The Tuberculosis Front

BERLIN – This has been a good decade in the fight against tuberculosis. We are likely to achieve the United Nations Millennium Development Goal of cutting TB prevalence and mortality in half by 2015, from 1990 levels. At least a dozen new vaccines and drug candidates are in clinical trials, and the World Health Organization a new diagnostic test called the GeneXpert.

This progress is all the more important given the complacency that led to a complete standstill in research and development for new TB interventions toward the end of the twentieth century. The TB drugs currently in use were developed between 1950 and 1970. Indeed, the Bacille Calmette–Guérin (BCG) vaccine is almost 100 years old, while the most widely used diagnostic test, microscopic detection of bacilli in sputum, was developed 130 years ago.

No wonder that the efficacy of these tools has weakened. The current vaccine prevents severe TB in infants, but not the most prevalent pulmonary TB in all age groups. The microscopic test gives false results in nearly half of all cases.

We like to think of TB as a malady of the past. In fact, nine million people develop the active disease every year, and one in five will die. This places the tubercle bacillus second only to human immunodeficiency virus (HIV) on the list of top microbial killers.

One-third of the world’s population is infected with the causative agent, though only one in ten develops the active disease. The bad news is that infected individuals carry the agent with them for their entire lives. When one’s immune system weakens, the disease may erupt. With the emergence in the 1980’s of HIV, which compromises the immune system, TB reemerged, and is the number-one killer of HIV-infected individuals. Roughly 15 million people suffer from co-infection of HIV and Mycobacterium tuberculosis, the primary causative agent in most TB cases.

Moreover, the tubercle bacillus engages in trench warfare, gaining resistance to conventional antibiotics and canonical vaccination approaches, as well as delaying diagnosis and determination of drug sensitivity. Whereas pandemics appear suddenly, spread rapidly, and raise enormous fears of an impending threat, TB has been spreading slowly but consistently for tens of thousands of years, patiently waiting for new opportunities.

Treatment of TB requires a minimum of three drugs administered over at least six months. Compare this with antibiotic treatment of, say, a urogenital infection, which lasts a few weeks at most. As a result, compliance with TB drug treatment is particularly weak, paving the way for the emergence of multidrug-resistant (MDR) TB, which can no longer be treated by conventional therapeutic regimes. Some 50 million people are infected with tubercle bacilli that are MDR.

While treating MDR-TB remains possible, doing so is arduous, with a treatment time of roughly two years, using drugs that are neither as efficient nor as benign as canonical drugs – and at a cost that rises by a factor of 10-100. While this additional cost can be borne by health-care systems in the rich world, it is excessive for poor countries, implying no, or insufficient, treatment.

Moreover, in 85 countries, extensively drug-resistant (XDR) TB, which is virtually untreatable, has been diagnosed. Indeed, surgical resection of affected lungs has become the treatment of choice in many XDR-TB hotspots. Welcome back to the pre-antibiotic era!

So, the question is not whether we need novel drugs, vaccines, and diagnostics, but when they will become available. The new GeneXpert test diagnoses not only TB, but also, in the same step, MDR-TB, which means that it can rapidly direct adequate treatment and prevent infection of contacts – a true breakthrough. Unfortunately, the test is expensive and sophisticated, putting it out of reach for many poor countries.

A number of other drugs – some new and some repurposed – are currently in the last stage of clinical trials, and one new drug has been approved by US regulators for treatment of MDR-TB even before such trials have been completed. But the first potential vaccine to be tested for efficacy recently failed miserably. So, the good news of the last decade is just a glimmer of hope.

We still have a long way to go, and accelerated R&D to develop new drugs and vaccines can be achieved only with increased funding. Unfortunately, private-sector incentives for developing new TB interventions are too weak. New approaches, such as partnerships between public research institutions and private industry, are needed. While clinical trials of the most promising drugs and vaccines need to be pursued, we also need to go back to the drawing board and develop entirely new tactics.

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