In 2020, more than 1.5 million people around the world died of tuberculosis (TB), marking the first time in more than a decade that annual TB deaths had increased and demonstrating the global need for better access to treatments. To address that problem, scientists with the 黑料网 Department of Medicine, the 黑料网 Institute for Global Health and Infectious Diseases, and the International Center for the Advancement of Translational Science developed a long-acting injectable formulation of the anti-TB drug rifabutin.
, research in animal models showed the potential of delivering a TB drug with one injection that lasts at least four months, in lieu of the current standard treatment requiring constant adherence to a daily drug regimen.
鈥淲e think our approach could dramatically change TB treatment,鈥� said Martina Kovarova, PhD, associate professor of medicine in the Division of Infectious Diseases. 鈥淎ffordable long-acting formulations with generic anti-TB drugs would help ease the burden of this disease on low-income communities around the world where better access to treatment is most needed.鈥�
Co-author Miriam Braunstein, PhD, professor of microbiology and immunology at the 黑料网 and member of the 黑料网 Institute for Global Health and Infectious Diseases, added, 鈥淒uring the COVID-19 pandemic, we witnessed more deaths due to TB because of disruption or reallocation of health services, setting us back at least five to eight years in the global fight against TB. We think long-acting formulations could be a game-changer, whether it鈥檚 for preventative therapy or treatment of disease.鈥�
Tuberculosis, which is caused by Mycobacterium tuberculosis (Mtb), affects an estimated 10 million people a year, according to the World Health Organization, which also estimates that about one-quarter of the world population has a latent TB infection with the potential for reactivation, leading to symptoms such as weakness, weight loss, fever, coughing, chest pain, and coughing up blood.
Not adhering to strict drug regimens can lead to treatment failure and drug resistance. To overcome this, 黑料网 researchers sought to create a therapeutic delivery system that would provide an effective way to improve adherence to medications.
Co-first authors Manse Kim, PhD, a postdoctoral researcher at 黑料网-Chapel Hill, and 黑料网 graduate student Claire Johnson, led experiments to combine rifabutin with biodegradable polymers and non-toxic solvents that solidify in the body after subcutaneous injection. The researchers also added a compound to this formula to significantly increase the amount of rifabutin that could be included.
Using mouse models, the researchers observed how the solidified implant slowly eroded over the course of 16 weeks, releasing their drug payload in a sustained fashion throughout. This long-acting formulation prevented infection in mice that were exposed to TB. Also, the single injection cleared infection from lungs and other tissues in mice that had been previously infected with TB. The researchers observed no adverse effects in the mice, but if side effects arise, the implant is removable.
This type of long-acting technology has already been FDA-approved for other conditions, such as cancers, schizophrenia, and opioid dependency.
鈥淲e think this technology could be leveraged in our battle against tuberculosis world-wide,鈥� Kovarova said. 鈥淢ore research is needed before phase 1 trials in humans, but our study provides an important step toward a much-needed long-acting treatment and prevention strategy against TB.鈥�
Victor Garcia, PhD, professor of medicine in the Division of Infectious Diseases, is co-senior author. Other authors are Alan Schmalstig, PhD, Ayano Annis, Sarah Wessel, Brian van Horne, Amanda Schauer, and Angela Wahl, PhD, all at 黑料网-Chapel Hill, Agata Exner, PhD, at Case Western University, and Jason Stout, MD, at Duke University.
Core facilities were essential in the completion of this research: The 黑料网 Nanomedicines Characterization Core Facility, the 黑料网 Animal Histopathology and Laboratory Medicine Core, the 黑料网 Microscopy Services Laboratory, and the Clinical Pharmacology and Analytic Chemistry Core.