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Treatment Strategy for Rifampin-Susceptible Tuberculosis - TRUNCATE-TB Trial
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NEJM Feb 20 2023
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Nicholas I. Paton, M.D., Christopher Cousins, M.B., Ch.B., Celina Suresh, B.Sc.,
Erlina Burhan, M.D., Ka Lip Chew, F.R.C.P.A., Victoria B. Dalay, M.D.,
Qingshu Lu, Ph.D., Tutik Kusmiati, M.D., Vincent M. Balanag, M.D.,
Shu Ling Lee, B.Sc., Rovina Ruslami, Ph.D., Yogesh Pokharkar, M.Sc.,
Irawaty Djaharuddin, M.D., Jani J.R. Sugiri, M.D., Rholine S. Veto, M.D.,
Christine Sekaggya-Wiltshire, Ph.D., Anchalee Avihingsanon, M.D.,
Rohit Sarin, M.D., Padmasayee Papineni, F.R.C.P., Andrew J. Nunn, M.Sc.,
and Angela M. Crook, Ph.D., for the TRUNCATE-TB Trial Team*
The results of the TRUNCATE-TB trial showed that a strategy involving initial treatment with an 8-week regimen that contained bedaquiline and linezolid was noninferior to standard treatment with respect to the risk of a composite clinical outcome at week 96. The efficacy of the strategy, as compared with standard treatment, was consistent across multiple subgroups that were defined according to baseline characteristics, including some that are indicative of severe disease and high relapse risk.
The results of this trial suggest that there may be value in considering a shift in tuberculosis management to a strategy involving initial treatment for the minimum duration needed to cure the majority of persons with tuberculosis, extended treatment for persistent clinical disease, and monitoring after treatment to detect relapse in the minority of persons who need retreatment. 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. Implementation research is vital to refine the strategy and evaluate outcomes in individual treatment programs and diverse populations before consideration of adoption at scale.
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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. opens in new tab.)
For more than four decades, the global standard treatment for drug-susceptible pulmonary tuberculosis has been a 6-month rifampin-based regimen. This treatment has cured more than 95% of persons with tuberculosis in the context of clinical trials but has underperformed in national treatment programs, in which long-term adherence is difficult for some persons and resource constraints limit the provision of adherence support.1-3 The unsatisfactory outcomes associated with standard treatment have contributed to the ongoing failure to meet global tuberculosis targets and to the generation of drug resistance.4 Exploration of new treatment approaches is essential.
In clinical trials, at least 85% of participants have been cured with 3-month and 4-month regimens, and the percentage is likely to be higher when these regimens contain fluoroquinolones or rifapentine.5-9 A similar probability of cure has also been observed with 2-month regimens that are administered for the treatment of smear-negative tuberculosis.5,10,11 Thus, the current 6-month regimen may lead to overtreatment in the majority of persons in order to prevent relapse in a minority of persons. This approach may be misaligned with the desires of persons who have tuberculosis and with efficient functioning of programs, thereby impairing outcomes.
We hypothesized that a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, follow-up after treatment, and prompt retreatment for the minority of persons who have a relapse might lead to long-term efficacy that would be noninferior to that of standard treatment, along with a reduced total duration of treatment and other secondary advantages for persons with tuberculosis and for treatment programs.
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