The results of a randomized clinical trial conducted in five countries suggests that an intensified drug regimen at the beginning of treatment could shorten treatment duration for tuberculosis (TB).
The results, published yesterday in The New England Journal of Medicine, show that a strategy involving initial treatment with an 8-week regimen of high doses of bedaquiline and linezolid was noninferior to the standard, 6-month TB treatment with respect to clinical outcomes, with no evident safety concerns. Participants also said they were more motivated to adhere to the 8-week initial course than the standard treatment.
The 6-month regimen has been the standard treatment for drug-susceptible TB for more than four decades. While that regimen has cured more than 95% in the context of clinical trials, the trial investigators say difficulties adhering to the multidrug regimen for 6 months has resulted in less success in real-world settings and made it essential to look for new, shorter alternatives. And they think the results of the trial have opened up a window to find those alternatives.
"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," the investigators wrote.
A 13-week reduction in treatment duration
For the Two-Month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-Sensitive Tuberculosis (TRUNCATE-TB) trial, an international team led by investigators with the National University of Singapore enrolled and randomly assigned adults with rifampin-susceptible TB from Indonesia, the Philippines, Thailand, India, and Uganda to two different treatment strategy groups. The standard treatment group received standard doses of rifampin and isoniazid for 24 weeks in combination with pyrazinamide and ethambutol for the first 8 weeks.
The rest of the participants were assigned to four alternative strategy groups, each with a different regimen for the first 8 weeks of treatment, followed by reassessment for persistent clinical disease. If the reassessment showed no disease, treatment was stopped. For patients with persistent clinical disease, treatment was continued for another 4 weeks. If persistent disease remained at 12 weeks, patients could switch to standard treatment.
The four regimens were a high dose of rifampin and linezolid, a high dose of rifampin and clofazimine, rifapentine and linezolid, and bedaquiline and linezolid. Each regimen was given in combination with isoniazid, pyrazinamide, and ethambutol.
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.
The primary outcome was a composite of death, ongoing treatment, or active disease at 96 weeks, with a non-inferiority margin of 12 percentage points. Because of enrollment issues, non-inferiority was assessed in just two of the strategy groups: the high-dose rifampin-linezolid group and the high-dose bedaquiline-linezolid group.
A total of 674 patients were included in the intention-to-treat analysis, with 4 withdrawing consent or lost to follow-up. A primary outcome event occurred in 7 of 181 patients (3.9%) in the standard treatment group, compared with 21 of 184 (11.4%) in the rifampin-linezolid group and 11 of 189 (5.8%) in the bedaquiline-linezolid group. Non-inferiority was met in the bedaquiline-linezolid group (adjusted difference, 0.8 percentage points; 97.5% confidence interval [CI], –3.4 to 5.1) but not in the rifampin-linezolid group (adjusted difference, 7.4 percentage points; 97.5% CI, –1.7 to 13.2).
The mean total duration of treatment was 180 days in the standard treatment group, 106 days in the rifampin-linezolid group, and 85 days in the bedaquiline-linezolid group, which equals a 13.5-week difference from the longest duration to the shortest. In the bedaquiline-linezolid group, 162 participants did not receive therapy beyond 8 weeks. Incidence of grade 3 or 4 adverse events was similar in all groups.
Increased motivation to stay the course
Participants in the two alternative-strategy groups reported low levels of difficulty and anxiety related to the strategy and said that the strategy increased their motivation to take treatment. In addition, more than 70% of patients in both alternative-strategy groups said they would recommend the strategy to others.
There was also no evidence that the alternative strategies promoted drug resistance, which has been one of the concerns with shorter treatments.
The investigators say the 13-week reduction in total treatment duration could help national TB programs by allowing them to redeploy their resources—which are currently focused on procuring, distributing, and supervising 6-month treatment regimens—into treatment adherence support over a shorter period.
"This support may synergize with the increased individual motivation to better sustain adherence and thereby prevent the decrease in effectiveness that has been seen with standard treatment in its translation from clinical trials to programs," they wrote.
Shorter treatments still require considerable resources
In an accompanying commentary, TB experts with the Center for Discovery and Innovation say the results aren't surprising, given that previous research has shown many TB patients don't relapse after 4 months of treatment, and several are cured after 2 months. They also note that bedaquiline and linezolid are used in regimens that have significantly shortened treatments for drug-resistant TB.
But they caution that the trial had far higher levels of treatment adherence—and monitoring—than might be seen in real-world settings.
"Lower adherence could mean increased treatment failure at 2 months," they wrote. "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."
Ultimately, they say the significance of the TRUNCATE-TB trial results is not the regimen itself but the trial design, which could enable researchers to rapidly test many other 2-month regimens.
"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.
