As part of an international organization with the goal to rid the world of the scourge of tuberculosis, Vanderbilt University Medical Center recently nabbed a $7 million grant to continue its investigations into more effective TB treatments.

 

According to the U.S. Centers for Disease Control and Prevention, TB is one of the world's deadliest diseases. Every year more than 9 million people develop the active disease, and nearly 2 million of them die. What's more, 2 billion people —one-third of the world's population — are latently infected with the bacterium but exhibit no symptoms.

 

"Most people who are infected do not progress to active disease, but there are high-risk groups that do, including those who have recently become infected and those who are immuno-compromised because of conditions such as HIV or renal failure or diabetes," explained Timothy R. Sterling, MD, professor in Vanderbilt's Division of Infectious Disease.

 

Sterling is principal investigator for the Vanderbilt site of the Tuberculosis Trials Consortium. The CDC funds the 28-site consortium, which began with just seven sites in 1993. Vanderbilt joined the initiative in 1996. Sterling said the $7 million grant will be received in installments during the next 10 years, with $510,000 on its way next year. The grant enables Vanderbilt to expand collaborations with the Metro Public Health Department, Meharry Medical College, Metro General Hospital and the Tennessee Department of Public Health. Vanderbilt is also collaborating with the Universidad Peruana Cayetano Heredia in Lima, Peru. All work to enroll both actively infected and latent patients for studies.

 

The aim is two-fold: to shorten the duration of TB treatment for people with active disease — who can spread it to others — and to shorten treatment for latent patients.

 

"We traditionally think of the active disease, people who are ill with TB, and the current duration of treatment is six-to-nine months. Because of that, the completion rates are not as high as they should be," Sterling said. "That may also contribute to development of drug resistance, just because people don't take the full course of therapy or all of the medications for the full course of therapy."

 

Drug-resistant TB falls into three categories of increasing severity. Bacteria might be resistant to just one medication, or the TB might be multi-drug resistant. That means it's resistant to at least two of the best anti-TB drugs, isoniazid and rafampicin, considered by the CDC to be the first line of defense used to treat all TB-infected people.

 

Fortunately, the third drug-resistant TB bacterium is relatively rare. Dubbed extensively drug-resistant, this strain of bacteria is resistant to isoniazid and rafampicin and is also resistant to any fluoroquinolone and at least one of three injectable second-line drugs: amikacin, kanamycin or capreomycin. Because extensively drug-resistant TB is resistant to first-line and second-line drugs, treatment options for patients infected with this obdurate strain are much less effective … and the infection is much more serious.

 

If the course of treatment is shortened from six-to-nine months down to three-to-four months, Sterling said the hope is patients would stick with it to the end and effectively kill the bacteria, thus resulting in fewer relapses and less drug resistance across the board.

 

When it comes to latent infection, efforts are underway to prevent high-risk people from developing active disease. "The TB Trials Consortium has been conducting a study over the last several years, evaluating a short-course regimen for treatment of latent infection," Sterling explained. "The current duration of therapy is nine months, and that's with isoniazid, and we are evaluating a three-month regimen of once weekly INH (isoniazid) and rafampicin."

 

It is estimated in the United States that about 10 million people have latent infection, including people who may have been infected many years ago. Sterling said most TB in America is among people born outside of the country or who have traveled to high-incidence areas. Most TB is in developing countries; India and China have the largest number of cases each year, but highest rates of TB are in sub-Saharan Africa.

 

"In the United States, and particularly in Tennessee, medication is given by directly observed therapy. So the Health Department administers the medications, and this helps to ensure that people do take all of the medication and complete their therapy," Sterling said. "But in the developing world, the countries don't have the resources to provide healthcare personnel who administer medications to everyone who has tuberculosis. That's where it gets a little more difficult."

 

Adding to the challenge is that a new anti-TB drug hasn't been introduced in more than 40 years. Yet, there are several drugs under evaluation now. "So this is an exciting time in TB research," Sterling said, "and we hope we'll be able to come up with a combination of medications that would allow for a shortening of the TB-treatment duration."