4.5 Implementation considerations

Given the paucity of evidence on the use of BPaL, and the concerns mentioned above, members of the GDG suggested that it should be implemented only in the context of operational research. The GDG emphasized that, despite the promising treatment success rates observed in the Nix-TB study, the regimen may not be considered for programmatic use worldwide until additional evidence on efficacy and safety has been generated. The group emphasized the need for this research to take the form of RCTs as well as observational studies. Given the conditionality of this recommendation in the context of additional research, certain standards and principles are prerequisites for the implementation of BPaL. Further, the GDG emphasized that the principles of good clinical practice should apply in any operational research study involving BPaL.

Patient selection. Overall, to reproduce the treatment success rates observed in the Nix-TB study, all efforts need to be made to carefully select eligible patients. Once those patients are enrolled, it is also important to provide effective patient support to enable adherence to treatment, and close monitoring for adverse events, response to treatment and emerging drug resistance. As outlined below, all efforts should be made to ensure proper patient inclusion; obtain signed patient informed consent; administer treatment under closely monitored conditions; and ensure active pharmacovigilance and proper management of adverse drug reactions, and prevention of complications from drug–drug interactions.

Ensure proper patient inclusion – use is not advised in pregnant and lactating women and in children, and the Nix-TB study gives other inclusion and exclusion criteria. Although DST is an important component of patient selection for the BPaL regimen (described below), another key implementation consideration is prior TB treatment history. Patients are eligible for the BPaL regimen if they have not received bedaquiline or linezolid for 2 weeks or more previously, and this was an eligibility criterion of the Nix-TB study. Given that the current WHO recommendation for longer treatment regimens for MDR/RR-TB includes bedaquiline and linezolid as priority medicines in Group A, some patients who have previously started treatment on a longer MDR/RR-TB regimen may in fact be ineligible for BPaL should they later develop fluoroquinolone resistance. This reaffirms WHO’s previous statements on the need to carefully select eligible patients for longer or shorter MDR/RR-TB treatment regimens, and once patients are receiving a regimen, to ensure patient support and close monitoring and follow-up, including monitoring for treatment failure and relapse, and emerging drug resistance, with DST performed when indicated. If resistance is suspected during treatment and DST is not available, the strains should be conserved and referred to a WHO SRL for further testing. Each operational research protocol on the use of BPaL in a given setting will need to include detailed inclusion and exclusion criteria.

Obtain signed patient informed consent – consent should be obtained after giving detailed explanations on the novel nature of the regimen and pretomanid, including the risks and benefits of the regimen. The GDG members thought that informed consent should not be overly burdensome for patients; consent forms should be adapted, contextualized, streamlined and provided in the local language(s) so that they are easy for patients to understand; and patients should be fully informed about the regimen, given that it also includes a new compound, pretomanid. As part of the informed consent process, patients should be:

• offered sufficient information on potential adverse events including low blood cell counts (e.g. anaemia, thrombocytopenia and neutropenia), liver toxicities, and peripheral and optic neuropathy;

• advised that reproductive toxicities have been observed in animal studies, and that the potential effects on human male fertility have not been adequately evaluated at this time; and

• informed that pretomanid is excreted in breast milk, and its safety in infants and children has not been adequately evaluated (94).  

A medication guide is available as part of the pretomanid product label; this guide may be used when informing patients about the BPaL regimen as part of a research study.

Administer treatment under closely monitored conditions – the aim is to enable optimal drug effectiveness and safety, and to monitor for the acquisition of emerging drug resistance, should it arise. Given that the regimen is a shorter regimen (i.e. it includes a new compound – pretomanid) and that its implementation is in the context of research, it may be especially important to monitor clinical progress after completion of treatment, to ensure relapse-free cure. Other design features of the Nix-TB study have implications for its implementation under operational research conditions. 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. Preventing treatment interruption increases the likelihood of treatment success. Measures to support patient adherence (e.g. by facilitating patient visits to health care facilities or home visits by health care staff or by using digital technologies for daily communication) may be important to retain patients on treatment, even though the regimen is comparatively short (29). WHO recommendations on the care and support of patients with MDR/RR-TB are provided in Section 8.

Active pharmacovigilance and proper management of adverse drug reactions, and prevention of complications from drug–drug interactions – the NTP should actively monitor drug safety to ensure proper patient care, to report any adverse drug reactions to the responsible drug-safety authority in the country, and to inform national and global policy.

The implementation of the BPaL regimen in the context of operational research implies that:

• a study protocol has been developed by appropriately skilled and experienced researchers, and that this research protocol has been submitted to a national ethics board or other ethical approval committee;

• prespecified inclusion and exclusion criteria are in place (noting the criteria used for the Nix-TB study);⁵⁴

• an appropriate schedule of safety monitoring and reporting is in place, including aDSM – usually overseen by a data safety monitoring board or similar independent research governance committee;

• a predefined schedule of clinical and microbiological monitoring is in place, preferably including post-treatment completion follow-up;

• individual patient informed consent is obtained;

• patient support is provided; and

• standardized reporting and recording is used, including for adverse events.

Review of treatment and management protocols by an independent group of experts in clinical management and public health (e.g. the national MDR-TB advisory group) is recommended.

