Обратная связьRecommendation
In children with MDR/RR-TB aged below 3 years delamanid may be used as part of longer regimens (conditional recommendation, very low certainty of evidence).
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).
Justification and evidence
PICO question: In MDR/RR-TB patients aged below 3 years, should an all-oral treatment regimen containing delamanid versus other regimens conforming to WHO guidelines without delamanid be used?
Historical context In 2014, the European Medicines Agency granted a conditional marketing authorization for delamanid for the treatment of adults (≥18 years of age) with pulmonary infections due to MDR-TB when an effective treatment regimen could not otherwise be devised for reasons of resistance or tolerability (90). In the same year, following a WHO convened expert group meeting that reviewed available data on efficacy and safety of delamanid, the WHO issued an interim policy guidance comprising a conditional recommendation based on very low confidence in estimates of effect, indicating that delamanid may be added to a WHO-recommended regimen in adults (≥18 years of age) with pulmonary MDR-TB (91).
In 2016, given more available data on the use of delamanid in children diagnosed with MDR-TB, the WHO convened another expert panel to assess new data and develop an addendum to the 2014 interim guidance on delamanid, with specific recommendations for children with MDR-TB. Based on the assessment of this evidence and recommendations from the expert panel, the WHO recommended that delamanid may be added to the WHO-recommended longer regimen in children and adolescents (6-17 years) (conditional recommendation, very low confidence in estimates of effect) (92). The WHO interim guidance on delamanid was based on data from phase I and phase II clinical trials (trials 242-12-232 and 242-12-233) and the results of other earlier studies. The use of delamanid was conditionally approved by the WHO given the limited alternative treatment options for people with MDR-TB, on the basis that the potential benefits probably outweighed the potential risks. The WHO recommendations were also conditional upon longer-term effectiveness and safety data becoming available in subsequent years, especially from phase III randomized controlled trials.
In 2016, the WHO convened a GDG meeting where the added benefit of delamanid was re-evaluated in conjunction with a WHO-recommended longer regimen for the treatment of MDR-TB but at that time, the GDG agreed that there was not enough evidence to prompt a change in the recommendation included in the interim guidance (93). In 2019, after convening a GDG meeting where newly available evidence from ongoing delamanid studies was reviewed, WHO issued the consolidated guidelines on DR-TB treatment (83). With respect to the use of delamanid in children younger than 6 years, the GDG judged that on the basis of findings in adults and on the pharmacological and safety data reviewed, extrapolations on efficacy should be restricted to children aged 3-5 years but not to children younger than 3 years, pending further evidence. Exposure profiles of children 3-5 years of age were comparable to adults and no higher than in children aged 6 years and older, for whom past GDGs convened by the WHO had already recommended the use of delamanid. Additionally, based on the laboratory and cardiac data provided, no safety signals distinct from those reported in adults were observed in children aged 3-5 years. Based on this, the WHO recommended that delamanid may be included in the treatment of MDR/RR-TB for children aged 3 years or more on longer regimens (conditional recommendation, moderate certainty in the estimates of effect); and in the priority grouping of medicines for use in longer regimens it was classified as a group C drug (83). The 2019 GDG nonetheless had concerns about the feasibility of administering the correct dose to children aged 3-5 years, given that the only tablet available at the time was the one used for adults (i.e. 50 mg), which presents challenges in manipulating its contents without compromising its effectiveness. Subsequent reviews of the WHO guidelines in 2020 did not prompt any change in the 2019 recommendation, which was the one in place at the time of the GDG meeting on child and adolescent TB during May-June 2021.
Gap: The recommendations that apply to children were based on extrapolation of efficacy data in adults, in combination with PK and safety data from phase II trials for children aged 3-17 years. However, a recommendation on the use of delamanid in children aged less than 3 years has not been possible in the past, due to a lack of evidence, particularly on PK, safety and tolerability. This has made it challenging for clinicians to design all-oral regimens for children under the age of 3 years, especially for children with (or a source case with) fluoroquinolone resistance, where choices are limited among group A and B drugs. The use of delamanid in children below 3 years of age was therefore identified as a gap to be addressed as part of the 2021 update of the child and adolescent TB guidelines.
Evidence: To answer the PICO question on the use of delamanid in children under the age of 3 years, data were reviewed by the GDG from a phase I, open-label, age de-escalation trial designed to assess the PK, safety and tolerability of delamanid administered twice daily for 10 days in children with MDR/RR-TB on treatment with an optimized background regimen (protocol 242-12-232)³⁴ and from the corresponding open-label extension study (protocol 242-12-233).³⁵ Data from cohorts 1 (age 12-17 years), 2 (age 6-11 years), 3 (age 3-5 years) and 4 (age 0-2 years) for both protocols were reviewed. Exposures in the 0-2 year age group were lower than those of children aged 3 years and older, necessitating a modelling/simulation approach to dosing. No cardiac safety signals distinct from those reported in adults were observed in children 0-2 years of age. However, these findings should be considered knowing that children had lower drug exposures compared to adults. However, pharmacodynamic simulations suggested that clinically meaningful changes in QT (i.e. prolongation) would be unlikely in children under 3 years of age, even if higher doses were used to reach drug exposures comparable to those achieved in adults.
