Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans.
Bibliographical noteFunding Information:
Al Z, PM, MB, and MH are supported by the European and Developing Countries Clinical Trials Partnership (grants REMOX, PANACEA, and TB-NEAT), Netherlands. AZ receives support from the UK Medical Research Council (MRC); UBS Optimus Foundation, Switzerland; University College London Hospitals (UCLH) Comprehensive Biomedical Research Centre, UK; and the UCLH National Health Service Foundation Trust, UK. IA is supported by the UK National Institute for Health Research and the UK MRC. SDL is supported by the Wellcome Trust, UK. The opinions expressed herein are those of the authors and should not be construed as representing the official views or policies of the US Department of Health and Human Services or the authors' national governments. Nor does mention of trade names, commercial practices, or organisations imply endorsement by the US Government or the authors' national governments. DF, MR, and MZ are staff members of WHO. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of WHO.
Several national and international partners—eg, the Global Alliance for TB Drug Development (TB Alliance), the US National Institutes of Health (NIH), the US Centers for Disease Control and Prevention (CDC), and the European and Developing Countries Clinical Trials Partnership (EDCTP)—have started animal and human studies to test the efficacy of drug combinations rather than individual drugs. These studies aim to shorten the time taken to derive an entirely new treatment regimen for both drug-susceptible and drug-resistant tuberculosis. 77 However, this approach will probably take 8–10 years because of regulatory, study design, and research grant-awarding processes. Efforts through the clinical trial plan funded by the NIH, and the PANACEA consortium funded by EDCTP with adaptive designs could make the process quicker. Although this work has tremendous long-term value, it does little to address the immediate needs of drug-resistant patients who are underserved by present treatments. The recent US Food and Drug Administration accelerated approval of bedaquiline, the soon expected approval of delamanid by the European Medicines Agency, and the advanced development of drugs such as PA-824 (TB Alliance) beg the question: how should we use these new drugs in the treatment of drug-resistant tuberculosis? 78 Clinical trials such as the MARVEL study (ACTG 5319) in development by the AIDS Clinical Trials Group in collaboration with the TB Alliance, will investigate treatment regimens that include both old and new drugs, and will provide answers within the next 3–4 years. The dual goals of developing completely new regimens and optimising existing or partly new regimens are not incompatible, and the poor treatment success and high mortality associated with drug-resistant tuberculosis treatment means that both approaches should be taken as a matter of urgency.