About 1·3 million people died of tuberculosis in 2012, despite availability of effective drug treatment. Barriers to improvements in outcomes include long treatment duration (resulting in poor patient adherence and loss of patients to follow-up), complex regimens that involve expensive and toxic drugs, toxic effects when given with antiretroviral therapy, and multidrug resistance. After 50 years of no antituberculosis drug development, a promising pipeline is emerging through the repurposing of old drugs, re-engineering of existing antibacterial compounds, and discovery of new compounds. A range of novel antituberculosis drugs are in preclinical development, several phase 2 and 3 trials are underway, and use of adjunct therapies is being explored for drug-sensitive and drug-resistant tuberculosis. Historical advances include approval of two new drugs, delamanid and bedaquiline. Combinations of new and existing drugs are being assessed to shorten the duration of therapy and to treat multidrug-resistant tuberculosis. There has also been progress in development of new antituberculosis drugs that are active against dormant or persister populations of Mycobacterium tuberculosis. In this Review, we discuss recent advances in antituberculosis drug discovery and development, clinical trial designs, laboratory methods, and adjunct host-directed therapies, and we provide an update of phase 3 trials of various fluoroquinolones (RIFAQUIN, NIRT, OFLOTUB, and REMoxTB). We also emphasise the need to engage the community in design, implementation, and uptake of research, to increase international cooperation between drug developers and health-care providers adopting new regimens.
Bibliographical noteFunding Information:
For development of table 1 , we thank Michael J Vjecha, from the Institute for Clinical Research, Washington, DC, USA, and Executive Coordinator for US Centers for Disease Control and Prevention Tuberculosis Trials Consortium. We thank Adam Zumla (UCL School of Pharmacy, University College London, London, UK) for technical and administrative assistance. AIZ is supported by UK European Union FP7Rid-RTI programme grant; European Developing Countries Clinical Trials Partnership TB NEAT, PanACEA, and REMox grants; and grants from UBS Optimus Foundation, Switzerland, and National Institute for Health Research Biomedical Research Centre, University College London Hospitals, London, UK. STC is supported by European Community's Seventh Framework Programme ( FP7/2007–13 ) under grant agreement number 260872. MH is supported by BmBF grants, European Developing Countries Clinical Trials Partnership PanACEA 2007.32011.013, TB NEAT, PanACEA, and REMox grants. SHG and TDMH are supported by Global Alliance for Tuberculosis Drug Development; and European and Developing Country Clinical Trials Partnership (grants IP.2007.32011.011, IP.2007.32011.012, and IP.2007.32011.013), including TB NEAT, PanACEA, and REMox grants; and Innovative Medicines Initiative Joint Undertaking grant 115337. MM is supported by the European Developing Countries Clinical Trials Partnership, TB NEAT, Vetenskapsrådet, VINNOVA, and HLF (Heart and Lung foundation) Sweden. MS is supported by National Institute of Allergies and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under contract number HHSN272200800014C .
The sponsors and research groups in the forum include the Global Alliance for Tuberculosis Drug Development, the National Institute of Allergy and Infectious Diseases and its AIDS Clinical Trials Group Network and Tuberculosis Research Unit, the US Centers for Disease Control and Prevention and its Tuberculosis Research Unit, the European and Developing Countries Clinical Trials Partnership and PanACEA, and the UK Medical Research Council and its funded investigators. The forum presently focused mainly on phase 2 studies and complements the objectives of the Critical Path to Tuberculosis Regimens (CPTR) to bring new combinations into phase 3 trials and gain regulatory approvals as soon as possible. A global trial outcomes registry would confirm safety and effectiveness of new drugs and treatment regimens. 117 There is also a need for producers, purchasers, and providers to cooperate, and for governments to become more flexible 116 in adopting new regimens, so that all patients with multidrug-resistant tuberculosis can get second-line treatments without stock-outs of drugs. Achievement of this aim will require more community engagement in design, implementation, and uptake of research.