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Tuberculosis and its future management
1. John C Moore-Gillon
1. Dr John C Moore-Gillon, Department of Respiratory Medicine, St Bartholomew’s and Royal London Hospitals, London EC1A 7BE, UK; john.moore-gillon{at}bartsandthelondon.nhs.uk

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Will we do better in the next 25 years?

Twenty-five years ago, most writers on tuberculosis (TB) would, if asked to predict what the position would be by 2007, have anticipated better diagnostics, safer drugs, shorter treatment times, a better vaccine, the near eradication of TB in the developed world and falling rates in the developing world. Some perceptive individuals were sounding the warning bells, but most pundits would have been profoundly wrong. They would have been closest to the mark if they had simply summed up their prediction of the position 25 years later, in 2007, as “Much the same, really—except where it’s much worse.”

Predictions about TB are particularly fraught with difficulty because the impact of factors beyond the control of clinicians, researchers and the pharmaceutical industry is far greater with TB than it is in diseases like asthma, chronic obstructive pulmonary disease and lung cancer. These views on TB and its future management are therefore contingent upon three assumptions—all, some or none of which may come to pass: a modest increase in overall global prosperity, wars and political instability being at least no worse than they are at present, and the development of a reasonably effective AIDS vaccine. We can be completely confident of only one thing: 25 years from now, the December 2032 issue of Thorax (whether on paper or not) will reproduce these December 2007 editorials with a commentary on the extent to which I (and my co-authors) got it wrong.

The Stop TB partnership, coordinated by the World Health Organisation, has set out the actions—and the funds—needed for TB control.1 Targets include the halving, by 2015, of TB prevalence and deaths compared with 1990 levels, and the elimination of TB as a global public health problem by 2050. Progress in vaccines, diagnostics and drugs is needed, but so is “advocacy, communications and social mobilisation” to ensure that an appropriate political and social—as well as medical—infrastructure is in place. There are clear milestones: a new TB drug (the first for 40 years) by 2010, a new and effective vaccine by 2015 and a 1–2 month duration treatment regimen soon after. But achieving these will cost big money—US$56 billion—and that is US$31 billion more than the funds currently identified. At last, though, there are signs that industry, the academic world and philanthropy are coming together, to varying degrees, in bodies like the Aeras Global TB Vaccine Foundation, the Global Alliance for TB Drug Development (the TB Alliance) and the Foundation for Innovative New Diagnostics (FIND). Backed up with money direct from the Gates Foundation (a name which keeps recurring in the TB field) and governments (including the USA, UK, Netherlands and the European Union), TB research and development is moving ahead.

Apart from the efforts of a few dedicated research groups, vaccine development had languished in the wilderness since BCG was introduced 80 years ago. BCG has at very best 80% efficacy—far less than this in many parts of the world—and there are some concerns about its use with the rising prevalence of HIV/AIDS. Approaches to vaccine development can use BCG as the starting point to produce modified recombinant BCG strains with higher immunogenicity, or may use Mycobacterium tuberculosis itself to develop knock-out mutants with the antigenic profile of TB but without (the researcher hopes) its pathogenicity. A further alternative is to use subunit vaccines containing antigens which confer additional protection by boosting the response occurring after priming by conventional BCG.2 Up to six vaccine candidates will enter phase I trials in 2007, one should enter phase II in 2008, and phase III trials may begin as early as 2010.

