Shorter TB regimen noninferior to standard 24-week treatment, study finds
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SEATTLE — An 8-week boosted regimen of bedaquiline and linezolid was noninferior to standard 24-week treatment for tuberculosis in terms of clinical outcomes, according to the results of a phase 2-3 trial.
The findings were presented here at the Conference on Retroviruses and Opportunistic Infections and published at the same time in The New England Journal of Medicine.
“For more than 4 decades, the global standard treatment for drug-susceptible pulmonary tuberculosis has been a 6-month rifampin-based regimen,” Nicholas I. Paton, MD, professor at the National University of Singapore, and colleagues wrote, adding that the treatment has cured more than 95% of people with TB in clinical trials but has “underperformed in national treatment programs.”
“The unsatisfactory outcomes associated with standard treatment have contributed to the ongoing failure to meet global tuberculosis targets and to the generation of drug resistance,” they wrote. “Exploration of new treatment approaches is essential.”
Paton and colleagues conducted an open-label, adaptive, noninferiority trial called TRUNCATE-TB, during which they randomly assigned participants with rifampin-susceptible pulmonary TB to receive either standard treatment — rifampin and isoniazid for 24 weeks in combination with pyrazinamide and ethambutol for the first 8 weeks — or one of four different strategies involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment and retreatment for relapse.
The four strategies included initial 8-week treatment with either high-dose rifampin and linezolid, high-dose rifampin and clofazimine, rifapentine and linezolid, or bedaquiline and linezolid. Each regimen was boosted with isoniazid, pyrazinamide and ethambutol, except for the rifapentine-linezolid group, which received levofloxacin instead of ethambutol.
The primary outcome of the study was the collective rate of primary-outcome events consisting of death, ongoing treatment or active disease at week 96.
Overall, according to the researchers, a primary-outcome event occurred in 3.9% of participants in the standard-treatment group and 5.8% of participants in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference = 0.8 percentage points; 97.5% CI, 3.4 to 5.1), which met the noninferiority margin.
A primary-outcome event occurred in 11.4% of participants in the rifampin-linezolid strategy group, which did not meet the noninferiority margin.
According to the study, 98.3% of participants in the standard treatment group completed the 24-week course, and 3.3% underwent retreatment. In the four strategy groups combined, 91.5% of participants completed the initial 8-week treatment course and stopped, 6.5% switched to standard treatment — which the researchers noted was mainly because of adverse events, which were similar in incidence across all groups — and completed a 24-week course, and 17% overall underwent retreatment.
“There's a chance that the strategy might actually deliver at least equivalent clinical outcomes, with potentially some advantages,” Paton said during a press conference at CROI.
In an related editorial, Véronique Dartois, PhD, a member Hackensack Meridian Health’s Center for Discovery and Innovation, and Eric J. Rubin, MD, PhD, an associate physician specializing in infectious disease at Brigham and Women’s Hospital and editor-in-chief of The New England Journal of Medicine, asked if the data will change practice.
“Two months of treatment might not be revolutionary but could be very helpful. However, some obstacles remain,” they wrote.
These obstacles, they said, include the likelihood that adherence, which was high in the trial, will likely be much lower in the real world, which could increase treatment failure. It also would require “considerable resources” to triage patients into groups based on their need for extended TB therapy, something that is easier to do in the confines of a trial, they said.
“For shorter treatments, positive results that are similar to the results for standard treatment and are observed across various patient populations, including those with a high burden of cavitary tuberculosis, would garner the confidence needed to influence practice in lower resource settings,” they wrote.
Paton NI, et al. Abstract 113. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 19-22, 2023; Seattle.
References:
- Dartois V, et al. N Engl J Med. 2023;doi:10.1056/NEJMe2300413.
- Paton NI, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2212537.
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Paton NI, et al. Abstract 113. Presented at: Conference on Retroviruses and Opportunistic Infections; Feb. 19-22, 2023; Seattle.
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