An international clinical trial, known as endTB, has identified three new, shorter, and all-oral treatment regimens for rifampin-resistant tuberculosis (RR-TB), offering a significant advancement over the current standard of care. The phase 3 trial, conducted across seven countries, demonstrated that these 9-month regimens are non-inferior to the standard 18- to 24-month therapy, with favorable outcomes observed in 85% to 90% of participants. This development promises to improve patient quality of life, treatment adherence, and overall recovery rates for the estimated 410,000 people affected by RR-TB annually.
The endTB trial, published in the New England Journal of Medicine, compared five different 9-month, all-oral drug regimens against the standard therapy for fluoroquinolone-susceptible, rifampicin-resistant TB. The study enrolled 754 participants aged 15 and older from Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa between February 2017 and October 2021. Participants were randomized to receive either standard therapy or one of five experimental regimens containing combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z).
The primary endpoint was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was set at -12 percentage points. In the modified intention-to-treat (mITT) analysis, favorable outcomes occurred in 80.7% of the standard therapy group. Four of the five alternative regimens demonstrated noninferiority, with risk differences compared to standard therapy as follows: BCLLfxZ, 9.8 percentage points (95% CI, 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5).
Impact on Treatment Landscape
The success rates observed in the alternative regimens are comparable to the 89% success rate reported in trials for the 6-month, all-oral BPaLM (bedaquiline, pretomanid, and linezolid, with or without moxifloxacin) regimen, which was recommended by the World Health Organization (WHO) in 2022. Notably, the three regimens found to be non-inferior (BLMZ, BCLLfxD, and BDLLfxZ) can be used in nearly all adults, children, and pregnant women, offering a broader application than the BPaLM regimen, which is restricted to non-pregnant individuals aged 14 and older. The WHO endorsed the use of these three regimens in August 2024.
Expert Commentary
"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," said Carole Mitnick, co-principal investigator of the trial and professor of global health and social medicine at Harvard Medical School. "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?"
Safety and Accessibility
While the proportion of participants with grade 3 or higher adverse events was similar across the regimens, hepatotoxic events were more common in the experimental groups, except for the BDLLfxZ group. Efforts to end patent exclusivity on bedaquiline have also made two of the endTB regimens and the WHO-recommended pretomanid-containing regimen more affordable, costing less than $500. This increased accessibility, coupled with the shorter treatment duration and all-oral administration, represents a significant step forward in the fight against drug-resistant tuberculosis.
