To mark the Stop TB Partnerships' World TB Day on Monday 24 March 2014, The Lancet journals will publish a special new collection of Reviews, Comment, and Articles to cast light, and the world's attention, on tuberculosis, in the hope of raising this disease higher up the agendas of international communities.
The new publications discuss topics ranging from extremely drug-resistant tuberculosis, to the role of advocacy in tuberculosis, and new anti-tuberculosis drugs, highlighting the key areas and challenges to be met if inroads are to be made into winning the battle against tuberculosis.
Extensively drug-resistant tuberculosis is a burgeoning global health crisis mainly affecting economically active young adults, and has high mortality irrespective of HIV status. In some countries such as South Africa, drug-resistant tuberculosis represents less than 3% of all cases but consumes more than a third of the total national budget for tuberculosis, which is unsustainable and threatens to destabilise national tuberculosis programmes. However, concern about drug-resistant tuberculosis has been eclipsed by that of totally and extremely drug-resistant tuberculosis—ie, resistance to all or nearly all conventional first-line and second-line anti-tuberculosis drugs. In this Review, Professor Keertan Dheda, University of Cape Town, South Africa, and co-authors, discuss the epidemiology, pathogenesis, diagnosis, management, implications for health care workers, and ethical and medico-legal aspects of extensively drug-resistant tuberculosis and other resistant strains. Finally, the authors discuss the emerging problem of functionally untreatable tuberculosis, and the issues and challenges that it poses to public health and clinical practice. The emergence and growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis—and increased funding to strengthen global control efforts, research, and advocacy—even more pressing.
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 anti-tuberculosis 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 anti-tuberculosis 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 anti-tuberculosis drugs that are active against dormant or persister populations of Mycobacterium tuberculosis. In this Review, Professor Alimuddin Zumla, of University College London, UK, and co-authors, discuss recent advances in anti-tuberculosis drug discovery and development, clinical trial designs, laboratory methods, and adjunct host-directed therapies, and provide an update of phase 3 trials of various fluoroquinolones (RIFAQUIN, NIRT, OFLOTUB, and REMoxTB). The authors 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.
In this Review, Professor Markus Maeurer, from Karolinska Institutet and Karolinska University Hospital in Stockholm, Sweden, and co-authors, highlight recent alarming increases in the number of patients with multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis, particularly in eastern Europe, Asia, and southern Africa. Treatment outcomes with available treatment regimens for drug-resistant tuberculosis are poor. Although substantial progress in drug development for tuberculosis has been made, scientific progress towards development of interventions for prevention and improvement of drug treatment outcomes have lagged behind. Innovative interventions are therefore needed to combat the growing pandemic of multidrug-resistant and extensively drug-resistant tuberculosis. Novel adjunct treatments are needed to accomplish improved cure rates for multidrug-resistant and extensively drug-resistant tuberculosis. A novel, safe, widely applicable, and more effective vaccine against tuberculosis is also desperately sought to achieve disease control. The quest to develop a universally protective vaccine for tuberculosis continues. So far, research and development of tuberculosis vaccines has resulted in almost 20 candidates at different stages of the clinical trial pipeline. Host-directed therapies are now being developed to refocus the anti-Mycobacterium tuberculosis-directed immune responses towards the host; a strategy that could be especially beneficial for patients with multidrug-resistant tuberculosis or extensively drug-resistant tuberculosis. As we are running short of canonical tuberculosis drugs, more attention should be given to host-directed preventive and therapeutic intervention measures.
In this Comment, Professor Markus Maeurer, from Karolinska Institutet in Stockholm, Sweden, and co-authors highlight the challenges presented by totally-drug-resistant tuberculosis: "The term totally-drug-resistant (TDR) tuberculosis has generated media hype but also important academic debate… Evidence-based, biologically, and clinically sound solutions combined with preventive measures such as food provision, reduction of poverty, improvement in living standards, host-directed therapies, and new effective vaccines for tuberculosis are required to provide renewed hope to banish the spectre of TDR tuberculosis."
In this Comment, Dr Ben Marais, from Sydney Medical School, Australia, and co-authors, highlight the challenges of treating childhood tuberculosis. According to the authors, "Historically, children were excluded from programmes for tuberculosis control that focused exclusively on the identification and treatment of infectious adult cases. Tuberculosis was included in the sixth Millennium Development Goal (MDG). This goal focused on major global epidemics, which reinforced the emphasis on epidemic control with little appreciation of the importance of tuberculosis in the context of child survival. This situation is changing [but] the rise of drug-resistant tuberculosis confronts traditional control efforts with the uncomfortable dilemma of personalised (contextualised) versus programmatic (one size fits all) management, and the involvement of children emphasises the need for greater cooperation and integration of tuberculosis and child health services. Improved integration and optimal-care delivery models pose a public health challenge globally, but urgent progress is needed to benefit children in tuberculosis-endemic areas."
Andrea DeLuca, from Johns Hopkins University, Baltimore, USA, and co-authors, outline in this Comment the changing role of advocacy in tuberculosis: "Tuberculosis advocacy has recently increased at a rapid pace and achieved successful outcomes; this trend must continue to reach global targets for tuberculosis elimination. At present, only a few trial sponsors engage communities in research; concrete and systemic engagement with communities is therefore needed from all tuberculosis scientists at each step of the research and development process, particularly in the pretrial and post-trial phases…An environment in which tuberculosis survivors and advocates can affect research and ensure access to lifesaving technologies needs respect for the independence, autonomy, and professionalism of activists, and the end of persistent stigma about the disease."
Professor Markus Maeurer, from Karolinska Institutet in Stockholm, Sweden, and co-authors describe "a new wave of unwarranted pessimism" about the continued global impact of tuberculosis "that needs to be replaced with optimism…Increases in funder, political, and scientific investments over the past 5 years have led to advances in development of an expanded portfolio of new tuberculosis vaccines, diagnostics, and drugs…[though] The focus on research for new tuberculosis instruments should not divert stakeholders from tackling the socioeconomic causes and drivers of the tuberculosis epidemic."
"People with diabetes are three times more likely to develop active tuberculosis than people without diabetes, and there are now more tuberculosis patients with concomitant diabetes than with HIV coinfection," say Reinout van Crevel, and Hazel Dockrell, writing for the TANDEM Consortium, which aims to unravel the causal relationship between tuberculosis and diabetes, in order to design more effective strategies for control of both diseases. Van Crevel and Dockrell outline some of TANDEM's different research strategies and priorities, concluding that, "TANDEM strives to develop methods for better screening and management of combined tuberculosis and diabetes, and to increase basic knowledge about the link between the two diseases."
Researchers from Brigham and Women's Hospital (BWH) and Harvard Medical School (HMS) in Boston have estimated that around one million children have tuberculosis annually—twice the number previously thought to have tuberculosis and three times the number that are diagnosed every year. The researchers also estimated that around 32,000 children have multidrug-resistant tuberculosis annually.
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