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Antibiotic Treatment For Drug-resistant Tuberculosis Found To Be Safe And Effective In Clinical Trial

A clinical trial published in the New England Journal of Medicine showed that the oral antibiotic levofloxacin taken once-daily for six months substantially reduced the risk of developing drug-resistant tuberculosis (TB), and almost halved adults' and children's risk of developing multidrug-resistant TB.

"Multidrug-resistant TB is a major global public health problem, affecting over 400,000 people each year. It is associated with significantly poorer outcomes than drug-susceptible TB," said Professor Gregory Fox, Director of the NHMRC Centre for Research Excellence in Tuberculosis who led the VQUIN trial at the University of Sydney's Woolcock Institute of Medical Research in collaboration with the Vietnam Tuberculosis Program.

"We now have a way of stopping people with early TB infection from becoming sick and spreading their infection to other people."

The trial enrolled 2,041 family members of people with drug-resistant TB. These family members had early infection, which had not yet developed into the active form of drug-resistant TB. The study was conducted across 10 provinces in Vietnam, a country with a high rate of drug-resistant TB.

The trial found that levofloxacin reduced the risk of multidrug-resistant tuberculosis (MDR-TB) in adults and adolescents by 45 percent. The trial findings were combined with a second trial, TB-CHAMP, that took place in South Africa and involved the same treatment in children. Together, the two studies demonstrated that levofloxacin could stop the risk of MDR-TB among family and other household members, curtailing the global impact of this dangerous pathogen. The combined analysis was published on the same day in the companion journal NEJM Evidence.

Evidence to date has been limited on MDR-TB preventive treatment since no randomised controlled trials had ever been conducted.

"The VQUIN trial is a major step forward in the fight against drug-resistant TB. "This evidence changes the way we care for people at risk of drug-resistant TB in Australia and globally. The benefits to the families and communities at risk of MDR TB is substantial," said Professor Fox, who is also research leader at the Woolcock Institute of Medical Research.

"MDR-TB is one of the most challenging diseases to cure, and children have always been the most neglected patients," said Professor Ben Marais, a Chief Investigator from VQUIN TB-CHAMP from the University of Sydney. "By finding a way to protect vulnerable family members, we help the whole family recover from the effects of MDR-TB. There are not just health benefits, but also economic and mental health benefits."

In the trial, 2,041 adults and children living with a person with MDR-TB in the household were given six months of levofloxacin and monitored for 30 months. The study found that there were 45 percent fewer cases of TB in the group given levofloxacin compared to the placebo group. A lower number of cases of TB occurred in the placebo group than expected. Overall, levofloxacin was found to be safe and well-tolerated in adults and children.

TB remains one of the top causes of death in children globally and is one of the top killers of children below five years of age. An estimated 400,000 people develop MDR-TB disease each year, which is complex to treat with current medications that have many side effects. The treatment is very costly for both families and health services.

In September 2024, the World Health Organisation issued new guidelines for MDR-TB preventive therapy. The guidelines were based on the findings of the VQUIN trial.

The trial also completed work on other important considerations such as acceptability of the drug regimen, feasibility, health economics, pharmacokinetics and antimicrobial resistance.

The teams from the VQUIN trial in Australia and TB CHAMP trial in South Africa collaborated before the trials were unblinded. They combined their data on efficacy and safety in traditional and novel Bayesian approaches. Jointly, they showed that across both trials, levofloxacin reduced the risk of developing TB by 60 percent.Novel Bayesian analysis showed similar results for each trial, individually.

New Drug Regimens Offer Hope Against Drug-Resistant Tuberculosis: NEJM

Tuberculosis remains one of the deadliest infectious diseases worldwide, with drug-resistant strains posing a significant challenge. In a major breakthrough, an international clinical trial has identified three new safe and effective drug regimens for tuberculosis resistant to rifampin, the most potent first-line antibiotic for TB treatment.

The research, published in the New England Journal of Medicine, was led by Harvard Medical School and members of the endTB project—a global collaboration involving Partners In Health, Médecins Sans Frontières, and Interactive Research and Development, along with researchers and clinicians from academic medical centers 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.

Reference:

Lorenzo Guglielmetti, Uzma Khan, Gustavo E. Velásquez, Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis, New England Journal of Medicine, DOI:10.1056/NEJMoa2400327

New Treatments Found For Drug-Resistant TB

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.

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