Book traversal links for 1.4 Subgroup considerations
Children were excluded from the ZeNix trial (aged 0–13 years) and the TB-PRACTECAL trial (aged 0–14 years); therefore, no analysis specific to this subgroup of patients could be performed. All medicines in the BPaLM regimen have been used in children except for pretomanid. New data on bedaquiline has been recently reviewed and its use has been expanded to all ages (see additional recommendation in Section 3 and (31)). The lack of safety data on pretomanid in children aged below 14 years was the main barrier for potential extrapolation of the BPaLM/BPaL recommendation to the threshold of being aged below 14 years. Thus, the recommendation of the BPaLM/BPaL regimen applies to adults and adolescents aged 14 years and older.
People living with HIV
HIV was diagnosed in 34 of 172 (19.8%) people enrolled in the ZeNix trial; however, it was impossible to perform any adjusted stratified analyses for people living with HIV (People with HIV), owing to the small sample size in sub-PICO comparisons 3.2, 3.3, 3.4 and 3.5. People with HIV were eligible for enrolment in the ZeNix trial if they had a CD4 count of more than 100 cells/mm3 and if they were using antiretroviral medications.21 No aspects specific to HIV status or CD4 count were in the list of TB-PRACTECAL exclusion criteria, and People with HIV represented 27% of those enrolled. The median CD4 count among People with HIV was 322 (interquartile range [IQR] 217–622) across the four arms.
It is important to take drug–drug interactions into account when administering TB and HIV medications in combination; such interactions are discussed below. Although some therapies are to be avoided, there are alternative antiretroviral agents that can be considered when pretomanid is used. Thus, the recommendation of the BPaLM/BPaL regimen applies to all people regardless of HIV status, although some caution should be used when enrolling patients with CD4 counts lower than 100 cells/mm3.
Pregnant and lactating women
Pregnant and lactating women were excluded from the ZeNix and TB-PRACTECAL trials owing to unknown effects of the new medicine, pretomanid, on fetal development; therefore, no analysis specific to this subgroup of patients could be performed. The use of bedaquiline in pregnancy has been associated with infants born with a lower mean birth weight than infants whose mothers did not take bedaquiline; however, when infants were followed up over time, no evidence of late adverse impacts was found (see Section 3.2). Breastfeeding is not recommended for women taking pretomanid (32). Thus, the recommendation of the BPaLM/BPaL regimen does not apply to pregnant and breastfeeding women. While the safety of pretomanid during pregnancy and breastfeeding is unclear, other treatment options need to be used.
Patients with extrapulmonary TB were excluded from the ZeNix and TB-PRACTECAL trials; therefore, no analysis specific to this subgroup of patients could be performed. The available data on the central nervous system (CNS) penetration of bedaquiline or pretomanid are limited. Although all forms of extrapulmonary TB were excluded from the clinical trials, the GDG felt that extrapolation to extrapulmonary TB and other forms of TB was warranted except in cases involving severe forms of TB that may require special treatment arrangements and decisions, particularly TB involving the CNS, osteoarticular and disseminated forms of TB. Thus, the recommendation of the BPaLM/BPaL regimen applies to people with pulmonary TB and all forms of extrapulmonary TB except for TB involving the CNS, and osteoarticular and disseminated (miliary) TB.
Several other groups of patients were excluded from the two trials; for example, patients with liver enzyme measurements three or more times over the upper limit of normal; people with a corrected QT interval by Fredericia (QTcF) more than 500 ms, or history of cardiac disease, syncopal episodes, significant arrythmias, congenital QT prolongation, torsade de pointes or cardiomyopathy; those with a current peripheral neuropathy of Grade 3–4; and moribund patients with very low BMI (<17). These groups of patients may only receive the regimen if the treating physician judges this to be the best option despite these contraindications.
21 In the ZeNix trial, permitted antiretroviral treatments were nevirapine in combination with any nucleoside reverse transcriptase inhibitors (NRTIs); lopinavir/ritonavir in combination with any NRTIs; tenofovir/lamivudine/abacavir (if normal renal function); triple NRTI therapy consisting of zidovudine, lamivudine and abacavir (noting the increased risk of peripheral nerve toxicity with zidovudine and linezolid); and raltegravir in combination with NRTIs.