New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects

• Published in: The Lancet infectious diseases Vol. 14; no. 4; pp. 327 - 340
• Main Authors: Zumla, Alimuddin I, Prof, Gillespie, Stephen H, Prof, Hoelscher, Michael, Prof, Philips, Patrick P J, PhD, Cole, Stewart T, Prof, Abubakar, Ibrahim, Prof, McHugh, Timothy D, Prof, Schito, Marco, PhD, Maeurer, Markus, Prof, Nunn, Andrew J, Prof
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 01-04-2014; Lancet Publishing Group; Elsevier Limited
• Subjects: Antiretroviral agents; Antitubercular Agents - adverse effects; Antitubercular Agents - therapeutic use; Bacterial diseases; Biological and medical sciences; Biomarkers; Clinical trials; Clinical Trials as Topic; Developing countries; Distribution costs; Drug Discovery; Drug dosages; Drug resistance; Drug Therapy, Combination; Drugs; Human bacterial diseases; Humans; Immunotherapy; Infectious Disease; Infectious diseases; International cooperation; Laboratory methods; LDCs; Medical sciences; Medication Adherence; Medicin och hälsovetenskap; Mortality; Public health; Research Design; Tuberculosis; Tuberculosis and atypical mycobacterial infections; Tuberculosis, Multidrug-Resistant - drug therapy; Tuberculosis, Pulmonary - drug therapy; Tuberculosis, Pulmonary - therapy; Infection; Human; Chemotherapy; Treatment; Tuberculosis; Bacteriosis; Antituberculous agent; Mycobacterial infection; Antibacterial agent; Therapeutic protocol
• ISSN: 1473-3099; 1474-4457; 1474-4457
• DOI: 10.1016/S1473-3099(13)70328-1

Summary 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.