Based on research evidence and expert experience, the panel identified subpopulations of people who might be affected differently than most by this recommendation; these subpopulations were People with HIV, children, pregnant women, breastfeeding women, patients with extrapulmonary TB and patients with extensive TB disease. The recent new recommendation for use of bedaquiline in children with MDR/RR-TB aged below 6 years was considered (31). The panel noted specific considerations for the subpopulations listed below.
People living with HIV
The data evaluated corresponded to a setting with a high prevalence of HIV; of particular significance was that most People with HIV (>90%) who started the 9-month regimens were receiving 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 People with HIV. It is necessary to consider significant clinical interactions that may increase bedaquiline exposure or that of other agents with potential for cardiotoxicity when these are co-administered with antiretroviral drugs. 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 (these drugs 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) (46–48). Neuropathy, liver enzyme elevations and CNS side-effects can be attributed to HIV or TB drugs or their interactions (49).
Children
The datasets included only small numbers of people aged below 15 years (n=69), and thus did not allow for reliable comparisons in both datasets from South Africa (n=69 and n=7) and in the 2021 IPD (n=7). However, analysis in the subgroup aged below 15 years showed a relative increase in treatment success of 42% (aRR=1.42, 95% CI: 0.7 to 2.89) in sub-PICO 1.1 and a 5% relative reduction (RR=0.95, 95% CI: 0.78 to 1.15) in sub-PICO 1.2. Although a small number of participants were aged between 10 and 15 years (19/50, 38% in the intervention group, and 75/162, 46% in the comparator group), extrapolation of the findings to children was deemed reasonable for efficacy because components of the regimen had been used safely in children based on other available data regarding linezolid use in children. This extrapolation was considered applicable to children of all ages, taking into account the recommendation for use of bedaquiline in children aged below 6 years (31).
Pregnant and lactating women
In the research studies analysed, pregnant women were not identified, and subgroup data were unavailable. Ethionamide 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), and this is the main reason that the 9-month regimen has not been recommended for this subgroup in the past. There is experience in using linezolid during pregnancy (50, 51). For pregnant and lactating women, it is therefore recommended to use the regimen with linezolid instead of ethionamide.
Extrapulmonary TB
A subgroup of people with extrapulmonary TB were included in the research studies (81 in the regimen containing linezolid and 23 in the regimen with ethionamide). In view of the unavailability of evidence on surrogates for severity or extent of disease, the use of this regimen in patients with severe forms of extrapulmonary TB is not recommended.