Constrained by resources, TB control programmes in resource-poor countries understandably must concentrate on detecting active pulmonary disease that is infectious to others. Sadly, politicians (and the newspapers) in some wealthier countries seem to believe that mass chest x rays would eradicate TB. The problem is that about one-third of the global population is already infected with TB, each with the potential for developing active disease. Intervention with chemoprophylaxis reduces that risk, but identification of those with latent TB infection using the tuberculin skin test is unreliable, particularly in BCG-vaccinated populations. More secure identification of those with latent TB infection using blood tests based on gamma-interferon release from TB-sensitised lymphocytes may help,3 and there will no doubt be further developments in this field. But might vaccines have a part to play here as well? Experience with other infectious diseases conditions us to think solely in terms of pre-exposure vaccines, but with TB a possible approach could be post-exposure vaccination aimed—like chemoprophylaxis—at reducing the risk of later progression to active disease.2 Certainly, mathematical modelling backs up what seems intuitively likely: that control of TB will not be achieved simply by treating cases of active disease.4 Finding and treating active infectious cases as quickly as possible is vital, but this “firefighting” approach will not eradicate TB.

Trials of fluoroquinolones in reducing the duration of TB therapy are under way, but really major steps forward will probably only occur with new classes of drugs, not discovered serendipitously but developed in a targeted way, driven by a deeper understanding of the molecular structure and cellular metabolism of the TB bacterium.5 6 In particular, we must unravel the mechanisms which enable TB to remain viable for long periods in an actual or near non-replicative state, and to largely camouflage its presence from the host’s immune system while it does so. Nitroimidazole derivatives are beginning to show promise in dealing with these dormant organisms, and developments in this area are crucial to reducing overall treatment times for TB. A very promising diarylquinoline7 with early and late bactericidal activity, no cross-resistance with existing TB drugs and activity against multidrug-resistant (MDR) TB is moving towards clinical trials. We must hope that, at last, wholly new drugs for TB really are on the horizon.

In terms of diagnosing active disease, problems with the sensitivity of nucleic acid assays when applied to primary specimens mean they have not been the hoped-for breakthrough in terms of timing, and they remain relatively expensive and demanding technically. There have, though, been drops in culture times, and there are developments in rapid identification of organisms using techniques that may be applicable in relatively resource-poor settings.8 9 Will we achieve the goal, predicted for decades but so far elusive, of a serodiagnostic method for active disease that is both highly sensitive and highly specific? Some innovative approaches may lead us in the right direction.10

A few years ago a conference on MDR TB at the Royal Society of Medicine in London was subtitled “From molecules to macroeconomics”. The future management of TB will depend on developments in both of these areas and at every level in between. At a strategic national and international level there are perhaps grounds for (very) cautious optimism which were not present even 5 years ago. Progress in vaccine development, improved diagnosis of latent TB infection and faster identification of active disease, the prospect of strengthened national TB programmes and the emergence of global goals backed up by expressions of political will (and a little money) are encouraging signs. They might achieve little, though, without an AIDS vaccine and the widespread availability of antiretroviral drugs, but HIV/AIDS programmes and TB programmes must work together and not divert funding away from each other.11 Further, extensively drug-resistant (XDR) TB is a very serious worry indeed, and could well sweep aside the slightly encouraging developments outlined above.1215

At the level of the individual patient, and specifically in resource-rich countries, there will be a powerful drive towards management of each case on a multidisciplinary basis, as with cancer.16 Indeed, given that (unlike cancer) the physical health and even the mortality of other people depend on the effective management of the initial patient, the case for wide professional involvement is a very strong one. Reliable identification of latent TB infection will be accompanied by a personalised assessment of the risk of progression to disease. Strain typing will improve techniques of contact tracing/active case finding, but probably only after a few years chasing red herrings, when molecular studies imply a clustering of cases where in fact there is no recent association. There will be yet faster diagnosis and drug susceptibility testing of active disease, and treatment regimens really will be shorter and less potentially toxic. I’m less optimistic about stigma. Twenty years ago, HIV/AIDS could reasonably be regarded as “the new leprosy” in terms of the public reaction to those with the condition. TB has now moved into that role and, unlike HIV/AIDS, it has too few articulate, high profile and powerful sufferers to alter public perceptions. If we are to do better in the next 25 years than we have done in the last 25, there must be social and political changes, not just scientific ones.17

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## Footnotes

• Competing interests: None.

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