OpiniãoHigh treatment success rates shown for the BPaLM and BPaL regimens in the Nix-TB study and in the ZeNix and TB-PRACTECAL trials, and favourable comparison with the current SoC regimens led to thorough discussions during the GDG meeting of an overall recommendation for implementation under routine programmatic conditions and of the implementation considerations for this regimen. Given that this recommendation is conditional, the results of additional or ongoing operational research will help to add further knowledge that can be used to adjust and improve implementation guidance for the regimen.
Patient selection
Overall, to reproduce the treatment success rates observed in the ZeNix and TB-PRACTECAL trials, it is important to carefully select eligible patients. Once those patients are enrolled, it is also important to provide effective patient support to enable adherence to treatment. It is also important to maintain close monitoring for adverse events, response to treatment and emerging drug resistance, and to properly manage adverse drug reactions and prevent complications from drug–drug interactions.
The selection of patients is best aligned with the eligibility criteria of two trials (also reflected in the subgroup consideration above). The patients that can be enrolled on the BPaLM/BPaL regimen should have bacteriologically confirmed MDR/RR-TB, with or without resistance to fluoroquinolones.
Drug susceptibility testing
It is important to pay attention to the previous use and susceptibility status of the medicines comprising this regimen. Patients with a known history of more than 1 month use of bedaquiline, pretomanid (or delamanid, given some degree of cross-resistance) and linezolid should not be enrolled on this regimen, unless the results of recent DST of these medicines has confirmed susceptibility. In cases where there is no prior use of these medicines or confirmed susceptibility, fluoroquinolone resistance testing should also be done before the start of treatment. However, fluoroquinolone resistance testing should not delay treatment initiation (e.g. in cases where this DST is not available or results are delayed). When DST results confirm fluoroquinolone susceptibility, treatment can be continued without any modifications. In cases of fluoroquinolone resistance, moxifloxacin should be dropped and the regimen continued as the BPaL combination only. This modification may seem counterintuitive, because patients with TB that is resistant to an increased number of drugs will receive fewer TB medicines. However, moxifloxacin is unlikely to provide a benefit in the presence of fluoroquinolone resistance and the BPaL regimen has been shown to have high efficacy without moxifloxacin. In the context of fluoroquinolone resistance, omitting moxifloxacin will help to avoid potential toxicity related to this medicine. Conversely, in the absence of fluoroquinolone resistance, the use of moxifloxacin further increases the efficacy of the regimen and may provide protection against acquired bedaquiline resistance, and thus is recommended. If fluoroquinolone DST results are unavailable, the GDG judged the likely benefits of retaining moxifloxacin as part of the regimen as outweighing the potential harms; therefore, WHO suggests using the BPaLM regimen in this situation.
The establishment and strengthening of DST services is a vital consideration for implementation of all treatment regimens for MDR/RR-TB. In patients with bacteriologically confirmed MDR/RR-TB, the Xpert® MTB/XDR (Cepheid) or GenoType® MTBDRsl (Hain Lifescience) assays may be used as the initial test, in place of culture and phenotypic DST, to detect resistance to fluoroquinolones (33, 34). 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. DST for pretomanid is not yet available; however, WHO expects to set critical concentrations for phenotypic DST in the next update of the technical report on critical concentrations for DST of medicines used in the treatment of DR-TB (35).
Currently, there is limited capacity globally for DST for bedaquiline and linezolid. As these medicines and regimens containing these medicines become more widely used, laboratory capacity in this area must be strengthened. National and reference laboratories will need to have necessary facilities and reagents to make DST available; also, they will need data on the minimum inhibitory concentration (MIC) distribution of all M. tuberculosis lineages that are circulating globally. Establishing or expanding capacity for sequencing of M. tuberculosis can provide a strong and future-proof platform for DST. If resistance to any of the component medicines in the BPaL regimen is detected, treatment with another recommended regimen should be started. The WHO TB Supranational Reference Laboratory (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 (35). Methods for testing pretomanid susceptibility are currently under development. When methods for DST are available, countries will need to add surveillance of resistance to new medicines to their routine efforts or surveys. These data can guide the adoption and use of new regimens and can also protect against amplification of resistance profiles.
