Declared a global health emergency by WHO 20 years ago, TB remains a leading cause of death by infectious disease worldwide. The growing threat of drug-resistant TB – both multidrug resistant TB (MDR), which is resistant to treatment with at least isoniazid and rifampin, the two most potent TB drugs, and extensively drug resistant TB (XDR), which is resistant to an even wider range of drugs – means that without concerted action from political leaders, health policy makers, funders, and others, health systems worldwide are at risk being overwhelmed by increasing numbers of patients with treatment-resistant TB.
In Drug-resistant tuberculosis: time for visionary political leadership (Series 5), the authors warn that the emergence of XDR TB in the last 8 years heralds the possibility of virtually untreatable TB, and without visionary political leadership and a radical shift in policymakers' perceptions of TB, global efforts to control TB will be threatened.
According to the authors, "For many decades, the response to global tuberculosis by governments in both wealthy and disease-endemic countries has been complacent and politically neglectful. A major conceptual change and visionary global leadership are needed to move away from the conventional view that tuberculosis is only a disease of poor nations."
"The widespread emergence of XDR tuberculosis could lead to virtually untreatable tuberculosis. With ease of international travel, and increased rates of MDR tuberculosis in eastern Europe, central Asia, and elsewhere, the threat and range of the spread of untreatable tuberculosis is very real," say the authors.
"To prevent further cases of MDR and XDR tuberculosis, a radical change in political and scientific thinking, and the implementation of specific measures worldwide are needed. The global economic crisis and reduced investments in health services threaten national tuberculosis programmes and the gains made in global tuberculosis control. The world needs to acknowledge the serious threat of drug-resistant tuberculosis, before it overwhelms health systems."
In some parts of eastern Europe and central Asia, more than 30% of newly-diagnosed TB patients have MDR TB, and the number of cases of MDR tuberculosis in the UK nearly tripled in the first decade of the millennium (from 28 cases in 2000 to 81 in 2011), with an increase of 26% in 2011 alone. While the number of UK cases of XDR tuberculosis remain small, 2011 saw the highest number yet (6 cases).
To eliminate TB as a public health problem by 2050, incidence will need to fall by an average of 16% per year for the next 40 years. Rates are currently declining at 2% per year, and despite major efforts to increase case detection, an estimated third of new TB cases are being missed each year. According to WHO estimates, 8.7 million people became ill with TB in 2011, and there were 1.4 million deaths from TB in the same year. 310 000 new cases of MDR TB are thought to have arisen in 2011, 9% of which were XDR.
Although new drugs are being developed to treat TB, they will not reach their potential – and may even accelerate the proliferation of drug-resistant TB – if advances in drug susceptibility testing (DST) do not keep pace with the development of new drugs, researchers write in the paper Alignment of new tuberculosis drug regimens and drug susceptibility testing: a framework for action (Series 4). Drug susceptibility testing involves identifying whether the TB strain infecting a patient is likely to be resistant to existing drug treatments, and means that treatment can take place more efficiently, at lower cost, and at least risk of contributing to drug resistance.
Whereas a number of drug regimens for treating TB are currently available – and more are to be expected soon – carefully planned and targeted drug susceptibility testing will be essential if rising drug resistance is to be curbed. Fewer than a third (63 out of 194) of WHO member states currently have TB surveillance systems that routinely use DST, and although DST would be too costly to implement universally, the authors suggest cost-effective ways in which it could be used in resource-limited settings, such as being used only when resistance to a given drug rises above a specific threshold. A further barrier to more widespread adoption of DST is an investment shortfall in the assays used to test for drug susceptibility, which are perceived to have little commercial opportunity and therefore remain under-researched, while companies pursue more lucrative opportunities.
According to the authors, "Further improvement [in controlling TB] is restricted by outdated and inadequate methods used to fight the epidemic: a vaccine with limited effectiveness; a drug regimen that is long and that places substantial demands on patients and health-care systems; and a diagnostic technique (smear microscopy) that detects only half of all cases and does not assess drug resistance of the infecting Mycobacterium tuberculosis strain."
TB a "barometer of poverty and deprivation" and cannot be controlled by medicine alone
Non-communicable diseases interact adversely with tuberculosis by increasing both individual vulnerability to disease and the likelihood that the epidemic will be sustained within a population. Links between TB and non-communicable diseases (NCDs) such as diabetes, smoking, and cancer have been established for some time, but as countries with a high burden of TB now begin to face unprecedented increases in the burden of NCDs, the integration and delivery of health services will need to undergo a radical shift if these colliding epidemics are to be adequately addressed, say the authors of the paper Tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts (Series 3).
