Tuberculosis remains one of the top infectious disease killers worldwide , a challenge amplified by drug-resistant forms of the disease. Now, in a major step forward, an international clinical trial has found three new safe and effective drug regimens for tuberculosis that is resistant to rifampin, the most effective of the first-line antibiotics used to treat TB.
The research, published Jan. 30 in the New England Journal of Medicine, was led by researchers at Harvard Medical School and other members of the endTB project, a collaboration among Partners In Health , Médecins Sans Frontières , and Interactive Research and Development , with help from researchers and clinicians at academic medical centers and research hubs worldwide.
The newly identified regimens take advantage of recently discovered drugs to expand the treatment arsenal and give physicians new ways to shorten and personalize treatment, minimize side effects, and treat patients using only pills instead of daily injections. They also offer alternatives in case of drug intolerance, medication shortages or unavailability, or drug resistance, the researchers said.
The endTB trial is one of four recent efforts to use randomized controlled trials to test new, shorter, less toxic regimens for drug-resistant TB. endTB uses two new drugs — bedaquiline and delamanid — which, when brought to market in 2012-2013, were the first new TB medicines developed in nearly 50 years.
To find shorter, injection-free drug combinations for people infected with TB resistant to rifampin, endTB tested five new, all-oral 9-month regimens using the two new drugs in combination with older medications.
A third drug, pretomanid, received emergency authorization from the FDA for specific use within a regimen against highly drug-resistant TB in 2019, after the endTB clinical trial was underway, and is not included in the regimens used in these trials.
Trial regimens were considered effective if they performed at least as well as the control group, which received a well-performing standard of care composed in accordance with a stringent interpretation of World Health Organization (WHO) recommendations.
The three successful new regimens were successful for between 85 and 90 percent of patients, compared with 81 percent success for people in the control group. The control group was treated with longer treatments, which also included the recently discovered medicines.
The trial launched in 2017 and enrolled 754 patients across seven countries: Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa. The goal was to improve treatment for patients with tuberculosis resistant to rifampin. The WHO estimates that some 410,000 people become sick with rifampin-resistant TB each year, including people who have multidrug-resistant TB (MDR-TB). Only 40 percent are diagnosed and treated, 65 percent of them successfully.
The study population included children as well as people infected with HIV or hepatitis C, both common in populations with high rates of TB. In another innovation, women who became pregnant while on treatment were included in the endTB trial. These groups are often excluded from clinical trials. In a special report published in August 2024, the WHO added the three noninferior regimens from the endTB trial to the list of treatment options for rifampin-resistant and multidrug-resistant TB (MDR-TB) treatment; the recommendations extend to these neglected groups as well as to pregnant women.
With recent efforts to end patent exclusivity on bedaquiline, two of the endTB regimens and the WHO-recommended pretomanid-containing regimen can all be purchased for less than $500, an access target set by activists more than 10 years ago, which has only just now been achieved. All of these innovations together mean the new shortened, all-oral regimens are available to more people than ever.
The endTB trial is part of a major transformation in how the world treats tuberculosis, said the trial's co-principal investigator, Carole Mitnick , professor of global health and social medicine in the Blavatnik Institute at HMS and PIH's director of research for the endTB project.
"This Harvard-led partnership among NGOs, ministries of health, and other academic partners identified three new regimens that will make lifesaving care dramatically more accessible," Mitnick said. "We also resolved a critical question left open by pharmaceutical industry trials that brought bedaquiline and delamanid to market: How can these new drugs be used to shorten and simplify treatment while retaining efficacy?"
Until recently, Mitnick said, poor treatment options and low-quality evidence made it difficult to stem the tide of preventable deaths from tuberculosis. For many years, the only approved treatment regimens lasted years and included daily injections and highly toxic medications with often-severe side effects.
Authorship, funding, disclosures
Additional authors include Lorenzo Guglielmetti, Uzma Khan, Gustavo E. Velásquez, Maelenn Gouillou, Amanzhan Abubakirov, Elisabeth Baudin, Elmira Berikova, Catherine Berry, Maryline Bonnet, Matteo Cellamare, Vijay Chavan, Vivian Cox, Zhanna Dakenova, Bouke Catherine de Jong, Gabriella Ferlazzo, Aydarkhan Karabayev, Nana Kiria, Mikanda Kunda, Nathalie Lachenal, Leonid Lecca, Helen McIlleron, Ilaria Motta, Sergio Mucching Toscano, Hebah Mushtaque, Payam Nahid, Lawrence Oyewusi, Samiran Panda, Sandip Patil, Patrick P.J. Phillips, Jimena Ruiz, Naseem Salahuddin, Epifanio Sanchez Garavito, Kwonjune J. Seung, Eduardo Ticona, Lorenzo Trippa, Dante E. Vargas Vasquez, Sean Wasserman, Michael L. Rich, and Francis Varaine.
The endTB trial was funded by Unitaid, Médecins Sans Frontières, and Partners In Health. Interactive Research and Development provided in-kind support for trial implementation and administration.
