Tuberculosis: Modernizing the Fight Against an Ancient Scourge

March 24 marks the anniversary of the discovery in 1882 by German microbiologist Robert Koch of the bacterium that causes tuberculosis (TB). With that knowledge in hand, one might expect that by now we would have the disease under control. Tragically, this is not the case. In 2013, thousands of years after the first human cases of TB were recorded and more than a century after Koch isolated the rod-shaped microbe that causes TB, this disease remains entrenched in many countries around the world.

TB bacteria are now thought to infect 1 out of every 3 people worldwide -- more than 2 billion in all . Although most of those individuals do not become sick, the World Health Organization (WHO) estimates that in 2011, approximately 8.7 million people fell ill with TB, and 1.4 million people died from the disease. The overwhelming majority of cases and deaths are among poor and vulnerable people living in low- and middle-income countries.

How did we get to this point? By the 1970s, annual TB cases had fallen sharply in the developed world, beginning two decades earlier after the introduction of effective antibiotics: first streptomycin, then isoniazid, and later rifampin and other medications. Unfortunately, that success in wealthier countries produced a false sense of security that TB was under control. The ensuing complacency proved devastating for developing countries. There, antibiotics were not as accessible, and TB continued to fester and spread, little noticed by the developed world.

Then in the 1980s HIV/AIDS emerged, and TB re-emerged along with it as an AIDS-related opportunistic infection, sounding the alarm that TB was not beaten. In the United States, for example, TB cases swelled in New York City in the late 1980s, and the evolution of drug-resistant TB strains increased insidiously. Concerted action by public health officials, at a cost of approximately $1 billion , eventually brought the New York City TB epidemic under control.

Globally, however, the emergence of HIV/AIDS in developing countries where TB was already endemic set up a perfect storm. HIV/AIDS came to be recognized not only as a problem in global health but also as a threat to economic stability worldwide. Subsequently, new international health programs such as the President's Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis, and Malaria, helped to reveal more clearly the health challenges in the developing world. In particular, they showed us the deadly synergy between HIV/AIDS and TB (1 in 4 HIV-related deaths is caused by TB), as well as the increasing problem of TB drug resistance. Together, these factors demonstrated the urgent need for a transformative approach to TB research -- to rein in TB was reason enough, but it would also help turn around the HIV/AIDS pandemic.

Fortunately, a renewed push to fight back against TB, while slow to come, is now occurring. Dedicated scientists and health care workers -- including scientific leaders in sub-Saharan Africa, Asia, and other hard-hit regions -- are collaborating with governments, health care organizations, advocacy groups, and philanthropists in focused and strategic ways to gain the upper hand against this ancient scourge. As a result of aggressive TB control programs, 51 million people with TB were successfully treated and 20 million lives were saved between 1995 and 2011, according to the WHO . New cases of TB have been falling steadily since 2006, and in 2011, they declined by 2.2 percent .

Yet, we still have a long road ahead. In the United States, where the problem of TB is relatively modest, officials remain on guard to keep TB cases contained. To get a real feel for the burden of endemic TB, you need to travel to sub-Saharan Africa. There, the difficulty of managing the coexisting pandemics of HIV and TB is obvious. For example, the interaction between drugs used to treat TB and those used to treat HIV are complex and makes treating both diseases simultaneously difficult. In addition, active TB enhances HIV replication in the body, and HIV weakens the body's defenses against TB. It is also apparent that the spread of multidrug resistant (MDR) as well as extensively drug resistant (XDR) TB is complicating our efforts to curtail the TB pandemic. The detection of MDR-TB cases is a slow process, and access to appropriate treatment is limited; and at last count, XDR TB has been identified in at least 84 countries.

Revitalized research efforts are slowly bearing fruit, however. Quick and accurate diagnosis is the key to effective treatment and control of TB. In this regard, in December 2010, the WHO endorsed the GeneXpert TB diagnostic. This new diagnostic test can detect active TB bacteria in sputum samples and the presence of drug resistance in two hours, much more quickly than the one month or longer required for standard sputum tests. By the end of 2012, according to the WHO, almost 1,000 GeneXpert instruments and nearly 2 million associated testing cartridges had been distributed at a reduced price in 77 countries. Although we still must do more to get the test widely used, and to bring down its cost, this point-of-care diagnostic has been welcomed by frontline health care workers.

In the area of TB treatment, current TB drug regimens are notoriously long in duration and complicated, and some drugs have severe side effects. Moreover, drug development lags behind the emergence of drug resistance. Encouragingly, however, the TB drug "pipeline" has more candidates than ever before and includes several new classes of drugs. Late last year, bedaquiline was the first new drug specifically developed for the treatment of TB that was approved by the Food and Drug Administration in nearly 40 years. It is designed to be used as a part of a combination treatment regimen for patients with MDR TB who do not respond to first-line regimens.

On the vaccine front, we were disappointed recently by the lack of efficacy seen in a clinical trial in Africa of a candidate vaccine known as MVA85A given to infants who had already received the licensed TB vaccine, BCG. Although the results were not as hoped, this was the first large-scale test of a new TB vaccine in more than 90 years, proving that such large studies are feasible. Moreover, scientists are carefully examining the trial data to learn how to improve TB vaccine design. A dozen or so other TB vaccines are currently in various stages of clinical testing. We have established momentum, and we look forward to the results of those vaccine trials.

Despite this valid reason for optimism, we still are faced with the challenge of overcoming decades of relative inertia in the arena of scientific pursuit. We face a lengthy war to be fought tenaciously on many fronts, and likely over many decades, as we move toward our goal of TB control and, ultimately, elimination.

To that end, it is crucial that we modernize the scientific and public health fight against TB. After centuries of inflicting suffering and death on the human race, TB remains a poorly-understood disease being fought with antiquated tools. We must continue to apply our most advanced technologies, such as an integrated, multidisciplinary approach, to better understand the biological and molecular-level interactions underpinning the disease, especially the dynamics that turn a quiescent latent infection into active disease. This increased understanding of TB disease in turn will help us to develop the up-to-date medical tools that patients deserve. We must improve our diagnostics, simplify our treatment regimens, and above all, develop effective vaccines to prevent pulmonary TB disease in children and adults. Equally important, we must make these interventions available to the countries and people who need them.

Progress is being realized, and the recent rapid deployment of a modern diagnostic test for TB and the gradual decline in TB cases and deaths are gratifying examples of this. In addition, we have built many extraordinarily strong and committed TB partnerships and collaborations, and this gives us hope that we will be able to sustain this fight over the long haul. Nonetheless, we must continue to work harder, faster, and smarter to advance the field toward the truly transformational approaches that are required to bring TB under control. Let this commemorative day remind us that we still have an enormous challenge ahead.

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