Drug–drug interactions
It is important to take drug–drug interactions into account when administering TB and HIV medications in combination, including the documented interactions between bedaquiline and efavirenz (36). Efavirenz reduces pretomanid exposures significantly; therefore, an alternative antiretroviral agent should be considered if pretomanid forms part of the BPaLM/BPaL regimen (32). The preferred ART regimens for co-administration with BPaLM/BPaL are dolutegravir-based regimens in combination with two nucleoside reverse transcriptase inhibitors.
The following medications should be avoided or may require additional precautions during treatment with BPaLM/BPaL:
- efavirenz;
- drugs known to significantly prolong the QTc interval, including neuroleptics-phenothiazines (e.g. thioridazine, haloperidol, chlorpromazine, trifluoperazine, pericycline, prochlorperazine, fluphenazine, sertindole and pimozide), ondansterone, quinoline antimalarials (e.g. halofantrine, chloroquine, hydroxychloroquine and quinacrine), anti-arrhythmic drugs (e.g. quinidine, procainamide, encainide, disopyramide, amiodarone, flecainide and sotalol) and fluoroquinolones other than those included in the trial regimens;
- strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital, St. John’s wort [Hypericum perforatum], rifamycins, and systemic, multiple dosing of dexamethasone)
- strong CYP3A4 inhibitors (e.g. azole antifungals: ketoconazole, voriconazole, itraconazole and ketolides such as telithromycin; and macrolide antibiotics other than azithromycin) for more than 2 weeks;
- monoamine oxidase inhibitors (phenelzine, isocarboxazid and tranylcypromine); and
- drugs known to induce myelosuppression (e.g. azathioprine and cytotoxic agents).
Care and support
Treatment administration coupled with support to patients can boost adherence and ensure optimal drug effectiveness and safety. 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 when a regimen is comparatively short (37). WHO recommendations on care and support and a related handbook are available on the web under the WHO consolidated guidelines on tuberculosis. Module 4: Treatment – tuberculosis care and support (38).
Active TB drug-safety monitoring and management
Close monitoring of adverse effects of treatment is particularly important for the shorter treatment regimens and for regimens including new medicines (e.g. this regimen includes a novel compound – pretomanid), to ensure relapse-free cure. Active pharmacovigilance and proper management of adverse drug reactions and prevention of complications from drug–drug interactions will ensure proper patient care; and reporting any adverse drug reactions to the responsible drug-safety authority in the country will inform national and global policy (39). Additional information about active TB drug-safety monitoring and management (aDSM) is available in the operational handbook.
Regimen composition, dosing of component medicines and frequency
The BPaLM/BPaL regimen consists of bedaquiline, pretomanid and linezolid, with or without moxifloxacin throughout the regimen duration. Pretomanid is administered at 200 mg once daily for the duration of the regimen. When moxifloxacin is part of the regimen, it is dosed at 400 mg once daily throughout the treatment course. The fluoroquinolone of choice used in the TB-PRACTECAL trial was moxifloxacin; given that no evidence on using other fluoroquinolones was available at the time of the GDG assessments, the replacement of moxifloxacin with levofloxacin or any other fluoroquinolone cannot be recommended at this stage. The frequency of dosing should be 7 days a week with treatment support or using video-supported therapy; that is, as it was administered in both the trials.
Bedaquiline dosing schemes
The TB-PRACTECAL and ZeNix trials used slightly different dosing schemes for bedaquiline although the overall drug exposure was comparable (23). The dosing schedule used in the TB-PRACTECAL trial was consistent with the product label whereas the dosing schedule used in the ZeNix trial presented the advantage of daily dosing throughout the regimen and may be used as one of the options for administration. Either of the bedaquiline dosing schemes may be used for programmatic implementation:
- daily throughout treatment: 200 mg once daily for 8 weeks followed by 100 mg once daily; and
- daily for loading dose and three times per week thereafter: 400 mg once daily for 2 weeks followed by 200 mg three times per week.
