Fighting tuberculosis should be priority, Fauci says

Dr. Anthony Fauci wrote this commentary, posted Nov. 17, for He is director of the National Institute of Allergy and Infectious Diseases in Bethesda, Md. An immunologist and HIV/AIDS researcher, Fauci advises the White House and Department of Health and Human Services on global AIDS issues, and on initiatives to bolster medical and public health preparedness against emerging infectious disease threats such as pandemic influenza.

Tuberculosis is one of the world's leading killers. Every year at least 9 million people are infected with TB, with almost 2 million deaths, according to estimates from the World Health Organization. Yet few citizens, scientists and policymakers are demanding more attention to TB research, treatment and prevention.

It's time to bring TB research into the 21st century. For the past 60 years we have treated tuberculosis patients with essentially the same therapeutic regimens. The only licensed vaccine against TB, the BCG vaccine, is more than 100 years old and does not prevent adult pulmonary (lung) TB, the most common and infectious form of the disease. Diagnostics for TB are antiquated, non-standardized, and imprecise.

No new classes of TB drugs have been licensed for decades and treatment regimens are cumbersome, lengthy and frequently lead to the emergence of drug-resistant forms of TB. Although a few new TB medicines have been developed, they have resulted in only incremental changes in TB therapy.

Where is the outrage over such meager progress?

One third of the world's population is thought to be infected with Mycobacterium tuberculosis, the microbe that causes TB. In 2007, 9.3 million people -- including 1.4 million HIV-infected individuals -- developed TB and 1.75 million people died, according to WHO. Multidrug resistant (MDR) and extensively drug resistant (XDR) forms of TB have emerged and threaten to undermine TB control efforts in both developed and developing nations.

Using HIV research as the model

When HIV/AIDS was first recognized in the United States in 1981, the response among members of the affected community was immediate and palpable. This was a new, mysterious disease and patients, friends and families were understandably frightened. This initial fear soon changed to anger and outrage as AIDS activists organized, expanded and held the government's feet to the fire, demanding the investment of resources necessary to address this rapidly expanding public health crisis. Even though it soon became apparent that the HIV/AIDS pandemic was disproportionately affecting low- and mid-income countries, people in the United States and other rich countries perceived AIDS as an immediate threat to them, and responded forcefully.

Partly, as a result of this early and extremely effective activism and the investment of substantial resources in biomedical research, more than 30 anti-HIV drugs were developed in less than three decades. There are now more drugs licensed against HIV than all other viral diseases combined. Although these anti-HIV drugs are not a cure, HIV infection is no longer the near-certain death sentence it once was, and patients with access to these drugs can expect to live long and productive lives.

In contrast to the relatively short history of HIV/AIDS, tuberculosis has been a scourge of mankind for thousands of years. Despite the massive human toll, we do not have dozens of new drugs for TB, the way we do for HIV/AIDS.

Fortunately, the disease has begun to garner considerable public attention, due in part to the high incidence of TB in HIV-infected individuals. These patients are benefiting from well-funded global HIV treatment, prevention and care programs, and the emergence and spread of drug-resistant forms of the disease. Alarm over the emergence of drug-resistant strains of TB throughout the world has heightened global awareness of the threat and has resulted in an increase in investment from biomedical researchers, pharmaceutical companies and public health officials.

We are beginning to see the winds of change, but what we really need is a storm. It is imperative that we transform the way we diagnose, treat, prevent, and control TB -- through biomedical research and public health measures -- to the same extent that we have done and will continue to do with HIV/AIDS.

Advances in TB research and treatment have come incrementally by trial and error. The current TB regimen was developed through tedious, repetitive clinical trials, in which new drugs were added to an already complex cocktail of existing drugs or substituted for individual drugs in the treatment regimen to provide the best-tolerated, shortest regimen to cure the disease.

Difficult treatment regimen

Currently, the treatment regimen is difficult for most people to maintain. Based on universal recommendations that guide therapy across the world, TB patients must take up to four drugs daily for six to nine months. We need to expand the pipeline of new drugs to create regimens that could be used to treat different populations of people with varying needs, ideally with much shorter durations of treatment and with drugs that are equally effective against drug-resistant and drug-sensitive TB.

We also need accurate, inexpensive, "point-of-care" diagnostic tests for TB that can be easily used by health workers, even in remote settings. Making the correct diagnosis quickly can inform health care workers whether the patient is infected with a drug-sensitive or resistant strain of M. tuberculosis so that the appropriate drugs can be administered.

A vaccine to prevent adult pulmonary TB is an urgent priority. To develop such a vaccine, we need to better understand at the basic scientific level how the human host defends itself against the TB microbe in the natural course of infection.

Most important, in order to develop better TB drugs, diagnosis and vaccines, we also need to understand TB as a disease of the whole organism -- the patient. We need to better understand the delicate balance between the host and pathogen in the context of the entire biological system. For example, M. tuberculosis remains latent in about 90 percent of people who are infected; only 10 percent of these will develop active disease in their lifetime (for persons also infected with HIV, the likelihood of developing active disease increases dramatically). Latency is unlikely an "on or off" mechanism but rather a spectrum of conditions.

Can we identify those people at the more vulnerable end of the spectrum and treat them before they develop active disease?

We also must realize that TB rarely manifests itself in a patient with no other infections or chronic diseases. In the "real world," TB affects patients who are malnourished, who have other diseases such as malaria and other parasitic infections, hepatitis, or HIV, or who suffer from chronic conditions such as diabetes or heart disease. We need to evaluate treatment options in patients afflicted with such "co-morbidities" that are the rule, not the exception.

Finally, in order to bring the many drugs, diagnostics and vaccines that are now being developed to the bedside, we need a more effective and informative system for testing these products. Many new experimental TB drugs have emerged over the past decade and are entering clinical trials, but these cannot be properly evaluated without well-designed and well-implemented clinical studies similar to those that have been carried out in the development of treatments for HIV/AIDS.

The field of TB research has suffered enormous neglect over the past several decades and the consequences have been striking. Generations of research advances and technologies have largely bypassed the field of TB research, particularly in the arena of pharmacology and product development. It is time to transform the field of TB research and begin to apply new technologies using a comprehensive approach.

The U.S. government and National Institutes of Health in particular have been longtime supporters of TB research. Other organizations, such as the Bill and Melinda Gates Foundation, have stepped up to the plate with enthusiasm. But we have much catching up to do, and the TB research effort will require a sustained and long-term commitment from government, academia, industry and philanthropy.

As we move forward, applying new technologies and coordinating multiple efforts, it is critical to question the usual assumptions that have driven the field of TB research, and think in new and innovative ways, employing all the modern tools of biomedical research. Only by doing so, can we develop the transforming innovations that are needed to end the global TB pandemic.

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