7. The bedaquiline, pretomanid and linezolid (BPaL) regimen for MDR-TB with additional fluoroquinolone resistance

The Nix-TB study was conducted in South Africa in 2015–2017 to assess safety, efficacy, tolerability and pharmacokinetic properties of a 6–9-month treatment regimen composed of bedaquiline, pretomanid and linezolid (BPaL) for treatment of XDR-TB, intolerant and non-responsive MDR-TB (95). Soon after the results of the Nix-TB study became available, WHO convened a guideline development group (GDG) meeting, in November 2019, to review the data for updating the WHO guidelines.

The evidence derived from the Nix-TB study included information on 108 patients for efficacy analyses and 109 patients for safety analyses. These data were compared to a subset of data (456 patients) from the IPD, which overall includes 13 273 individual patient records from different countries. For the primary analyses, the comparator group included patients from the IPD on longer treatment regimens (with a mean duration of treatment of 21.0–25.5 months), who received both bedaquiline and linezolid as part of the regimen. Overall, the treatment success rate was high, being 97.0% in the treatment group compared with 91.7% in the comparator group (1). The BPaL regimen was associated with a high rate of adverse events that were considered to be related to the study drugs. Of the 109 patients in the Nix-TB study, 28 (25.7%) experienced at least one serious adverse event, with one (0.9%) death related to acute haemorrhagic pancreatitis, 18 patients (16.5%) experiencing adverse events that required or prolonged hospitalization, 11 patients (10.1%) experiencing adverse events that were considered life threatening and two patients (1.8%) experiencing adverse events that resulted in persistent or significant disability or incapacity. There were signals of reproductive toxicity, with the potential effects on human male fertility that have been observed in the preclinical data from animal studies (1).

aBPaL regimen: 6–9 Bdq- Pa-Lzd

After considering the evidence, the GDG recommended that the BPaL regimen be used under operational research conditions conforming to WHO standards, which include research subject to ethical approval, patient-centred care and support, pre-defined eligibility criteria, patient informed consent, implementation according to the principles of good clinical practice, active drug safety monitoring and management, treatment monitoring, outcome evaluation, and comprehensive, standardized data collection.

Pretomanid is a novel medicine that has recently been studied as part of the BPaL regimen for the treatment of MDR-TB with additional fluoroquinolone resistance. Pretomanid possesses activity against both replicating and non-replicating M. tuberculosis (Abdel-Rahman SM. unpublished data, Children’s Mercy Hospital, Kansas City, United States of America, November 2019). In vitro, preclinical and clinical data support a role for pretomanid as part of the BPaL regimen (6–9 Bdq-Pa-Lzd). Because there is no experience of the use of this medicine in other combinations, pretomanid is not recommended for use outside the context of the BPaL regimen. Safety signals related to pretomanid include hepatologic, gastrointestinal, dermatologic and reproductive adverse effects.

WHO recommendation on the use of BPaL regimen (1)

Recommendation 4.1 A treatment regimen lasting 6–9 months, composed of bedaquiline, pretomanid and linezolid (BPaL), may be used under operational research conditions in multidrug-resistant tuberculosis (MDR-TB) patients with TB that is resistant to fluoroquinolones, who have either had no previous exposure to bedaquiline and linezolid or have been exposed for no more than 2 weeks.

(Conditional recommendation, very low certainty in the estimates of effect)

Book navigation