Assessing What’s PRACTECAL in Rifampicin-Resistant Tuberculosis

Tuberculosis (TB) is the leading cause of death worldwide from a single infectious agent. TB is caused by the bacillus Mycobacterium tuberculosis, infecting about a quarter of the world’s population. Drug-resistant TB continues to be a threat to public health; in 2019, approximately 465,000 patients worldwide had rifampicin-resistant disease, and 78% of these patients had multidrug-resistant TB (i.e., resistance to both rifampicin and isoniazid).

In patients who are sensitive to rifampicin, it is very effective, inhibiting RNA synthesis by its action on RNA polymerase. Rifampicin can cause secretions to change to a reddish-orange color, is a powerful inducer of the cytochrome P450 pathway, and is associated with multiple drug interactions. Due to hepatotoxicity developing in some patients, monitoring transaminases is necessary during treatment. When resistance develops, longer treatment durations for up to 20 months with alternative regimens, including injectable drugs, are often required. Testing for rifampicin resistance typically involves mycobacterial culture and drug susceptibility testing but can also be detected with the Xpert MTB/RIF assay using nucleic acid amplification to detect known resistance mutations.

In an open-label, two-stage, phase 2–3 multinational, randomized, controlled, noninferiority trial (Pragmatic Clinical Trial for a more Effective, Concise and Less Toxic Regimen[TB- PRACTECAL]), Nyang’wa et al. evaluated the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampicin-resistant TB.

In stage 1, patients were randomly assigned to local standard-care treatment or to one of three investigational regimens (oral therapy with bedaquiline, pretomanid, and linezolid (BPaL); or BPaL plus moxifloxacin (BPaLM) or clofazimine (BPaLC). At 8 weeks, 77% of patients who received the BPaLM regimen converted from positive to negative culture versus 67% culture conversion with BPaLC and 46% with BPaL.

In stage 2, the 24-week BPaLM regimen was compared to a 9-to-20-month standard-care regimen based on locally accepted protocols aligned with WHO guidelines. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, lost to follow-up or recurrence of tuberculosis). The study was terminated early for benefit after recruitment of 75% of the planned sample because 11% versus 48% of patients had unfavorable outcomes (89% of the patients who received the BPaLM treatment had favorable outcomes versus 53% of standard-care recipients). BPaLM was more effective and had a better safety profile than current standard regimens.

This pragmatic, patient-centered trial was broadly representative of the patient population of rifampicin-resistant TB with the inclusion of patients with fluoroquinolone-resistant TB and HIV co-infection. The results of this study are consistent with data from other trials of shorter duration regimens. In December 2022, the World Health Organization updated guidelines to include the BPaLM regimen as a recommended treatment for multidrug-resistant or rifampicin-resistant TB.

The following NEJM Journal Watch summary provides more details of the study:

Richard T. Ellison III, MD, reviewing Nyang'wa B-T et al. N Engl J Med 2022 Dec 22 Diacon AH. N Engl J Med 2022 Dec 22

Several trials have demonstrated the efficacy of bedaquiline-based regimens for drug-resistant tuberculosis (TB), although the utility of all-oral regimens has only been assessed in one country (NEJM JW Infect Dis May 2020 and N Engl J Med 2020 382:893; NEJM JW Infect Dis Mar 2022 and Am J Respir Crit Care Med 2022; 205:1214; NEJM JW Infect Dis Oct 2022 and N Engl J Med 2022; 387:810; and NEJM JW Infect Dis Nov 21 2022; [e-pub] and Lancet 2022 Nov 8; [e-pub]). In a two-stage, phase 2–3 trial involving 552 patients, investigators assessed the efficacy of three all-oral regimens for rifampin-resistant pulmonary TB. In stage 1, patients were assigned to standard care; oral therapy for 24 weeks with bedaquiline, pretomanid, and linezolid (BPaL); or this regimen with additional moxifloxacin (BPaLM) or clofazimine (BPaLC), with a primary endpoint of culture conversion 8 weeks after enrollment. In stage 2, the primary outcome was unfavorable treatment status at 72 weeks (death, treatment failure, treatment discontinuation, loss to follow-up, or recurrent TB).

Incidence of culture conversion at 8 weeks was 77% (BPaLM), 67% (BPaLC), and 46% (BPaL), with 8%, 6%, and 10%, respectively, discontinuing treatment or dying. The BPaLM group was chosen for stage 2 analysis, but the study was prematurely terminated when analysis of patients with microbiologically confirmed rifampin-resistant TB found that 32 of 66 patients (48%) in the standard-treatment group versus 7 of 62 (11%) in the BPaLM group had unfavorable status. Efficacy was not affected by age, sex, HIV status, sputum smear findings, cavitary disease, or fluoroquinolone susceptibility. Fewer serious adverse events occurred with BPaLM than standard therapy.

Comment: This study confirms the efficacy of relatively short-course therapy with BPaLM for drug-resistant pulmonary TB, a regimen now recommended by the WHO. However, an editorialist notes that, even while this regimen has yet to be assessed in children and adolescents, worrisome signs threaten its long-term efficacy: Bedaquiline will be coming off patent in several high-endemic nations that will allow unregulated usage, linezolid requires careful monitoring for toxicity, pretomanid carries high risk for resistance, and fluoroquinolone-resistant Mycobacterium tuberculosis strains are already prevalent in several regions. We cannot relax our efforts to find new treatments for this ancient pathogen.

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Robert Smyth, MD, MSc, is a 2022–2023 NEJM Editorial Fellow. He is currently an Assistant Professor of computational biomedicine at the Boston University School of Medicine.