A strategy for the treatment of tuberculosis (TB) involving just an 8-week treatment regimen — along with close posttreatment monitoring and treatment extension if needed — shows potential as an effective alternative to the standard 24-week regimen.
“We found that if we use the strategy of a bedaquiline–linezolid five-drug regimen for 8 weeks and then followed patients for 96 weeks, [the regimen] was non-inferior, clinically, to the standard regimen in terms of the number of people alive, free of TB disease, and not on treatment,” said lead author Nicholas Paton, MD, of the National University of Singapore, in a press conference at the Conference on Retroviruses and Opportunistic Infections (CROI) 2023.
“The total time on treatment was reduced by half — instead of 160 days, it was 85 days for the total duration.”
Commenting on the study, which was published concurrently in the New England Journal of Medicine, Richard E. Chaisson, MD, noted that although more needs to be understood, the high number of responses is nevertheless encouraging.
“Clinicians will not feel comfortable with the short regimens at this point, but it is remarkable that so many patients did well with shorter treatments,” Chaisson, who is a professor of medicine, epidemiology, and international health and director of the Johns Hopkins University Center for Tuberculosis Research in Baltimore, MD, told Medscape Medical News.
Importantly, the study should help push forward “future studies [that] will stratify patients according to their likelihood of responding to shorter treatments,” he said.
The current global standard for TB treatment, practiced for four decades, has been a 6-month rifampin-based regimen. Although the regimen performs well, curing more than 95% of cases in clinical trials, in real-world practice, the prolonged duration can be problematic, with issues of nonadherence and loss of patients to follow-up.
Previous research has shown that shorter regimens have potential, with some studies showing as many as 85% of patients cured with 3- and 4-month regimens, and some promising 2-month regimens showing efficacy specifically for those with smear-negative TB.
These efforts suggest that “the current 6-month regimen may lead to overtreatment in the majority of persons in order to prevent relapse in a minority of persons,” the authors assert.
To investigate a suitable shorter-term alternative, the authors conducted the phase 2-3 prospective, open-label TRUNCATE-TB trial, in which 674 patients with rifampicin-susceptible pulmonary TB were enrolled at 18 sites in Asia and Africa.
The patients were randomly assigned to receive either the standard treatment regimen (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks; n = 181), or one of four novel 5-drug regimens to be administered over 8 weeks, along with extended treatment for persistent clinical disease of up to 12 weeks, if needed, and a plan for retreatment in the case of relapse (n = 493).
Two of the regimens were dropped due to logistic criteria; the two remaining shorter-course groups included in the study involved either high-dose rifampin plus linezolid or bedaquiline plus linezolid, each combined with isoniazid, pyrazinamide, and ethambutol.
Of the patients, 62% were male, and four withdrew or were lost to follow-up by the end of the study at a final follow-up at week 96.
Among patients assigned to the 8-week regimens, 80% stopped at exactly 8 weeks, while 9% wound up having extended treatment to 10 weeks and 3% were extended to 12 weeks.
For the primary endpoint, a composite of death, ongoing treatment, or active disease at week 96, the rate was lowest in the standard 24-week therapy group, occurring in 7 of 181 patients (3.9%), compared with 21 of 184 patients (11.4%) in the rifampin plus linezolid group (adjusted difference, 7.4 percentage points, which did not meet non-inferiority criterion), and 11 of 189 (5.8%) in the group in the bedaquiline plus linezolid group (adjusted difference, 0.8 percentage points, meeting non-inferiority criterion).
The mean total duration of treatment through week 96 in the standard treatment group was 180 days, vs 106 days in the rifampin–linezolid group, and 85 days in the bedaquiline–linezolid strategy group.
The results were consistent across multiple subgroups defined according to baseline characteristics, including some that could be linked to severe disease and a high risk for relapse.
In terms of safety, there were no significant differences between the groups in terms of grade 3 or 4 adverse events.
Of note, only 2 patients (1.1%) in the bedaquiline plus linezolid group acquired a resistance, which Paton said was “encouraging,” because of concerns about resistance to that drug.
“Unfavorable” Composite Also Evaluated
In an updated analysis of the study that Paton presented at the meeting, the authors looked at a revised “unfavorable” primary outcome — a composite including treatment failure, relapse, death, or nonattendance at week 96 without evidence of prior disease clearance.
The rate remained lowest in the standard 24-week therapy group (3.9%), vs 25% in the rifampin plus linezolid group, and 13.8% in the bedaquiline plus linezolid group.
Though the lower rate with the standard treatment was expected, Paton said the results nevertheless hold promise, at least for some patients, for successful treatment with the 8-week bedaquiline plus linezolid strategy.
“What the trial has told us is that even with that 13.8% relapse rate, we can manage patients within this strategy and people can do fine at the end, because with some simple clinical biomarkers, we can pick the people who may have a high chance of achieving a cure.”
Chaisson expressed concern over the higher unfavorable rates, but said the results help pave the way for refining a workable-shorter term strategy.
“TRUNCATE-TB did find that most patients could be successfully treated in 2 months with the novel regimen of bedaquiline plus linezolid, but the failure rate was still unacceptably high,” he said.
“This regimen will not be widely adapted at this point, but additional analyses may identify subsets of patients who will do well with shorter regimens, and future studies will stratify patients according to their likelihood of responding to shorter treatments.”
The authors of an accompanying editorial further comment that the benefits of a shorter treatment strategy could very well outweigh possible shortcomings.
“Treatment algorithms such as that used in the TRUNCATE-TB trial are fundamental to tuberculosis control,” write Véronique Dartois, PhD, Center for Discovery and Innovation, Nutley, New Jersey, and Eric J. Rubin, MD, PhD, the editor-in-chief of NEJM. “Although implementing them could be a challenge, any added burden might be offset by reduced costs, better adherence, and increased patient satisfaction. Thus, for tuberculosis, a strategy might be more than just a regimen.”
The good news, as summed up by CROI vice-chair Landon Myer, MD, PhD, in the press conference, is that “we’re moving closer and closer to the holy grail of a short, efficacious regimen for TB treatment. We’re getting there slowly, but we’re getting there.”
The study received grant funding from the Singapore National Medical Research Council; a grant from the Department of Health and Social Care; the Foreign, Commonwealth, and Development Office; the Medical Research Council; and Wellcome Trust; and a grant from the UK Research and Innovation Medical Research Council. The study authors’ disclosures are detailed in the original article. Dartois reports no relevant financial relationships. Rubin is editor-in-chief of the New England Journal of Medicine. Chaisson had no disclosures to report.
Conference on Retroviruses and Opportunistic Infections/CROI 2023: Abstract 113. Presented February 20, 2023.
N Engl J Med. Published online February 20, 2023. Abstract, Editorial
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