Dosing of linezolid
The ZeNix trial used several different dosing and duration schemes of linezolid, with the aim of determining the optimal administration schedule for this medicine. Linezolid is known to cause several potentially serious adverse effects; among those of most concern are peripheral neuropathy, optic neuritis and myelosuppression (40). The GDG review of the ZeNix trial data identified the optimal dosing for linezolid to be 600 mg once a day for 26 weeks, and this arm of the ZeNix trial was used for the main comparisons. Study participants in this arm of the trial received 600 mg of linezolid once daily for 26 weeks, with a reduction to 300 mg daily allowed in the event of linezolid specific toxicities. In the TB-PRACTECAL trial, dosing of linezolid was slightly different – participants were given 600 mg daily for 16 weeks and then 300 mg daily for the remaining 8 weeks (the duration of BPaLM in this trial was 24 weeks).
The GDG panel considered that it would be preferable to use linezolid 600 mg/daily throughout the regimen, but the dose can be reduced to 300 mg/daily if necessary to mitigate toxicity.
Regimen duration, changes and extensions
The BPaLM and BPaL regimens have been studied as the standardized courses of treatment. Therefore, modification of the regimen through early discontinuation or replacement of any of the component medicines may result in different (and possibly worse) treatment outcomes. In the TB-PRACTECAL trial, patients received 24 weeks of BPaLM. In the ZeNix trial, treatment was extended to a total of 9 months in patients on the BPaL regimen who remained sputum culture positive or who reverted to being sputum culture positive between months 4 and 6, or whose clinical condition suggested they may have progressive TB. In cases where treatment was interrupted and treatment duration was extended to make up for missed doses, it was necessary for patients to complete 6 months of the regimen (i.e. 26 weeks of prescribed doses) within 8 months; also, for patients in whom treatment was extended, it was necessary to complete 9 months of treatment (i.e. 39 weeks of prescribed doses) within 12 months.
Eligible patients with susceptibility to fluoroquinolones can be started on the BPaLM regimen for 6 months, with dosing of individual medicines as described above. This combination of medicines can be continued throughout the regimen without any prolongation (unless there is a need to make up the missed doses). In cases where resistance to fluoroquinolones is identified before or after treatment initiation, moxifloxacin can be discontinued. When the regimen is BPaL from the start or is changed to BPaL, it can be extended to a total of 39 weeks (counting from the start of the therapy with BPaLM/BPaL). This extension is justified in cases of failure to convert culture between months 4 and 6 while on treatment; alternatively, it can be based on the clinical judgement of the treating physician. Up to 1 month can be added to the overall treatment duration if there is a need to make up the missed doses.
The GDG panel acknowledged these slight differences in the treatment duration of the BPaLM and BPaL regimens as studied in these two trials, and suggested standardizing the treatment duration of BPaLM to 6 months (26 weeks) during programmatic implementation; for BPaL they suggested the possibility of extension to a total of 9 months (39 weeks) if sputum cultures are positive between months 4 and 6. All medicines in the regimen are to be used throughout treatment duration, including a potential extension from 26 to 39 weeks (when BPaL is used). Ideally, missing doses of all three or four drugs in the regimen should be avoided; however, if doses are missed, any interruption of longer than 7 days should be made up by extending the treatment duration (for the number of missed doses); therefore, 26 or 39 weeks of prescribed doses should be completed within an overall period of 7 or 10 months, respectively.
Missing doses and tolerances for treatment interruptions
The TB-PRACTECAL and ZeNix trials used different tolerances for treatment interruption and missing doses, and the ZeNix trial protocol provided specific rules for linezolid administration.
The GDG panel suggested standardizing the allowable missing doses and the approach to linezolid administration. The following pragmatic approach is suggested to guide clinical judgement and potential minor deviations in individual cases:
- all possible efforts should be made to support the patient and manage the adverse events to ensure uninterrupted treatment and intake of all medicines in the regimen; however, when medicine cannot be tolerated it should be stopped;
- consecutive treatment interruption (of all medicines in the regimen) of up to 2 weeks should be made up and added to the treatment duration;
- nonconsecutive missed doses of all medicines in the regimen up to a cumulative total of 4 weeks should be made up and added to the treatment duration; and
- after consecutive administration of linezolid at recommended doses (600 mg/daily) for at least 9 weeks, in case of intolerability the dose can either be adjusted down (to linezolid 300 mg/daily) or omitted (while other medicines in the regimen are continued) for a total of a maximum of 8 weeks throughout the treatment course.
In case any single one of these tolerances is exceeded, a thorough assessment of the patient’s status will be required to decide whether to continue the treatment strategy or modify it.