Tuberculosis continues to be one of the leading causes of death from infectious diseases around the globe, with the problem worsened by the presence of drug-resistant strains. In a significant advancement, an international clinical trial has identified three new safe and effective drug regimens to combat tuberculosis that is resistant to rifampin, the most potent first-line antibiotic used in TB treatment.
The study, published on January 30 in the New England Journal of Medicine, was spearheaded by researchers from Harvard Medical School and other collaborators in the endTB project, which involves Partners In Health, Médecins Sans Frontières, and Interactive Research and Development, along with various academic medical centers and research institutions globally.
The new regimens utilize recently developed TB drugs, broadening treatment options and enabling healthcare providers to tailor treatments, reduce side effects, and administer all necessary medications in pill form rather than through daily injections. The researchers noted that these regimens also provide alternatives in cases of drug intolerance, shortages, or resistance.
The endTB trial is part of a set of four recent studies that employed randomized controlled trials to explore new, shorter, and less toxic treatment courses for drug-resistant TB, incorporating two new drugs—bedaquiline and delamanid—which were the first new TB medications introduced in nearly half a century when approved in 2012-2013.
To identify shorter, injection-free treatment combinations for patients with rifampin-resistant TB, endTB evaluated five new all-oral regimens over a nine-month period, combining the two new drugs with existing ones.
A third drug, pretomanid, received emergency use authorization from the FDA in 2019 for specific regimens targeting highly drug-resistant TB while the endTB trial was already in progress, though it is not part of the regimens tested in these studies.
The regimens were deemed effective if they matched or surpassed the performance of the control group, which received a standard treatment that adhered to rigorous World Health Organization (WHO) guidelines.
The three newly identified regimens proved effective for 85 to 90 percent of patients, in contrast to an 81 percent success rate among control group members, who underwent longer treatment involving recently introduced drugs.
The trial commenced in 2017 and enrolled 754 patients from seven nations: Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa, aiming to enhance care for those with rifampin-resistant tuberculosis. The WHO estimates that around 410,000 individuals develop rifampin-resistant TB annually, including those with multidrug-resistant TB (MDR-TB). Of those, only 40 percent receive proper diagnosis and treatment, with 65 percent achieving successful outcomes.
The study included children and individuals infected with HIV or hepatitis C, which are prevalent in regions with high TB rates. Additionally, pregnant women who were on treatment were integrated into the endTB trial, a departure from the usual exclusion of such groups from clinical studies. In an upcoming report from August 2024, the WHO will add the three successful regimens from the endTB trial to its recommendations for treating rifampin-resistant and multidrug-resistant TB, which now includes those previously overlooked, such as pregnant women.
With recent movements to end patent protections on bedaquiline, two regimens from endTB and the WHO-endorsed regimen containing pretomanid can each be acquired for under $500, achieving a price target set by activists over a decade ago. Collectively, these advancements ensure that the new shortened, all-oral treatment options are now accessible to a greater number of individuals.
The endTB trial represents a significant shift in the global approach to tuberculosis treatment, stated Carole Mitnick, co-principal investigator of the trial and professor of global health and social medicine at the Blavatnik Institute at HMS, as well as director of research for the endTB project at PIH.
“This Harvard-led collaboration among NGOs, health ministries, and academic partners has resulted in three new regimens that will vastly improve access to critical care,” Mitnick stated. “We have also addressed a key question left unanswered by pharmaceutical trials that released bedaquiline and delamanid: How can these innovative drugs be utilized to streamline and shorten treatment while maintaining effectiveness?”
Mitnick emphasized that previously, inadequate treatment alternatives and subpar research made it challenging to address the preventable fatalities caused by tuberculosis. For many years, the only available treatment regimens spanned several years and involved daily injections, alongside highly toxic medications that often led to severe side effects.
