4.4 Subgroup considerations

Children. Children (aged 0–13 years) were excluded from the Nix-TB study; therefore, no analysis specific to this subgroup of patients could be performed. It is recommended that children with pulmonary MDR/RR-TB with additional resistance to fluoroquinolones be given the same consideration for longer treatment regimens as adults, to include components with a safety profile that is better established. Bedaquiline is currently only recommended for children aged 6 years and above.⁵¹ Additional data on the use of BPaL in eligible children would be useful, and this may be a feature of carefully planned and monitored future research.

People living with HIV. PLHIV represented half of those enrolled in the Nix-TB study; however, it was impossible to perform any adjusted stratified analyses for PLHIV, owing to the small sample size.

PLHIV were eligible to enrol in the Nix-TB study if they had a CD4 count of more than 50 cells/µL and if they were using permitted antiretroviral medications.⁵² It is important to note drug–drug interactions when administering TB and HIV medications in combination, including the documented interactions between bedaquiline and efavirenz (see also (36)). Efavirenz also reduces pretomanid exposures significantly – therefore, an alternative antiretroviral agent should be considered if pretomanid or the BPaL regimen is to be used (94). Regimens including zidovudine should be used with special caution because zidovudine and linezolid may both cause peripheral nerve toxicity, and they are known to have myelosuppression cross toxicity.

Pregnant and lactating women were excluded from the Nix-TB study; therefore, no analysis specific to this subgroup of patients could be performed. For pregnant and lactating women, a longer regimen should be individualized to include components with a safety profile that is better established. Where this is the case, the outcomes of treatment and pregnancy (including infant characteristics), and postpartum surveillance for congenital anomalies should be documented to help inform future recommendations for MDR-TB treatment during pregnancy. The use of bedaquiline in pregnancy has been shown to be associated with infants born with a lower mean birth weight, when compared with infants whose mothers did not take bedaquiline; however, this did not appear to be a clinically significant finding when infants were followed up over time (see Section 3.2). Breastfeeding is not recommended for women taking BPaL (94).

Extrapulmonary TB. Patients with extrapulmonary TB were excluded from the Nix-TB study; therefore, no analysis specific to this subgroup of patients could be performed. The WHO recommendations on MDR-TB regimens apply to patients with extrapulmonary disease, including for those with TB meningitis. There are few data on the CNS penetration of bedaquiline or pretomanid.

Patients with very limited treatment options. In some instances, patients will have extensive drug-resistance profiles that may make it difficult (or impossible) to construct a regimen based on existing WHO recommendations. In such situations, the patient’s life may be endangered. Therefore, for individual patients for whom it is not possible to design an effective regimen based on existing recommendations,⁵³ the BPaL regimen may be considered as a last resort under prevailing ethical standards. In such patients, the use of BPaL should be accompanied by individual patient informed consent, adequate counselling on the potential benefits and harms, and active monitoring and management of adverse events. Patients should also be 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.

⁵¹ Based on the results of an RCT conducted by the manufacturer, the US FDA has extended approval for the use of bedaquiline for children aged 5 years and above. However, these data have not yet been assessed by WHO.https://www.accessdata.fda.gov/scripts/ cder/daf/index.cfm?event=overview.process&ApplNo=204384

⁵² These permitted antiretroviral treatments were: 1. nevirapine in combination with any nucleoside reverse transcriptase inhibitors (NRTIs), 2. lopinavir/ritonavir in combination with any NRTIs, 3. tenofovir/lamivudine/abacavir (if normal renal function), 4. triple NRTI therapy consisting of zidovudine, lamivudine and abacavir (however, noting the increased risk of peripheral nerve toxicity with zidovudine and linezolid), and 5. raltegravir in combination with NRTIs.

⁵³ Usually this group of patients would include those with an extensive drug-resistance profile who have very limited treatment options as part of a longer treatment regimen.

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