1. A 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) resulted in lower mortality, treatment failure, and discontinuation compared to the standard of care regimen for rifampin-resistant tuberculosis.

2. The incidence of serious adverse events was lower in the BPaLM group compared to the standard of care group. 

Evidence Rating Level: 1 (Excellent)

Study Rundown: The recommended standard of care treatment for rifampin-resistant tuberculosis is nine to 20 months, including up to 20 tablets daily. A treatment regimen that is more cost-effective and has fever-associated adverse events is needed. In this randomized control trial, the standard of care treatment and three variants of the BPaL regimen were evaluated for their efficacy and safety in patients with rifampin-resistant tuberculosis. The treatment variants of BPaL include BPaL alone, BPaLM, and BPaL plus clofazimine (BPaLC). Analysis was conducted at two stages: week eight for stage one and weeks 24 to 108 for stage two. At stage one, culture conversion at eight weeks was highest with the BPaLM treatment, and therefore BPaLM was selected for analysis for stage two of the trial. At stage two, the primary outcome (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) was lower in the BPaLM group compared to the standard of care group. Subgroup analysis did not reveal any significant treatment effects from age, sex, human immunodeficiency virus infection, sputum smear status, cavities on chest radiographs, fluoroquinolone resistance, or country of recruitment. For safety outcomes, the incidence of serious adverse events was lower in the BPaLM group compared to the standard of care group. The most common were hepatic disorders, QTcF prolongation, and peripheral neuropathy. As a limitation, the study used an open-label design that could bias outcomes. Standard of care regimen was updated throughout the trial, which resulted in variations in the control group over time.

A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis

Relevant Reading: A trial of a shorter regimen for rifampin-resistant tuberculosis

In-Depth [randomized controlled trial]: This randomized control trial evaluated the efficacy and safety of three 24-week BPaL regimens versus standard of care treatment in patients with rifampin-resistant tuberculosis. Patients over the age of 15 with rifampin-resistant tuberculosis (n=552) were randomized at equal proportions into BPaL, BPaLM, BPaLC, and standard treatment groups in stage one (week eight), and in a one-to-one ratio into BPaLM and standard treatment groups in stage two (weeks 24 to 108). A subset of patients (n=303) was included in stage two. Patients were followed for a total of 108 weeks. In stage one, the primary efficacy outcome was culture conversion at eight weeks and the primary safety outcome was the incidence of death or discontinuation for any cause at eight weeks. In stage two, the primary efficacy outcome was a composite score of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis at 72 weeks. The primary safety outcome was adverse events at weeks 72 and 108. In stage one, culture conversion occurred in 77%, 67%, and 46% of the BPaLM, BPaLC, and BPaL groups, respectively. Discontinuation and deaths occurred in 8%, 6%, and 10% of the BPaLM, BPaLM, and BPaL groups respectively. In stage two, the primary efficacy outcome was observed in 53% and 24% of the standard care and BPaLM groups respectively. In the modified intention-to-treat analysis that included only patients with microbiologically proven rifampin-resistant tuberculosis who received at least one dose of trial medication, the primary efficacy outcome occurred in fewer patients in the BPaLM group than the standard care group (unadjusted risk difference, -37 percentage points; 96.6% Confidence Interval [CI], -53 to -22). For the primary safety outcome, there were fewer serious adverse events in the BPaLM group compared to the standard care group (risk difference, -40 percentage points; 96.6% CI, -55 to -24). The present study suggests that treatment with BPaLM is more effective and has a better safety profile than standard of care for patients with rifampin-resistant tuberculosis.

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