Shortening the Duration of Tuberculosis Treatment

By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: In patients with rifampin-susceptible tuberculosis, a planned eight-week regimen of bedaquiline plus linezolid together with isoniazid, ethambutol, and pyrazinamide, combined with a careful follow-on strategy, was non-inferior to a standard six-month regimen.

SOURCE: Paton NI, Cousins C, Suresh C, et al; TRUNCATE-TB Trial Team. Treatment strategy for rifampin-susceptible tuberculosis. N Engl J Med 2023;388:873-887.

The standard regimen for treatment of drug-susceptible pulmonary tuberculosis includes administration of four drugs for the first two months followed by just two of the drugs for an additional four months to complete a total six-month course. The four-drug regimen consists of isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA), while only INH and RIF are given to complete the course of treatment. Recent studies have found that shorter durations with various regimens also may be successful.

Paton and colleagues reported the results of TRUNCATE-TB, an adaptive, open-label non-inferiority trial. Adults with rifampin-susceptible pulmonary tuberculosis were randomized to receive either the standard six-month course or one of four eight-week courses, each with an associated strategy consisting of extended treatment for those with persistent clinical disease, monitoring, and treatment of relapse. The eight-week regimens were: high-dose RIF plus linezolid (LZD), high-dose RIF plus clofazimine, rifapentine plus LZD, and bedaquiline plus LZD — each together with INH, PZA, and EMB (but with levofloxacin substituted for EMB in the rifapentine plus LZD regimen).

The assessment of regimens relative to standard therapy was limited to only the two regimens that were able to have complete enrollment — bedaquiline plus LZD and RIF plus LZD. The primary endpoint was a composite of death, a need for continuing treatment, or active disease at 96 weeks, and the non-inferiority criterion was 12 percentage points.

The primary endpoint occurred in 7/181 (3.9%) with standard treatment. In comparison, with initial rifampin plus linezolid, it occurred in 21/184 (11.4%), with an adjusted difference of 7.4 percentage points and 97.5% confidence interval (CI), 1.7 to 13.2. Thus, rifampin plus LZD did not meet the prespecified non-inferiority criterion. In contrast, with initial bedaquiline plus LZD, the primary event occurred in 11/189 (5.8%) with an adjusted difference of 0.8 percentage points and 97.5% CI of -34 to 5.1. Thus, the bedaquiline plus LZD regimen met the non-inferiority criterion relative to standard therapy.

Patients initially treated with bedaquiline plus LZD had a mean total duration of treatment of 8.5 weeks, 13.5 weeks less than in the 180 days in the standard treatment group, and 162/189 (85.7%) required no treatment beyond the planned eight weeks.

The regimens all were similarly tolerated, but treatment adherence was greater in the eight-week regimen groups. Only two patients, both in the bedaquiline plus LZD group, had treatment-emergent drug resistance to both bedaquiline and clofazimine.

COMMENTARY

This study demonstrated that a strategy of initial administration of bedaquiline plus LZD planned for eight weeks’ duration, when combined with continued treatment in those with persistent disease, close monitoring, and treatment of relapse, was non-inferior to a standard six-month treatment regimen. Unsurprisingly, adherence was improved with the eight-week regimens. However, 14.3% of patients required treatment beyond eight weeks, demonstrating the importance of the specified ongoing management. Relapse, assessed as relapse-associated transmission risk (to account for the value of close monitoring and reinitiation of therapy), did not significantly differ between groups.

As indicated in the title of the article, this trial, rather than simply assessing the efficacy of a particular drug regimen, evaluated a total strategy of tuberculosis management. Thus, in addition to examining therapeutic regimens given for a planned duration of only eight weeks, included assessment of the efficacy of that planned regimen in the context of a strategy that included close follow-up, continued treatment of initial drug failure, and rapid detection of relapses with swift restarting of therapy.