Two Months of TB Therapy Non-Inferior to 6-Months of Treatment in TRUNCATE-TB Trial

A dramatically shortened course of tuberculosis treatment consisting of an initial 8 weeks of bedaquiline-linezolid proved non-inferior to the standard 6-month TB treatment regimen in the open-label, randomized TRUNCATE-TB clinical trial published online Feb. 20 in The New England Journal of Medicine.

Total treatment times were, on average, 13 weeks shorter in the intensified regimen group compared to those receiving standard therapy, with similar safety profiles and outcomes among the two groups.

The mean total treatment length among participants in the bedaquiline-linezolid treatment group was 84.8 days, compared to 180.2 days in participants receiving standard, 6-month TB therapy.

The bedaquiline and linezolid treatment strategy was also as efficacious as standard therapy across subgroups defined at baseline, including patients with severe disease and those at high risk for relapse, wrote Nicholas Paton, MD, of the Yong Loo Lin School of Medicine, Singapore, and colleagues.

"This treatment has cured more than 95% of persons with tuberculosis in the context of clinical trials but has underperformed in national treatment programs in which long-term adherence is difficult for some persons and resource constraints limit the provision of adherence support," they wrote.

They added that the burdens associated with the 6-month treatment course have "contributed to the ongoing failure to meet global tuberculosis targets and to the generation of drug resistance."

Clinical trials exploring shorter regimens, including those limiting treatment to 3- or 4-months, have generally shown cure rates of 80 percent or higher, with fluoroquinolone- and rifapentine-containing regimens eliciting the highest cure rates.

The researchers hypothesized that a treatment strategy involving initial treatment with an 8-week regimen, with treatment time extended in patients with persistent TB, monitoring following treatment cessation, and prompt re-treatment of those who relapse "might lead to long-term efficacy that would be non-inferior to that of standard treatment, along with a reduced total duration of treatment and other secondary advantages for persons with tuberculosis and for treatment programs."

The TRUNCATE-TB trial originally included four shortened therapy groups receiving different initial regimens, but non-inferiority was assessed in just two of these groups due to incomplete enrollment in the other two groups.

A total of 181 patients with rifampin-susceptible TB were assigned to the standard treatment group, consisting of 8 weeks of isoniazid, rifampin, ethambutol and pyrazinamide, followed by 16 weeks of isoniazid and rifampin.

A total of 184 patients received initial treatment consisting of high-dose rifampin and linezolid, and 189 were assigned to receive 8 weeks of bedaquiline and linezolid.

Patients were assessed throughout for persistent disease, and treatment was stopped after 8 weeks in patients who were asymptomatic with negative sputum smears. Those who did not meet these benchmarks continued treatment for another 4 weeks, and those who remained sputum positive could be switched to standard treatment to complete 24 weeks.

Patients who relapsed in any group up to week 96 were retreated with a standard regimen, with adjustments made according to antibiotic susceptibility.

The study’s primary outcome was a composite of death, ongoing treatment, or active disease at week 96. For the treatment strategy to be declared non-inferior, the upper limit of the confidence interval for the difference between the strategy group and the standard-treatment group in the risk of the primary outcome had to be less than 12 percentage points.

Of the 674 participants in the intention-to-treat population, only four (0.6%) withdrew consent or were lost to follow-up.

Primary outcome events occurred in 3.9% of the standard-treatment group, compared to 11.4% in the strategy group with an initial rifampin–linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% CI, 1.7-13.2). The non-inferiority goal was not met in this strategy treatment group.

Non-inferiority was met in the bedaquiline-linezolid patients, however, with a primary outcome event occurring in 5.8% (adjusted difference, 0.8 percentage points; 97.5% CI, −3.4 to 5.1).

The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin–linezolid strategy group, and 85 days in the bedaquiline–linezolid strategy group.

Grade 3 or 4 adverse events and serious adverse events were similar in the three groups.

The researchers cited the study’s pragmatic design and the use of relevant clinical outcome measures as strengths, while the open-label design and the lack of HIV-positive participants were cited as study limitations.

They concluded that the study findings suggest "there may be value in considering a shift in tuberculosis management to a strategy involving initial treatment for the minimum duration needed to cure the majority of persons with tuberculosis, extended treatment for persistent clinical disease, and monitoring after treatment to detect relapse in the minority of persons who need retreatment."

"This treatment strategy provides a framework for the development of new, short, potent drug regimens and biomarkers for treatment monitoring to maximize cost-effectiveness and outcome benefit," they wrote. "Implementation research is vital to refine the strategy and evaluate outcomes in individual treatment programs and diverse populations be- fore consideration of adoption at scale."

In commentary published with the study, Veronique Dartois, PhD, of the Center for Discovery and Innovation, Nutley, New Jersey, and NEJM editor-in-chief Eric J. Rubin, MD, PhD, noted that while bedaquiline carries a black-box warning due to early trials showing increased mortality and linezolid has been shown to have dose-limiting toxic effects, toxic effects with the bedaquiline-linezolid regimen in TRUNCATE-TB were limited.

"This is one of many trials that suggest that the original concerns about bedaquiline might be overstated, at least for patients who undergo pre-screening with electrocardiography," Dartois and Rubin wrote.

They added that obstacles remain to making 2-month initial treatment standard therapy for patients with rifampin susceptible tuberculosis.

"There was a very high degree of adherence to treatment in this trial, far higher than the level likely to occur outside the context of a clinical trial," they wrote. "Lower adherence could mean increased treatment failure at 2 months. In addition, the treatment strategy involved careful assessments of patients to identify those who would receive extended courses of therapy.

"Although this approach is possible within the confines of a trial, it could require considerable resources that are not now available in many tuberculosis control programs," they concluded.

This research was funded by the Singapore National Medical Research Council.

Paton reported receiving grants from Janssen Pharmaceuticals for research related to the TRUNCATE-TB trial.

Paton NF, et al "Treatment strsategy for rifampin-susceptible tuberculosis" N Engl J Med 2023; DOI: 10.1056/NEJMoa2212537.

Dartois V, Rubin EJ "Shortening tuberculosis treatment - a strategic retreat" N Engl J Med 2023; DOI: 10.1056/NEJMe2300413.