The University of Texas Health Science Center at Tyler (UTHSCT) researcher Dr. Shashi Kant is proposing a pragmatic trial approach that could significantly shorten the therapy duration for patients with nontuberculous mycobacteria (NTM).
Kant is an associate professor of pulmonary immunology who has led a research team of scientists, clinicians and mathematicians working from all over the world to develop a new, effective, short-course treatment for NTM that could effectively shorten a two-year course of treatment to possibly six months or less.
Mycobacterium kansasii (M. kansasii), one of the NTM, causes chronic infection that resembles pulmonary tuberculosis and warrants public health attention. M. kansasii is classified as a rare disease by the U.S. Genetics and Rare Diseases Center.
“UTHSCT has led the way in nontuberculous mycobacterial research across the country,” said Julie Philley, MD, executive vice president for health affairs at UTHSCT. “Dr. Kant’s publication by a prestigious medical journal is further validation for his excellent work as it expands the wealth of knowledge on this rare disease and eventually may lead to further improvements in patient care.”
His research on the new short-course therapy and morphism mapping for M. kansasii pulmonary disease has been recently accepted for peer-reviewed publication in the journal Antimicrobial Agents and Chemotherapy, published by the American Society for Microbiology.
Kant’s work in progress has served as a basis of research grants from the American Thoracic Foundation and, recently, a two-year $412,862 research grant from the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH).
Working with other researchers, Kant tested several combination regimens in preclinical models that could shorten the treatment duration. The currently employed standard regimen of isoniazid, rifampin and ethambutol is administered for 12 months from the time of a negative sputum culture, which makes the total therapy duration greater than 18 months to two years.
Kant and team first examined the kill trajectories of M. kansasii in the sputum of 32 Taiwanese patients on standard therapy to identify time to extinction of the bacterial burden. Next, they identified time to extinction of M. kansasii in the hollow fiber model system treated with standard therapy and identified time to extinction in the preclinical model.
“Using morphism mapping from set theory, we identified a transformation factor to translate the hollow fiber system results to patients, an approach that has been derived and validated in tuberculosis using clinical data from thousands of patients and hundreds of hollow fiber systems,” Kant said. “We found our results to be highly accurate.
“Next, we performed new experiments of head-to-head comparisons of standard therapy versus three experimental regimens in the hollow fiber system,” he said. “Then we used the transformation factor identified earlier to translate to minimum duration of therapy in patients.”
Kant’s new findings of his research concluded that the time-to-extinction mathematics in serial sputum of patients from Taiwan revealed excellent model fits, and that the time-to-extinction for more than 95% of patients on standard therapy was about two years. He also emphasizes that mapping of time to extinction from the hollow fiber system to patients on standard therapy was not a single scalar value but was multi-staged and non-linear.
“Then we performed a head-to-head comparison of different experimental regimens versus standard therapy in the hollow fiber system and then translated the time to extinction to 1,000 patients using the nonlinear multistaged transformation factor,” Kant said. “Standard therapy achieved this in more than 90.7% of patients in one year and 99.5% in two years — which was consistent with clinical observations.
“That means our translations approach worked,” Kant said.
“In our clinical trial simulation, at the six-month mark, the proportion of patients who would achieve bacterial extinction, which meant cured, was at 66% for the standard, 99.8% for the standard therapy plus a high-dose moxifloxacin, 99.9% for patients using isoniazid, rifampin and a high-dose moxifloxacin and was 92.2% for those taking the standard dose rifampin, tedizolid and moxifloxacin.
“Based on these results, we proposed a pragmatic trial to compare experimental regimens for a six-month duration versus standard two-year therapy,” he said.
UTHSCT attracts some of the top researchers from around the world to its 150,000-square-foot research facility in Tyler, Texas, where new medications, protocols and cures are developed. Researchers have earned nearly $300 million in grant-funded research to offer hope to patients in need.