Remarks

• This recommendation complements the current WHO recommendation on longer regimens that contain delamanid (9):
• Delamanid may be included in the treatment of MDR/RR-TB patients aged 3 years or more on longer regimens (conditional recommendation, moderate certainty in the estimates of effect).

Subgroup considerations Extrapulmonary TB: The use of delamanid in children with extrapulmonary MDR/RR-TB may be considered (as part of longer regimens used for children with extrapulmonary MDR/RR-TB) by extrapolating data from those with PTB; the delamanid trials, however, have studied PK and safety among children with pulmonary MDR/RR-TB. Children living with HIV: Children living with HIV were not enrolled in trials 242–12–232 and 233. Although evaluated in healthy adult volunteers, reports from antiretroviral drug-drug interaction studies suggest that the CYP3A4 inhibitor lopinavir/ritonavir increases delamanid total body exposure up to 25% [GMR: 1.22 (90% CI 1.06,1.40)] (90). This increase is not clinically relevant and does not necessitate any dose adjustments. No change in delamanid exposure was observed with co-administration of either tenofovir [GMR: 0.96 (90% CI 0.84,1.10)], a CYP1A2 inhibitor, or efavirenz [GMR: 0.94 (90% CI 0.72,1.23)], a weak CYP3A4 inducer. Delamanid does not affect plasma exposure of the antiretroviral drugs tenofovir, lopinavir/ritonavir or efavirenz (94). No drug interaction studies of delamanid together with integrase inhibitors have been performed, but based on knowledge of metabolic pathways, the risk of metabolic drug interaction potential is expected to be low (95). Therefore, based on available evidence, delamanid can be given to CLHIV with MDR/RR-TB on ART regimen without dose adjustments.

Implementation considerations Delamanid has been in use for adults and adolescents since 2014 and for children since 2016 (from 6 years of age) and 2019 (from 3 years) and therefore the implementation considerations related to its use in children below 3 years of age are an extension of those currently in place. The main implementation considerations specifically applicable to this age group are dosing based on the availability of the 25 mg dispersible formulation and the neuropsychiatric side effects. Delamanid formulations: In the trial, delamanid was dosed with the dispersible 25 mg tablet tested in children aged 3–5 years. Bioavailability of delamanid may be altered when the 50 mg adult tablet is split, crushed or dissolved. There are also concerns that the adult tablet may shatter if attempts are made to split it, and its contents are exceedingly bitter and unpalatable. The tablets are susceptible to oxidation and heat; thus, retaining pill fragments for use at any time other than the time of administration is likely to result in the delivery of lower-than-expected active compound and unspecified oxidation by-products. The child-friendly formulation of delamanid (25 mg dispersible tablet, unscored) has been included in the 8th WHO Essential Medicine List for Children (EMLc), released in October 2021 (88), was approved by the European Medicines Agency in September 2021 and has been available through the Stop TB Partnership GDF since October 2021. Children in the 0–2-year cohort in study 242–12–233 were administered a 5 mg paediatric dispersible formulation that is not expected to be commercialized. There has been no direct bioequivalence comparison for the 5 mg paediatric formulation and the 50 mg adult tablet. In a crossover bioequivalence study, neither Cmax [90%CI GMR 0.701,0.809] nor AUC [90%CI GMR 0.775,0.909] satisfied the criteria for bioequivalence as specified by regulatory agencies. As such, the 5 mg paediatric and the 50 mg adult formulations are not interchangeable (96). Dosing guidance for the use of delamanid in children below 3 years of age is provided in the operational handbook, based on an expert consultation on dosing that was conducted after the GDG meeting. The guidance takes into account the availability of the 25 mg dispersible delamanid formulation. Administration of delamanid: Bioavailability of delamanid was optimized in the trials by administering delamanid with a high-fat meal; and therefore administration of delamanid with food is an important aspect to consider for practical implementation. In neonates, there are higher feeding frequencies, which aligns well with the goal of administering with higher-fat content. Regimen building of longer regimens: Guidance on how to construct optimal treatment regimens for children with MDR/RR-TB (with drugs based on WHO recommended drug classification as well as optimal treatment duration) who are not eligible for shorter, all-oral regimens is provided in the operational handbook. Duration of treatment: Shortening the total treatment duration to less than 18 months may be considered for children without extensive disease (61). Extensive (or advanced) TB disease refers to the presence of bilateral cavitary disease or extensive parenchymal damage on CXR. Severe EPTB refers to the presence of miliary TB or TBM in adolescents and adults over 15 years of age. In children aged below 15 years, extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression) are considered as severe (adapted from (86)). Concurrent use of delamanid and bedaquiline, and use of delamanid beyond six months: With regards to concurrent delamanid and bedaquiline use, evidence assessed by a GDG in November 2019 included new data on concurrent bedaquiline and delamanid use. The new evidence was insufficient to allow the GDG to make a statement about the effectiveness of concurrent use of both medicines. However, the group concluded that the safety data assessed in 2019 suggest no additional safety concerns with regard to the concurrent use of bedaquiline and delamanid. Therefore, bedaquiline and delamanid may be used in people with MDR/RR-TB who have limited options for other treatment, such as those with few effective drugs that can be included in their regimen, for example due to an extensive drug-resistance profile or intolerance to other second-line TB medications. Appropriate schedules of safety monitoring (at baseline and throughout treatment) should be in place for these patients, including ECG and electrolyte monitoring, and clinicians should be aware of other medicines in the regimen that can either prolong the QT interval or cause other potential adverse events. The available evidence of delamanid use is currently limited to the on-label 6-month duration alongside other medicines i