Patient selection and decisions to start the 9-month regimens
Patient selection and decisions to start the 9-month regimens in newly diagnosed patients should be made through an informed decision-making process that includes patient preference and clinical judgement, and DST results available before the start of treatment.
These regimens can be a preferred option over the longer regimens and can be used in those who are not eligible for the shorter BPaLM/BPaL regimens. Patients with confirmed MDR/RR-TB and in whom resistance to fluoroquinolones has been ruled out are expected to benefit the most from 9-month regimens. Proper patient selection would not only lead to improved treatment outcomes but would also contribute to protecting against the development of bedaquiline resistance. In this respect, the regimen is to be implemented only in settings where routine DST for rifampicin and fluoroquinolones can be guaranteed.
Patients should be informed about the advantages and possible disadvantages so that they can make an informed decision on the regimen of choice. Previous exposure of less than 1 month duration to the second-line medicines used in the regimen needs to be ascertained; it can then be considered along with any additional DST results available. Based on the available evidence, this regimen can be used in patients with confirmed MDR/RR-TB (with at least confirmed resistance to rifampicin) in whom resistance to fluoroquinolones has been ruled out, in the following situations: no exposure to previous treatment with second-line medicines in the regimen for more than 1 month (unless susceptibility to these medicines is confirmed); or no extensive TB disease and no severe extrapulmonary TB.
Drug susceptibility testing
DST for bedaquiline and linezolid is an important implementation consideration that will need to be enhanced in many countries, given the increasing use of these medicines in all regimens for MDR/RR-TB and the possible further inclusion of new medicines in MDR-TB treatment regimens. The implementation of these recommendations must be accompanied by continued efforts to increase access to DST for all medicines for which reliable methods are currently available, and for the development and roll-out of DST methods for newer medicines. Access to WHO-recommended rapid DST is essential, especially for detecting resistance to rifampicin and fluoroquinolones, before starting the 9-month regimens. Baseline DST will confirm eligibility for different regimen options; therefore, the establishment and strengthening of DST services is a vital consideration for implementation. The DST methods for identifying resistance to bedaquiline and linezolid have been developed on available phenotypic platforms and need to be implemented in all settings where these medicines are being used. Resistance to other anti-TB drugs should be monitored in accordance with WHO recommendations.
One of the exclusion criteria for all shorter regimens in the datasets from South Africa was mutations in both inhA promoter and katG regions, confirmed using a line probe assay (LPA). This means that patients with only inhA or only katG mutations were included. A first-line LPA (MTBDRplus) and Xpert MTB/XDR cartridge can determine mutations in the inhA promoter or katG regions; both mutations confer resistance to isoniazid, with the resistance being low level when inhA mutations alone are present, or high level with katG gene mutations alone or inhA promoter and katG gene mutations combined. Mutations at the inhA promoter are also associated with resistance to ethionamide and prothionamide. The presence of mutations in both the inhA promoter and katG suggests that isoniazid at high dose and thioamides are not effective, and that the 9-month regimen may not therefore be used. In the absence of information on mutation patterns for an individual patient, the decision can be informed by knowledge of the frequency of the concurrent occurrence of both mutations, obtained from drug-resistance surveillance (52). Phenotypic DST for some medicines included in the regimen (e.g. ethambutol and ethionamide) is not considered reliable and reproducible; therefore, this testing should be employed with caution to inform the use of this regimen.25
Currently, there is limited capacity globally to carry out DST for bedaquiline; however, laboratory capacity should be strengthened in this area as new medicines and regimens begin to be used more widely. National and reference laboratories will need to have the relevant reagents available to enable DST to be carried out and will need data on the MIC distribution of all M. tuberculosis lineages that are circulating globally. The WHO TB 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 susceptibility testing for the fluoroquinolones, bedaquiline, delamanid, clofazimine and linezolid (35).
Selection of fluoroquinolones
Selection of fluoroquinolones may take into account the evidence from South Africa available for the review – 83% of patients analysed using the 2017 dataset received levofloxacin and the rest received moxifloxacin at standard dose (400 mg daily). Both levofloxacin and moxifloxacin have shown similar efficacy for treating DR-TB. The choice between levofloxacin and moxifloxacin was guided by the potential risk of cumulative cardiotoxicity, using moxifloxacin in a shorter regimen with injectables and levofloxacin in an all-oral shorter regimen. Levofloxacin is often preferred because of moxifloxacin’s slightly higher potential for cardiotoxicity; however, levofloxacin has been associated with musculoskeletal disorders in paediatric populations. Therefore, irrespective of the choice of fluoroquinolone, NTPs need to implement aDSM in all patients enrolled on treatment of DR-TB (39, 54).
Assessment of TB disease
To determine regimen options, it is important to know the extent of TB disease, in addition to the DST results and other considerations mentioned above. Extensive TB disease is defined in this document as the presence of bilateral cavitary disease or extensive parenchymal damage on chest radiography. In children aged below 15 years, advanced disease is usually defined by the presence of cavities or bilateral disease on chest radiography. This highlights the importance of chest radiography as part of the diagnostic and clinical management work-up for patients.
Regimen duration
The regimen comprises an intensive phase of 4 months that may be extended to 6 months when no bacteriological conversion is seen at the end of the fourth month of treatment, and a continuation phase of 5 months; hence, if extended, the regimens may last 11 months. In the dataset reviewed, the duration of bedaquiline and linezolid was restricted to 6 and 2 months, respectively.
Patient-centred approach
Efforts are required to provide patient support to enable full adherence to treatment.
25 See the list of high-confidence resistance-conferring mutations in the WHO guide on the use of next-generation sequencing technologies, WHO (2018) (53).