TB Treatment Strategy Has Potential to Drastically Slash Therapy Duration

SEATTLE -- An 8-week tuberculosis (TB) treatment strategy where additional therapy is reserved only for persistent disease or at relapse led to less overall treatment and similar clinical outcomes compared with the standard 6-month approach, an open-label randomized study showed.

In the TRUNCATE-TB trial, a primary outcome event -- a composite of death, continued treatment, or active disease at 96 weeks -- was recorded in 3.9% of those on standard 6-month rifampin-based regimens, as compared with 5.8% of participants assigned to an 8-week strategy with bedaquiline (Sirturo) plus linezolid, which required subsequent monitoring for retreatment.

The adjusted 0.8-percentage point difference (97.5% CI -3.4 to 5.1) between those two arms met criteria for non-inferiority, Nicholas Paton, MD, of the National University of Singapore, reported here at the Conference on Retroviruses and Opportunistic Infections.

Overall, 86% of participants in the bedaquiline-linezolid arm no longer required further therapy after 8 weeks, and the mean total treatment time was more than halved in this group compared with standard treatment (85 vs 180 days), according to the findings, which were published simultaneously in the New England Journal of Medicine.

TB treatment has been the same for 30 years, Paton told MedPage Today following his presentation, "with people just thinking, 'Carry on and try and do it more fastidiously.'"

"Many people were opposed to doing the trial initially, because they said: 'No, you can't do that, it's not safe, it's unethical' -- all those kind of things," said Paton. "I think what TRUNCATE-TB has done is challenged the treatment paradigm to say there might be an alternative way of doing this."

Efficacy of the 8-week strategy was consistent across subgroups, including in groups with markers of severe disease or at high risk for relapse.

Another 8-week strategy tested in the trial, which involved high-dose rifampin plus linezolid, failed to demonstrate noninferiority to the standard approach, with 11.4% reporting a primary outcome event (adjusted 7.4-percentage point difference, 97.5% CI 1.7-13.2). In this group, the average total treatment time was 106 days.

"We now need to look at how we can learn further from the trial about the biomarkers for selecting people who might do better with the 8-week regimen, and who might need a bit longer," Paton said, though he cautioned that even if the length of treatment is shortened, patients still need to be monitored due to the risk for risk of relapse.

In an editorial that accompanied the paper, Véronique Dartois, PhD, of the Center for Discovery and Innovation in Nutley, New Jersey, and NEJM editor-in-chief Eric Rubin, MD, PhD, of Brigham and Women's Hospital in Boston, said while a 2-month TB regimen "might not be revolutionary," it could be very helpful.

"Our current treatment regimen for tuberculosis, which goes by the somewhat ironic name of 'directly observed therapy, short course,' is anything but short," they wrote. "Perhaps the biggest accomplishment of this trial is a step forward in the adaptive clinical trial design that may help to accelerate regimen development and to rapidly test many more 2-month therapies that are selected on the basis of recent treatment-shortening trial results."

Dartois and Rubin highlighted the two cases of drug resistance in the bedaquiline-linezolid arm, as compared with none in the standard-treatment group. One of the drug-resistant patients who relapsed at week 52 had isoniazid resistance and missed 14 days of treatment (12 days consecutively). The other relapsed at week 36. Both had phenotypic and genotypic resistance to bedaquiline, as well as to clofazimine.

"Bedaquiline has a long terminal half-life that generates lingering subtherapeutic concentrations for several months after the end of therapy, which results in de facto monotherapy and a prolonged window for the potential acquisition of drug resistance in cases of relapse," Dartois and Rubin explained. "Although a much larger number of patients would need to be treated to detect any significant difference, the small number of cases of drug resistance in this trial does not pose substantial concerns."

No safety signals were seen, the researchers said, with similar rates of respiratory disability, grade 3/4 adverse events (AEs), and serious AEs between groups.

Despite a black-box warning with bedaquiline due to increased mortality reported in earlier trials, and dose-limiting toxic effects reported with linezolid, Dartois and Rubin noted that toxicity with the combination "appeared to be quite limited" in the trial.

"In fact, this is one of many trials that suggest that the original concerns about bedaquiline might be overstated, at least for patients who undergo prescreening with electrocardiography," they said.

TRUNCATE-TB included 674 adult participants with rifampin-susceptible pulmonary TB in the intention-to-treat population. Patients were randomized to standard rifampin-based treatment -- rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks (n=181) -- or to one of four 8-week strategy groups:

• High-dose rifampin plus linezolid (n=184)
• High-dose rifampin plus clofazimine (n=78)
• Rifapentine-linezolid (n=42)
• Bedaquiline-linezolid (n=189)

Each 8-week strategy group also received isoniazid, pyrazinamide, and ethambutol (except the rifapentine-linezolid group, which received levofloxacin instead of ethambutol). After 8 weeks, those with persistent clinical disease or who missed doses could continue treatment to week 12, at which point patients with persistent clinical disease or who had an adverse event could be switched to the standard 24-week regimen.

The researchers noted that while the follow-up visits after completion of treatment may represent an additional burden, "only a few participants discontinued visits or reported difficulty with prolonged follow-up."

Participants were enrolled at 18 sites in Indonesia, the Philippines, Thailand, Uganda, and India, and ranged in age from 18 to 65 years, with a majority (57%) age 18 to 34 years.

Overall, 62% were men, 49% were former or current smokers, and median body mass index (BMI) was 19, with under-nutrition recorded in 43% (BMI <18.5). Half had 25-50% chest involvement on x-ray, and about 60% were deemed intermediate risk for relapse, with 12% high risk.

The trial design had early stopping rules for two of the 8-week strategy groups, and ultimately the efficacy analysis included the standard 6-month treatment arm versus the bedaquiline-linezolid and high-dose rifampin/linezolid strategy arms.

The non-inferiority margin for the primary outcome was set at 12 percentage points, and the study's main secondary outcomes were total treatment time, grade 3/4 AEs, and acquired drug resistance.

Deaths before 96 weeks occurred in 1.1% of the standard-treatment group, 0.5% of the bedaquiline-linezolid strategy group, and 2.7% of the high-dose rifampin/linezolid strategy group. Ongoing treatment at this timepoint was observed in 1.1%, 2.6%, and 2.7%, respectively.

Active disease at 96 weeks was seen in 0.6% of patients in the standard-therapy group, 1.6% of those in the bedaquiline-linezolid strategy group, and 2.2% of the high-dose rifampin/linezolid strategy group.

Participant-based secondary endpoints found that those assigned to the strategy groups reported a higher level of motivation to adhere to the 8 weeks of treatment, according to the researchers.