Given the limited evidence on the use of BPaL, and the concerns mentioned above, the implementation of the BPaL regimen should be in the context of operational research only. Despite the promising treatment success rates observed in the Nix-TB study, the regimen may not currently be considered for programmatic use worldwide until additional evidence on efficacy and safety has been generated. Operational research is intended to generate this evidence. The implementation of the BPaL regimen in the context of operational research implies that:
• a study protocol needs to be developed and submitted to a national ethics board or any other ethics approval committees;
• pre-specified inclusion and exclusion criteria are in place;
• an appropriate schedule of safety monitoring and reporting is in place (including aDSM):
• a pre-defined schedule of clinical and microbiologic monitoring is in place, preferably including post-treatment completion follow-up;
• individual patient informed consent is obtained;
• patient support is provided; and
• a standardized reporting and recording system is used, including for adverse events.
Details on a generic operational research protocol, data collection and other aspects that can be adapted for the BPaL operational research can be found in the ShORRT research package developed by WHO and TDR (36).
Patients should be fully informed about the regimen, and especially that it includes a new compound, pretomanid. Individual patient informed consent is necessary but should not be overly burdensome for patients – consent forms should be adapted, contextualized and streamlined so that they are easy for patients to understand. As part of the informed consent process, patients should be advised of the reproductive toxicities seen in animal studies and advised that the potential effects on human male fertility have not been adequately evaluated. A medication guide is available as part of the pretomanid product label, and it may be used when informing patients. In any operational research study involving the BPaL regimen, the principles of good clinical practice should apply. All efforts need to be made to carefully select eligible patients and then, once patients are enrolled, to provide effective patient support to enable adherence to treatment and close monitoring for adverse events and response to treatment.
DST is an important implementation consideration, which will need further enhancement in many countries given the increasing potential use of bedaquiline and linezolid (even for longer regimens for MDR/RR-TB) and the inclusion of new medicines – such as pretomanid – in MDR-TB treatment regimens. Baseline DST will confirm eligibility for the BPaL regimen; therefore, the establishment and strengthening of DST services will be a vital implementation consideration. For patients with confirmed MDR/RR-TB, the MTBDRsl assay is considered as the initial test, in preference to culture and phenotypic DST, to detect resistance to fluoroquinolones and, if necessary, to the second-line injectable drugs (94). If DST is available for bedaquiline or linezolid, it is highly desirable that this is also carried out at baseline. DST for pretomanid is being developed. In settings in which laboratory capacity for DST to fluoroquinolones is not yet available, it will be difficult to carry out operational research on BPaL. Patients with strains resistant to any of the medicines used in the BPaL regimen should commence treatment with a longer MDR-TB regimen. In addition, because access to DST should be improved for all component medicines of the BPaL regimen, there will be a need to have the medicine powders available and to have data on the MIC distribution of all M. tuberculosis lineages that are circulating globally.
In the Nix-TB study, all medications were administered with food throughout and study medications were supervised according to local site practices, as a form of patient support. It was necessary for patients to complete 6 months (i.e. 26 weeks of prescribed doses) within 8 months; for those who had treatment extended, it was necessary for patients to complete 9 months of treatment (i.e. 39 weeks of prescribed doses) within 12 months (1).
Preventing treatment interruption is important to increase the likelihood of treatment success. Measures to support patient adherence tailored to patient needs are important to retain patients on treatment and to ensure good treatment outcomes, such as a relevant model of care, DOT provided in the community or at home and by a trained treatment supporter, social support and digital health interventions for communication with the patient (see Section 9) (1, 2).