RetourThis section refers to the new short, 6-month (or 26-week) treatment regimen for MDR/RR-TB: the bedaquiline, pretomanid, linezolid and moxifloxacin (BPaLM) regimen. This regimen should be the initial choice for all eligible patients diagnosed with MDR/RR-TB. The recommendation in the updated 2022 WHO guidelines states:
Recommendation 1.1. WHO suggests the use of a 6-month treatment regimen composed of bedaquiline, pretomanid, linezolid (600 mg) and moxifloxacin (BPaLM) rather than the 9-month or longer (18-month) regimens in MDR/RR-TB patients. (Conditional recommendation, very low certainty of evidence)
Remarks
- Drug susceptibility testing (DST) for fluoroquinolones is strongly encouraged in people with MDR/ RR-TB, and although it should not delay initiation of the BPaLM, results of the test should guide the decision on whether moxifloxacin can be retained or should be dropped from the regimen – in cases of documented resistance to fluoroquinolones, BPaL without moxifloxacin would be initiated or continued.
- This recommendation applies to:
- People with MDR/RR-TB or with MDR/RR-TB and resistance to fluoroquinolones (pre-XDR-TB).
- People with confirmed pulmonary TB and all forms of extrapulmonary TB except for TB involving CNS, osteoarticular and disseminated (miliary) TB.
- Adults and adolescents aged 14 years and older. d. All people regardless of HIV status.
- Patients with less than 1-month previous exposure to bedaquiline, linezolid, pretomanid or delamanid. When exposure is greater than 1 month, these patients may still receive these regimens if resistance to the specific medicines with such exposure has been ruled out.
- This recommendation does not apply to pregnant and breastfeeding women owing to limited evidence on the safety of pretomanid.
- The recommended dose of linezolid is 600 mg once daily, both for the BPaLM and the BPaL regimen.2
The BPaL regimen was first investigated as part of the Nix-TB study. The study was conducted in South Africa from 2015 to 2017, and investigated the safety, efficacy, tolerability and pharmacokinetic properties of a 26-week treatment regimen with BPaL to treat MDR/RR-TB and MDR/RR-TB that was resistant to any fluoroquinolone and any second-line injectable drugs, or MDR-TB patients intolerant or non-responsive to the previous MDR-TB treatment. In 2019, WHO convened a GDG that recommended the use of the BPaL regimen under operational research for the treatment of MDR-TB patients with fluoroquinolone resistance and less than 2-week exposure to bedaquiline and linezolid.
Since the publication of the guidelines, two further studies – the TB-PRACTECAL and ZeNix trials – have confirmed the efficacy and safety of BPaL and BPaL-based regimens for a wider group of DR-TB patients. As a result, in February–March 2022, WHO again convened a GDG to consider new recommendations for the treatment of MDR/RR-TB.
The Nix-TB was a single-arm uncontrolled unblinded intervention study, in South Africa, with 108 participants, which investigated the BPaL regimen with high-dose linezolid (1200 mg daily). The ZeNix study was a partially blinded randomized controlled trial (RCT) of 181 patients, conducted in Georgia, Republic of Moldova, the Russian Federation and South Africa, investigating four different arms of the 26-week BPaL regimen with different doses (1200 mg or 600 mg) and durations (9 or 26 weeks) of linezolid. Both the Nix-TB and ZeNix trials were conducted by TB Alliance. The TB-PRACTECAL was a Phase 2–3, open-label RCT of 419 patients, investigating three different 24-week regimens containing a backbone of BPaL against the locally approved standard of care (SoC) that was based on WHO recommendations at the time of the study. The trial was conducted by Médecins Sans Frontières and the London School of Tropical Medicine & Hygiene, in Belarus, South Africa and Uzbekistan.
A total of eight BPaL-based regimens were investigated by these trials:
- Nix-TB study: BPaL for 26 weeks with 1200 mg of linezolid for the entire duration;
- ZeNix trial: BPaL for 26 weeks with 1200 mg of linezolid for the entire duration;
- ZeNix trial: BPaL for 26 weeks with 1200 mg of linezolid for 9 weeks;
- ZeNix trial: BPaL for 26 weeks with 600 mg of linezolid for the entire duration;
- ZeNix trial: BPaL for 26 weeks with 600 mg of linezolid for 9 weeks;
- TB-PRACTECAL: BPaL for 24 weeks with 600 mg linezolid for 16 weeks, followed by 300 mg for 8 weeks;
- TB-PRACTECAL: BPaL with moxifloxacin (BPaLM) for 24 weeks with 600 mg linezolid for 16 weeks, followed by 300 mg for 8 weeks; and
- TB-PRACTECAL: BPaL with clofazimine (BPaLC) for 24 weeks with 600 mg linezolid for 16 weeks, followed by 300 mg for 8 weeks.
For the 2022 guidelines, the GDG considered comparisons between each of the eight regimens. Additionally, comparison was made with the TB-PRACTECAL SoC comparator, and three other cohorts treated with all-oral regimens for MDR/RR-TB:
- a 2019 South African cohort, using a bedaquiline, linezolid and fluoroquinolone containing regimen with a treatment duration of 9-months (4244 patients);
- a 2017 South African cohort, using a bedaquiline and fluoroquinolone containing regimen for 9 months (880 patients); and
- an external cohort, from different countries, of MDR/RR-TB patients treated with bedaquilinecontaining regimens, with a treatment duration of 18–24 months (850 patients).
A successful treatment outcome was achieved in more than 80% of participants, at the end of treatment, for all eight investigational regimens, with 89% treatment success in the BPaLM arm of the TB-PRACTECAL. The treatment success rates were 52% in the SoC regimens in TB-PRACTECAL, 66% in the 2019 South Africa cohort, 69% in the 2017 South Africa cohort and 75% in the multicountry cohort. Based on programmatic data, 59% treatment success rates are reported globally to WHO for MDR/RR-TB (20).
2 Dosages of the other drugs are in Table 4.1.