Treatment Strategy for Rifampin-Susceptible Tuberculosis

Abstract

Background: Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear.

Methods: In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points.

Results: Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). 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. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups.

Conclusions: A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).

Figure 1. Screening, Randomization, Evaluation, and Analysis.

In the standard-treatment group, two participants received less than 154 days of treatment because they died; these participants were not excluded from the per-protocol analysis.

Figure 2. Subgroup Analysis.

Shown is the percentage of participants who had a primary-outcome event in the strategy group with an initial rifampin–linezolid regimen (Panel A) and in the strategy group with an initial bedaquiline–linezolid regimen (Panel B), as compared with the standard-treatment group, according to prespecified subgroups. Differences were estimated with a generalized linear model with adjustment for country. The widths of the confidence intervals have not been adjusted for multiple comparisons, and the intervals cannot be used to infer treatment effects. In a post hoc subgroup analysis, the estimated difference between the rifampin–linezolid strategy group and the standard-treatment group in the percentage of participants with a primary-outcome event was 4.6 percentage points (95% CI, −2.7 to 12.0) among those who were enrolled before the high dose of rifampin was reduced and 10.6 percentage points (95% CI, 3.2 to 18.1) among those who were enrolled after the rifampin dose reduction. Body-mass index is the weight in kilograms divided by the square of the height in meters. The Medical Research Council (MRC) breathlessness scale ranges from grade 1 to grade 5, with higher grades indicating a greater degree of activity-related breathlessness. For relapse risk, low risk is defined as a negative smear and the absence of a cavity measuring more than 4 cm on a chest radiograph; intermediate risk as a positive smear of grade 2+ or lower and the absence of a cavity measuring more than 4 cm on a chest radiograph; and high risk as a positive smear of grade 3+, the presence of a cavity measuring more than 4 cm on a chest radiograph, or both. WHO denotes World Health Organization.

Figure 2. Subgroup Analysis.

Shown is the percentage of participants who had a primary-outcome event in the strategy group with an initial rifampin–linezolid regimen (Panel A) and in the strategy group with an initial bedaquiline–linezolid regimen (Panel B), as compared with the standard-treatment group, according to prespecified subgroups. Differences were estimated with a generalized linear model with adjustment for country. The widths of the confidence intervals have not been adjusted for multiple comparisons, and the intervals cannot be used to infer treatment effects. In a post hoc subgroup analysis, the estimated difference between the rifampin–linezolid strategy group and the standard-treatment group in the percentage of participants with a primary-outcome event was 4.6 percentage points (95% CI, −2.7 to 12.0) among those who were enrolled before the high dose of rifampin was reduced and 10.6 percentage points (95% CI, 3.2 to 18.1) among those who were enrolled after the rifampin dose reduction. Body-mass index is the weight in kilograms divided by the square of the height in meters. The Medical Research Council (MRC) breathlessness scale ranges from grade 1 to grade 5, with higher grades indicating a greater degree of activity-related breathlessness. For relapse risk, low risk is defined as a negative smear and the absence of a cavity measuring more than 4 cm on a chest radiograph; intermediate risk as a positive smear of grade 2+ or lower and the absence of a cavity measuring more than 4 cm on a chest radiograph; and high risk as a positive smear of grade 3+, the presence of a cavity measuring more than 4 cm on a chest radiograph, or both. WHO denotes World Health Organization.