Following the GDG’s assessment of the current evidence and judgements, the considerations were discussed for specific subgroups, as outlined in this section.
People living with HIV. The data evaluated corresponded to a setting with a high prevalence of HIV (slightly above 70% in the dataset). More than 95% of PLHIV initiated on the all-oral bedaquilinecontaining regimen were on ART. In view of the treatment outcomes described in the analysis, there were no grounds to believe that the regimen would perform any differently in PLHIV. However, because the data evaluated did not include information on changes to the regimen as a result of management of adverse drug reactions, or complications from drug–drug interactions, the GDG reiterated that it is worth paying attention to any potential drug–drug interactions or overlapping drug toxicities that may not have been captured. For example, bedaquiline concentrations can be reduced by efavirenz (they should not be co-administered) or increased by boosted protease inhibitors (resulting in a need for greater vigilance in monitoring for drug-related QT effects) (53–55). Neuropathy, liver enzyme elevations and central nervous system (CNS) side-effects can be attributed to HIV or TB drugs or their interactions (56).
Children. Although the analysis attempted to provide further insights into the use of the all-oral bedaquiline-containing regimen in special populations, the limited sample of children aged under 14 years in the database (n=6) meant that no direct outcome estimations could be drawn for this population. However, because the components of the all-oral bedaquiline-containing regimen have been used in children, extrapolation was deemed reasonable, provided that considerations for the implementation of bedaquiline in children are followed (11). Earlier recommendations on the composition of longer regimens indicated that bedaquiline could also be included in such regimens for patients aged 6–17 years (11); hence, the all-oral bedaquiline-containing regimen may be used in eligible children aged 6 years³³ and above, taking into account considerations for specific medications.
Pregnant and lactating women. The intervention regimen contains ethionamide, which is usually contraindicated in pregnancy, because animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans. Although more compelling evidence is needed on toxicity causes attributed to the use of specific anti-TB drugs during pregnancy and lactation, individualized longer regimens can be designed to avoid known toxicities until better safety profiles are established.
Extrapulmonary TB. The evaluated shorter all-oral bedaquiline-containing regimen was also implemented in individuals confirmed with MDR/RR-TB and with uncomplicated extrapulmonary TB disease. No evidence was available to discern the impact of this regimen in patients with extensive TB disease or severe forms of extrapulmonary TB.
³³ 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