Treatment

People with HIV represented 19.5% of those enrolled in the ZeNix trial, 51% of those enrolled in the Nix-TB study and 26.7% of those enrolled in the TB-PRACTECAL trial. People with HIV were eligible to enrol in the ZeNix trial if they had a CD4 count of more than 100 cells/uL, and in TB-PRACTECAL regardless of CD4 count. Thus, patients can be enrolled in the BPaLM/BPaL regimen irrespective of the CD4 count; however, care should be taken when CD4 counts are below 100 cells/mm³.

Children were excluded from the Nix-TB, ZeNix (0–13 years) and TB-PRACTECAL (0–14 years) studies; therefore, no analysis specific to this subgroup of patients could have been performed. Although bedaquiline, linezolid and fluoroquinolones have been used to treat MDR/RR-TB in children, there are no data about the use of pretomanid in children, and further study is required to expand the use of BPaLM/BPaL to children. It is recommended that children aged below 14 years with pulmonary MDR/RR-TB be given consideration for the 9-month treatment regimen.

The BPaLM/BPaL regimen may need to be discontinued in some patients. In such cases, patients need to be evaluated and treatment switched to an individualized longer regimen, based on the WHO guidelines for regimen design using priority grouping of medicines. The most common situations in which the regimen may be discontinued are treatment failure, inability to use linezolid for enough time owing to adverse effects (discussed above) or pregnancy that occurs during treatment.

The only experience using these new regimens stems from two clinical trials; it is therefore suggested that the programmatic implementation be aligned with this experience. Safe management of adverse events may warrant dose reduction or discontinuation of the component drugs. However, the BPaLM/ 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 drugs may result in poor treatment outcomes.

Linezolid is by far the most toxic drug in the BPaLM and BPaL regimens; it requires significant monitoring and at times a mitigation strategy to reduce adverse effects. Although it is preferred to continue linezolid at the full dose for the entire duration, the dose of linezolid can be reduced to 300 mg or discontinued (and restarted when possible) if there is significant toxicity. In general, action should be taken in the following manner for the common toxicities associated with linezolid:

Patients with susceptibility to fluoroquinolones can be started on the BPaLM regimen for 6 months (26 weeks). In the case of resistance to fluoroquinolones, identified after treatment initiation, moxifloxacin may be discontinued and the regimen can be continued as BPaL. When the regimen is BPaL from the start or is changed to BPaL, it can be extended to a total of 9 months (39 weeks) (continuing from the start of the therapy with BPaLM/BPaL).

The BPaL regimen can be prescribed for those who have proven fluoroquinolone resistance. In cases of possible fluoroquinolone resistance (e.g. a history of >4 weeks of fluoroquinolone use or close contact with a person infected with a fluoroquinolone-resistant strain), it is best to use the BPaLM regimen until DST for fluoroquinolones is available, to decide whether or not moxifloxacin should be continued. Where DST is pending, BPaLM can be commenced, subsequently dropping moxifloxacin from the regimen once fluoroquinolone resistance is confirmed.

Patients who receive BPaLM/BPaL need to be tested at baseline and then monitored during treatment using schedules of relevant clinical and laboratory testing. If feasible, it is also important to follow up patients 12 months after the completion of treatment for possible relapse, including with sputum culture and smear.

Patients who receive the (H)REZ–levofloxacin regimen need to be monitored during treatment, using schedules of clinical and laboratory testing. The definitions to use when assigning outcomes are the same as those used for drug-susceptible TB (79). Signs of non-response or treatment failure should be followed up with DST for rifampicin resistance and, if possible, for fluoroquinolones and pyrazinamide.

Children

In the IPD review, only 2% of Hr-TB patients were children; thus, a separate estimate of effect for paediatric patients was not possible. However, there is no reason why the results and recommendations cannot be extrapolated from adults to children, considering that the regimen components have been standard paediatric TB medicines for many years.

Patients with extensive disease