DST is an important implementation consideration that 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 (e.g. pretomanid) in MDR-TB treatment regimens. Baseline DST will confirm eligibility for the BPaL regimen; hence, the establishment and strengthening of DST services will be a vital consideration for implementation.

In patients with bacteriologically confirmed MDR/RR-TB,⁵⁵ the MTBDRsl assay may be used as the initial test, in preference to culture and phenotypic DST, to detect resistance to fluoroquinolones (conditional recommendation; certainty of evidence for direct testing of sputum from low to moderate (33)). In settings in which laboratory capacity for DST to fluoroquinolones is not yet available, or cannot be accessed, it will be difficult to carry out operational research on BPaL. If testing for susceptibility to bedaquiline or linezolid is available, it is highly desirable to also carry this out at baseline and in the absence of culture conversion during treatment; however, such testing need not be a prerequisite for treatment initiation. Drug susceptibility testing for pretomanid is not yet available.

Currently, there is limited capacity globally for DST for bedaquiline and linezolid; as these medicines and regimens become more widely used, laboratory capacity in this area should be strengthened. National and reference laboratories will need to have the reagents for DST available, and will need data on the MIC distribution of all M. tuberculosis lineages that are circulating globally. If resistance to any of the component medicines in the BPaL regimen is detected, treatment with a longer MDR-TB regimen should be started. The WHO SRL Network is available to support national TB reference laboratories in performing quality-assured DST. A WHO technical consultation in 2017 established critical concentrations for DST for the fluoroquinolones, bedaquiline, delamanid, clofazimine and linezolid (58). Methods for testing pretomanid susceptibility are currently under development.

Dosing of linezolid. The linezolid dosage used in the Nix-TB study was 1200 mg per day. Initially, all study participants received 600 mg of linezolid BID, because that was the approved dose used to treat bacterial infections for up to 28 days at the time the study commenced. However, in May 2018, the protocol was changed to dosing of 1200 mg QD. According to the protocol, dose reduction to 600 mg daily, and further to 300 mg daily or temporary cessation of linezolid, was permitted for up to 35 consecutive days for any known linezolid adverse reactions of myelosuppression, peripheral neuropathy and optic neuropathy. If toxicity prohibited further treatment with linezolid, patients could remain on bedaquiline and pretomanid, provided that they had received the 1200 mg per day dose for at least the first 4 consecutive weeks, were sputum smear negative, and were responding to treatment based on clinical monitoring and follow-up. Missed doses of linezolid were not made up during the Nix-TB study, and dose modifications for bedaquiline and pretomanid were not allowed. Overall, 18 patients (17.3%) in the Nix-TB study completed a full course of linezolid at the 1200 mg dose, 38 (36.5%) completed with a 600 mg dose, 16 (15.4%) completed with a 300 mg dose and 32 (30.7%) stopped linezolid early due to an adverse event. The experience of the Nix-TB study suggests that it may be necessary to modify the dose of linezolid during treatment based on adverse events, highlighting the importance of close monitoring and patient follow-up, and aDSM. Additional studies such as the ZeNix study (TB Alliance) are underway to assess the optimal dosing and duration of linezolid for the treatment of drug-resistant TB; however, the results of these studies are not yet available for review.

To date, the BPaL regimen has been studied as a standardized course of treatment. Modification of the regimen through early discontinuation or replacement of any of the component medicines may result in poor treatment outcomes. The pretomanid product label recommends that if either bedaquiline or pretomanid tablets are discontinued, the entire BPaL regimen should also be discontinued. If linezolid is permanently discontinued during the initial 4 consecutive weeks of treatment, bedaquiline and pretomanid should also be discontinued. If linezolid is discontinued after the initial 4 weeks of consecutive treatment, clinicians should continue administering bedaquiline and pretomanid, consistent with the Nix-TB study protocol. In the Nix-TB study, it was necessary for patients to complete 6 months of the regimen (i.e. 26 weeks of prescribed doses) within 8 months; for those in whom treatment was extended, it was necessary for patients to complete 9 months of treatment (i.e. 39 weeks of prescribed doses) within 12 months. Patients who remained culture positive or who reverted to being culture positive between months 4 and 6, and whose clinical condition suggested they may have ongoing TB infection, had their treatment extended to a total of 9 months.

⁵⁴ The protocol for the Nix-TB study is available at: https://clinicaltrials.gov/ct2/show/NCT02333799.

⁵⁵ MDR/RR-TB is usually confirmed by rapid molecular tests that detect resistance to rifampicin and M. tuberculosis. Current WHO recommendations state that Xpert MTB/RIF should be used rather than conventional microscopy, culture and DST as the initial diagnostic test in adults suspected of having MDR-TB or HIV-associated TB (strong recommendation, high-quality evidence). Xpert MTB/RIF should also be used rather than conventional microscopy, culture and DST as the initial diagnostic test in children suspected of having MDR-TB or HIV-associated TB (strong recommendation, very low quality evidence) (24). A recent WHO rapid communication reinforced the high diagnostic accuracy and improved patient outcomes of rapid molecular diagnostic tests such as Xpert MTB/RIF, Xpert MTB/RIF Ultra and TrueNat (31).

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