SLU-led project receives NIH funding for clinical trial on potential treatment for MDR-TB

Saint Louis University is leading a multi-national clinical trial of what could become a regimen for drug resistant tuberculosis (TB) that does not require injectable medications. The project is funded by a $6.4 million task order from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).

Daniel Hoft, M.D., Ph.D., director of Saint Louis University's Division of Infectious Diseases, Allergy & Immunology, is the principal investigator for the trial.

The research grew out of the NIH's commitment to finding new treatments for infections that no longer respond to commonly prescribed antibiotics and can turn deadly, a worsening problem that poses a critical public health risk.

TB causes more deaths world-wide than any other infectious disease, including HIV. One quarter of the world's population is thought to be infected with the bacterium that causes TB and more than 10 million people develop TB each year, resulting in close to 2 million deaths annually.

TB can become resistant to drugs such that none of the available first-line therapies can kill the bacteria. This can occur when patients don't take all of their TB drugs, get the wrong dose, take them irregularly or have medicines of poor quality.

A form of TB known as multi-drug resistant (MDR)-TB is a growing health threat, with about one half million persons diagnosed with this form. Health officials believe the problem could be significantly larger and estimate 80 percent of those who have MDR-TB are not diagnosed and treated. They unknowingly spread their infection to others before it usually kills them. In addition, as MDR-TB becomes increasingly unresponsive to medicines, patients have fewer and fewer treatment options.

Currently, patients with MDR-TB typically take five to seven drugs for up to 24 months, coupled with an injected aminoglycoside antibiotic, for six months. This combination, particularly because of the antibiotics that need to be injected, is very painful and can cause hearing loss and kidney problems that make it difficult for the patients to complete treatment.

Furthermore, since injections have to be provided by trained medical professionals, patients have to be seen in skilled health care facilities that are often not available in resource limited countries where drug resistant TB is a problem.

Although relatively uncommon in the United States, the problem of MDR-TB may worsen in America as residents travel to countries where the infection is present and bring it home, Hoft predicts.

"We already have had MDR-TB in the U.S., and if we don't pay attention to it, the problem will get a lot worse," Hoft says.

Therapy for MDR-TB in the U.S. can be grueling, disruptive and costly. While treatment of drug sensitive TB costs about $18,000, MDR-TB can cost more than $494,000, according to the CDC.

"If the oral regimen we are studying works, it could be a game changer for treating drug-resistant TB, especially in developing countries," Hoft said. "Ultimately, we need new treatments for drug-resistant TB that are shorter, safer and better tolerated by patients, and specifically do not require daily injections."

Saint Louis University, a member of NIAID's network of Vaccine and Treatment Evaluation Units (VTEUs), is partnering with Aurum Institute in Johannesburg, South Africa, the University of Maryland VTEU and Makerere University in Kampala, Uganda, for the phase 4 clinical trial.

Study participants will be recruited in South Africa and Uganda, where MDR-TB is prevalent and clinical data will be analyzed by Saint Louis University and University of Maryland. Researchers will study two groups of volunteers -- those who receive the standard therapy for MDR-TB and those who receive a regimen that substitutes an oral medication named delamanid for the shot. In both groups, the efficacy and safety of the tested medications will be analyzed.

Delamanid was recently approved by the FDA to add to the therapy of MDR-TB in patients who have no other treatment options. It works by a different mechanism than other currently used drugs, which could help solve the problem of drug-resistance by attacking the TB bacterium on a different front.

"If we can replace the injectable antibiotics with an oral drug with similar or better safety and efficacy, it will transform the field, likely increasing treatment completion rates and reducing the likelihood of further drug resistance developing," Hoft says.