An international clinical trial has revealed three new treatment schedules for drug-resistant tuberculosis (TB) that could result in faster, safer, and more accessible care.
Findings from the endTB trial, published in the New England Journal of Medicine, offer new options to target this major global health threat using pills instead of daily injections.
The three all-oral regimens provide opportunities to personalize treatment where patients are intolerant to certain drugs or when these are unavailable or in short supply.
The trial deployed bedaquiline and delamanid, which became the first new TB medicines for nearly 50 years when they were first marketed in 2012–13. These were tested in combination with older medications as part of five, novel nine-month regimens.
“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 co-author Carole Mitnick, PhD, a Harvard professor of global health and social medicine.
“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?”
Tuberculosis that is resistant to rifampin, a key antituberculosis drug, develops in an estimated 410,000 people each year according to the World Health Organization.
It is traditionally treated for 18–24 months with agents that include injectable aminoglycosides or polypeptides, but these regimens can be poorly received and have toxic effects.
Believing that shorter, entirely oral alternatives including newer drugs could provide effective alternatives, researchers examined the impact of five nine-month versions of such regimens among 754 patients in seven countries across Eastern Europe, Asia, Africa and South America with high burdens of disease.
All participants had rifampin-resistant, fluoroquinolone-susceptible pulmonary tuberculosis were 15 years or older, and 62% were male.
They were randomly assigned to either standard therapy or to one of five, nine-month all-oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z).
The primary efficacy outcome was a favorable outcome at 73 weeks, which was defined by two consecutive negative sputum cultures or by favorable bacteriologic, radiologic, and clinical evolution.
In the 699 participants in the modified intention-to-treat population, four of these regimens were noninferior to standard therapy for a favorable outcome.
In that analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes.
The risk difference between standard therapy was 9.8% in favor of BCLLfxZ over standard therapy; 8.3% for BLMZ; 4.6% for BDLLfxZ; and 2.5% for DCMZ.
The 562 participants in the per-protocol analysis showed findings were similar, apart that DCMZ combination was no longer noninferior to standard therapy.
The three other regimens produced favorable outcomes in more than 85% of participants, representing an improvement over the global average.
Grade 3 or 4 hepatotoxic events were more common in the experimental groups than with standard therapy, apart from with BDLLfxZ. Overall, 11.7% of all participants experienced these events versus 7.1% with standard therapy.
During study enrollment, WHO treatment guidelines changed twice, with these updates having a modest effect on the composition of the standard-therapy regimens.
“The results of this trial support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis,” the researchers concluded.
“The results of the endTB trial improve prospects for effective, simple, all-oral treatment for adults and children with this disease.”