Historically, the treatment and control of communicable and non-communicable diseases have had little in common. However, although TB is a communicable disease, the authors point out that the management of an episode of TB has more in common with non-communicable diseases. Public health policy makers in countries with a high TB burden will need to implement innovative joint health promotion strategies, reciprocal screening, and coordinated management programmes to effectively counter the effect of a rising tide of NCDs in areas where TB already exerts an undue strain on the health system.
However, even if health care strategies to deal with NCDs and TB can be effectively integrated, traditional biomedical approaches to curing TB are likely to have only "limited effect", state the authors. An increased focus on the social determinants of health – the fact that poorer, less empowered, and lower status communities tend to suffer from a higher burden of disease – will be necessary if TB is to be effectively controlled. "Tuberculosis provides a barometer of poverty and deprivation, since its incidence is driven by socioeconomic factors, poor access to and delivery of health services, inconsistent treatment practices, HIV, and migration from countries that are highly endemic for tuberculosis." Research has indicated that nearly 50% of a variation in levels of TB infection is accounted for by a nation's wealth and level of egalitarianism.
In Engaging communities in tuberculosis research (Series 6), the authors emphasise the critical importance of engaging communities in TB research, an area that has received little research attention and where the authors say that "a clear account and shared understanding of how these community engagement mechanisms work is still missing".
"The tuberculosis epidemic is fuelled by economic instability, poverty, migration, discrimination, stigma, social marginalisation, inadequate access to health and social services, and lack of political voice. Understanding how these factors operate at individual trial sites is essential to ensure that they are not inadvertently exacerbated by the trial, and that they do not threaten the successful completion of the trial…The key challenge is to overcome scepticism about the value of community engagement in research and about whether community engagement should rightfully receive a proportion of tuberculosis trial budgets…funders and sponsors need to better recognise that the ultimate public health effects of new drugs and vaccines will be determined by social as well as biological factors."
Funding for TB diagnostics "not a level playing field"
A recent development in TB diagnosis has been the emergence of the Xpert MTB/RIF assay, which uses technology originally developed by the US postal service to detect anthrax in sorting offices, to rapidly screen for characteristic DNA sequences in different strains of TB bacteria, enabling it to identify TB infection with around 95% reliability. While the Xpert assay represents a huge step forward in TB diagnosis – among other advantages, it is substantially more accurate, quick, and simpler than traditional sputum smear microscopy – the authors of the paper Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test (Series 1) stress that the Xpert assay is still not the ideal TB testing system, and research efforts to develop cheaper, more accurate tests that could be used in the community need to be developed.
The limited implementation of Xpert MTB / RIF in resource-limited settings thus far has been heavily financially subsidised, and the authors express concern that this reliance on donor assistance may adversely affect the development and entry of new diagnostic tests for TB. According to the authors,
"Commercially, funding is not a level playing field…Furthermore, the prospect of the emergence of cheaper rapid tests more applicable at the periphery (community level) poses an interesting dilemma as to whether investment should be made in current more costly technology, or whether it might be better to wait for the next generation of tests to become available."
One of the reasons why TB diagnosis can be so challenging is that although up to a third of the population are estimated to be infected with M tuberculosis, only a small proportion of those infected become ill. Clinical diagnosis and cure of the disease can take months, and so reliable biomarkers – characteristic features of M tuberculosis infection that could be used to determine whether a patient is likely to fall ill (or whether they are likely to get better) – would have enormous implications in the ongoing fight against TB. Although a reliable biomarker for TB disease has yet to be found, in the paper Tuberculosis biomarkers discovery: developments, needs, and challenges (Series 2), the authors describe current promising lines of research in this area. Major efforts are underway to establish a global biobank of TB samples, which would greatly facilitate the search for TB biomarkers, although the authors warn that further investment in this area of TB research is sorely needed, describing insufficient funding, not lack of scientific knowledge, as being the "main barrier" to developing useful biomarkers.
The Series is published ahead of the UCL World TB Day Meeting, to be held at UCL's Royal Free Campus, London, UK on Monday 25 March 2013. The theme of the meeting is Targeting zero deaths from TB: progress, reality and hope; for further information and meeting registration, please see http://uclworldtbday.eventbrite.com/.
Journal
The Lancet