Central nervous system effects were included in the delamanid label for both adults and children (paraesthesia, tremors, anxiety, depression and insomnia) as important potential safety concerns for the drug. In March 2021, the study sponsor released a statement of intent to modify the labelling to include hallucinations as an adverse reaction. This new safety signal has been more prevalent among children (versus adults) with 15 reports in 14 children 2-16 years of age in India, Philippines, South Africa, Tajikistan and Ukraine. Children experiencing this safety signal included some with extensively resistant forms of TB (MDR/XDR-TB) treated with delamanid under programmatic conditions (12 reports) as well as children enrolled in a clinical trial studying delamanid for TB prevention (three reports). Seven of the 15 reports were for children also receiving cycloserine (under programmatic conditions). The GDG noted the importance of side-effects involving the central nervous system in young children, considering their dynamic brain development.
In addition to data from the trials, data from a paediatric DR-TB IPD were analysed descriptively (24 231 records from all six WHO regions, the majority from India and South Africa). The search was conducted in April 2020. Just under 20 000 of these records were used for a matched analysis of treatment outcomes in children being treated for DR-TB. The paediatric DR-TB IPD included only seven children aged below 3 years treated with delamanid, 14 children aged 3-6 years, and 69 children aged 6-12 years. All 21 children aged below 6 years were successfully treated. The number of children was insufficient for a matched analysis.
GDG considerations: The GDG noted that when the delamanid phase II trial was started, many of the companion drugs in the optimized background regimen were not widely available (such as linezolid and moxifloxacin). By the time the phase III trial started, linezolid and moxifloxacin became more accessible, which meant that the optimized background regimens in the trial were likely more effective, making it more difficult to prove the added effect of a drug (i.e. delamanid) in the intervention regimen. The GDG concluded that the desirable effects are small. The GDG discussion around the undesirable effects focused on adverse events, including those related to the central nervous system and cardiac toxicities, as well as the newly reported adverse event of hallucinations which was of some concern to GDG members given the period of dynamic brain development in children. The GDG considered that the risks and benefits (and balance of both) are very different for treating a child with resistant forms of TB (i.e. MDR/RR-TB and XDR-TB) and with limited treatment options, compared to a healthy child at future risk of developing MDR-TB (i.e. where delamanid is used for prevention). Therefore, the GDG concluded that the balance between desirable and undesirable effects probably favours the intervention. The GDG further stated that with the 25 mg dispersible tablet, that would be available in the future, the resource implications could vary. Delamanid containing longer treatment regimens were thought to potentially increase equity and be acceptable to stakeholders. In addition, the GDG judged that the use of delamanid in children of all ages would probably be feasible, especially as the child-friendly formulation of delamanid was expected to become available later in 2021 (this formulation is now available). This judgement also considered that adult tablets cannot be split, crushed or dissolved to ease administration in children without potentially altering bioavailability.
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 pulmonar y 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 in a longer regimen; prolongation beyond 6 months can be considered on a case-by-case basis (9).
Monitoring and evaluation
In children, smear and culture monitoring of the response to treatment may be challenging, due to difficulties in obtaining appropriate specimens for testing, for the same reasons it is difficult to obtain a bacteriological confirmation of the diagnosis. In children with a bacteriologically confirmed diagnosis, all reasonable efforts should be taken to demonstrate bacteriological conversion. Once cultures have become negative or in children who never had a confirmed diagnosis, repeated respiratory sampling may not be useful if the child is otherwise responding well clinically. Resolution of clinical symptoms and weight gain can be used as indicators of improvement. All children should have regular clinical follow-up, including weight and height monitoring. Drug dosages should be adjusted with weight gain, as needed.
The risk of emergence of delamanid resistance should be a key consideration when the drug is being used. Due to the difficulties in obtaining a suitable sample from children aged below 3 years, performing DST may be challenging. However, if there are concerns about acquired drug resistance, every effort should be made to obtain a suitable sample, such as through gastric aspirate, sputum induction or NPA.
No cardiac safety signals distinct from those reported in adults were observed in children 0-2 years of age; however, these are largely based on subtherapeutic concentrations. Given that a QTc evaluation prior to delamanid administration may not always be feasible, it may be important to adapt risk mitigation strategies when administering delamanid in combination with other agents that prolong QTc (such as electrolytes which are stable).
Monitoring the emergence of neuropsychiatric effects (including hallucinations) in children treated with delamanid - both who are admitted to hospitals and treated in households - will be very important. Particular attention should be paid to children who are receiving other medications that have known neuropsychiatric effects, such as cycloserine. Therefore, active TB drug safety monitoring and management systems must be functional to detect, manage and report suspected or confirmed drug toxicities in a timely manner.
Recording and reporting of details on the diagnosis, treatment regimens, clinical monitoring and treatment outcomes of children and adolescents with MDR/RR-TB is important for monitoring the programmatic implementation of newly recommended regimens as well as for efforts to improve case finding of children with DR-TB. Data from national programmes on the use of delamanid in children of all ages is important to expand the evidence base.
³⁴ Pharmacokinetic and safety trial to determine the appropriate dose for pediatric patients with multidrug resistant tuberculosis (https:// clinicaltrials.gov/ct2/show/NCT01856634, accessed 21 January 2022).
³⁵ A 6-month safety, efficacy, and pharmacokinetic (PK) trial of delamanid in pediatric participants with multidrug resistant tuberculosis (MDR-TB) (https://clinicaltrials.gov/ct2/show/NCT01859923, accessed 21 January 2022).