Truncating the duration of treatment to 2 months using a bedaquiline-linezolid regimen was noninferior to the standard 6-month regimen in patients with pulmonary tuberculosis (TB) in terms of clinical outcomes, according to the results of the multicenter TRUNCATE-TB trial published in The New England Journal of Medicine. The findings of the trial were also presented at the recently concluded Conference on Retroviruses and Opportunistic Infections in Seattle, Washington.

To investigate the outcome of a shorter course of anti-TB treatment, Paton et al selected 674 adult patients, aged 18-65 years, with rifampicin-susceptible pulmonary TB at 18 sites in Indonesia, the Philippines, Thailand, Uganda, and India for this open-label, non inferiority trial. Nearly half of the participants were either former or current smokers. Forty-three percent were undernourished; 60% were found to be at intermediate risk for relapse, while 12% were at high risk of suffering a relapse.

Four short-course regimens were examined: high-dose rifampin + linezolid, bedaquiline-linezolid, high-dose rifampin + clofazimine and rifapentine-linezolid. The last two were not considered because of logistic criteria; hence, only the first two were considered in the analysis.

A total of 181 participants were randomized to standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks); 184 subjects were randomized to initial treatment with either high-dose rifampin + linezolid and 189 were assigned to bedaquiline + linezolid for the first 8 weeks, each combined with isoniazid, pyrazinamide and ethambutol with provisions for extended treatment for persistent clinical disease up to 12 weeks (if required), monitoring post-treatment and re-treatment if the disease relapsed.  

The primary outcome event, which was a composite of death, ongoing treatment or active disease at week 96 occurred in 7 patients (3.9%) in the standard treatment group compared to 11 patients (5.8%) treated with the 8-week regimen of initial bedaquiline + linezolid regimen (adjusted difference of 0.8 percentage points met the criterion for noninferiority). In the 8-week rifampin + linezolid treatment group, 21 patients (11.4%) reported the primary outcome event compared to the standard treatment group with an adjusted difference of 7.4 percentage points, which did not meet the non inferiority criterion. The total treatment time (mean) was 180 days in the standard treatment group vs 85 days in the bedaquiline–linezolid group. In the rifampin–linezolid group, the mean total treatment time was 106 days.

The occurrence of grade 3 or 4 adverse events, a secondary outcome of the study, was comparable between the three treatment groups (severe and undesirable adverse events are categorized as Grade 3, while life threatening or disabling adverse events are Grade 4). Acquired drug resistance, also a secondary outcome, was noted in just two patients (1.1%) in the bedaquiline + linezolid group, whereas no patient in the standard treatment group developed the drug resistance.

In the 8-week treatment groups, 80% patients required no further treatment after 8 weeks; 9% needed extended treatment up to 10 weeks, while 3% required extension of treatment to 12 weeks.

At week 96, 1.6% patients in the bedaquiline-linezolid group still had active disease when compared with 2.2% in the high-dose rifampin/linezolid group and 0.6% in the standard treatment group.

This study demonstrates the noninferiority of an initial 8-week bedaquiline +linezolid regimen to the standard 24-week treatment indicating that most patients could be successfully treated with this 2 month regimen although the treatment failure rate was higher. The total treatment duration was shorter and there were no major safety concerns. This study suggests the feasibility of shorter treatment regimens for TB together with close post-treatment monitoring and extension of treatment if required. Compared to 6 months of standard treatment, which often has many dropouts, a shorter regimen may have better adherence.

How will these findings translate into the real world and whether they will change clinical practice remains to be seen.

They may be especially pertinent to India, which has the highest prevalence of global TB. Moreover, it has committed to eliminate TB from the country by 2025.

References

1. Paton NI, et al; TRUNCATE-TB Trial Team. Treatment strategy for rifampin-susceptible tuberculosis. N Engl J Med Feb 20. 2023;doi:10.1056/NEJMoa2212537.
2. 8-week TB treatment strategy shows potential - Medscape - Feb 20, 2023.
3. https://www.medpagetoday.com/meetingcoverage/croi/103197, Feb. 21, 2023.