chemical_list: D000890:Anti-Infective Agents; D000995:Antitubercular Agents; D015415:Biomarkers