In children with MDR/RR-TB aged below 6 years, an all-oral treatment regimen containing bedaquiline may be used(conditional recommendation, very low certainty of the evidence).
- This recommendation applies to and complements current WHO recommendations on shorter and longer regimens that contain bedaquiline(9):
-A shorter all-oral bedaquiline-containing regimen of 9-12 months duration is recommended in eligible patients with confirmed multidrug- or rifampicin-resistant tuberculosis (MDR/ RR-TB) who have not been exposed to treatment with second-line TB medicines used in this regimen for more than 1 month, and in whom resistance to fluoroquinolones has been excluded.(Conditional recommendation, very low certainty in the evidence)
-Bedaquiline should be included in longer multidrug-resistant TB (MDR-TB) regimens for patients aged 18 years or more.(Strong recommendation, moderate certainty in the estimates of effect)
-Bedaquiline may also be included in longer MDR-TB regimens for patients aged 6-17 years.(Conditional recommendation, very low certainty in the estimates of effect)
Justification and evidence
PICO question:In MDR/RR-TB patients aged below 6 years, should an all-oral treatment regimen containing bedaquiline versus other regimens conforming to WHO guidelines without bedaquiline be used?
Historical context:In 2012, for the first time in over 40 years, a new TB drug with a novel mechanism of action - namely bedaquiline - was granted accelerated approval by the United States Food and Drug Administration (US-FDA) for the treatment of MDR-TB among adults ((80).In 2013, following an expert group meeting which reviewed available Phase IIb trial data on the efficacy and safety of bedaquiline, the WHO issued an interim policy guidance comprising a conditional recommendation and based on very low confidence in the estimates of effect, indicating that bedaquiline may be added to a WHO-recommended regimen in adults with MDR-TB ((81).
In 2016, after the introduction and roll-out of bedaquiline in an increasing number of countries and with more data available on its use, the WHO convened a GDG meeting to re-evaluate the added benefit of bedaquiline in conjunction with a WHO-recommended longer regimen for the treatment of MDR-TB. At this time, the GDG agreed that there was not enough evidence to prompt a change in the 2013 recommendation(82).
In 2019, after a GDG meeting where new evidence was reviewed from the adult IPD and two ongoing paediatric studies (TMC207-C211 and IMPAACT P1108), WHO issued the consolidated guidelines on DR-TB treatment(83),where bedaquiline was recommended for inclusion in longer MDR-TB regimens for persons aged 18 years or more (strong recommendation,moderate certainty in the estimates of effect) and in longer MDR-TB regimens for children and adolescents aged 6-17 years (conditional recommendation, very low certainty in the estimates of effects). Also in 2019, following the review of available data on the programmatic implementation of a shorter, all oral treatment regimen including bedaquiline in South Africa, the WHO recommended a shorter, all-oral bedaquiline containing regimen of 9-11 months for eligible persons with confirmed MDR/RR-TB who were not exposed to treatment with second-line TB medicines used in this regimen for more than 1 month, and in whom resistance to fluoroquinolones was excluded (conditional recommendation,very lowcertainty in the evidence)(9).This recommendation on the shorter all-oral bedaquiline-containing regimen replaced earlier recommendations on shorter regimens which contained an injectable agent. In a new IPD meta-analysis used as evidence for the 2020 WHO guidelines, bedaquiline use resulted in significantly fewer episodes of treatment failure, relapse and death(84).At the time, there was limited experience in the use of bedaquiline in children aged under 6 years, but experience of its use in adolescents, patients with EPTB disease and people living with HIV was growing. Earlier recommendations on the composition of longer regimens indicated that bedaquiline could also be included in such regimens for patients aged 6-17 years; hence, the all-oral bedaquiline-containing regimen was also conditionally recommended for use in eligible children and adolescents aged 6 years and above.
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 in children aged 6-17 years. However, a recommendation on the use of bedaquiline in children aged less than 6 years was not possible in the past, due to a lack of evidence, particularly on PK, safety and tolerability. The medicines that compose the shorter all-oral bedaquiline-containing regimen have been part of MDR-TB regimens for many years, in similar combinations, for both adults and children. The associated adverse drug reactions have been widely described and the drug dosages established. This however did not apply to bedaquiline at the time of the 2019 GDG on DR-TB, and the use of bedaquiline for young children in both shorter and longer regimens 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 bedaquiline in children under the age of 6 years, data from two phase II trials (TMC207-C211 and IMPAACT P1108) were reviewed by the GDG. TMC207-C211 is a phase II, open-label, single-arm study to evaluate the PK, safety, tolerability and anti-mycobacterial activity of bedaquiline in combination with a background regimen of MDR-TB medications for the treatment of children and adolescents 0-17 years of age who have bacteriologically confirmed or clinically diagnosed pulmonary and selected forms of extrapulmonary MDR-TB.³²IMPAACT P1108 is a phase I/II dose finding modified age de-escalation study to evaluate the PK, safety and tolerability, of bedaquiline in combination with optimized individualized MDR-TB regimens in HIV-infected and HIV-uninfected children with clinically diagnosed or confirmed pulmonary (intrathoracic) and selected forms of extrapulmonary MDR-TB.³³
As data reviewed from TMC207-C211 corresponded to children aged 5-18 years and that from IMPAACT P1108 included children aged 0-6 years, the review of PK and safety data focused mainly on data from IMPAACT P1108. Although the sample size of the available interim data for review was small (N= 12), the GDG concluded that in children 0-6 years of age, cardiac safety signals were not distinct from those reported in adults. Population PK models from both studies suggest that drug exposures observed in adults can be reached in most children receiving bedaquiline, although some dose modification may be necessary depending on the age and weight of the child.
In addition, data from a paediatric MDR/RR-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 analysis included 40 children aged below 6 years and 68 children aged 6-12 years who received bedaquiline. In the matched analysis, bedaquiline was significantly associated with shorter treatment duration and a lower adjusted odds ratio of injectable TB drug use. There was no statistically significant difference in successful treatment outcomes between childrenaged less than 6 years receiving an all-oral bedaquiline-based regimen versus those not receivingbedaquiline (89% versus 97%, p=0.9). Residual confounding (including confounding by indication) was thought to be likely.
A child-friendly formulation of bedaquiline (20 mg scored uncoated tablet) is being used in the Janssen C211 study to dose children aged below 5 years and will also soon be used in an updated protocol of IMPAACT study P1108 (this study has used the 100 mg formulation to date in all age groups). No head-to-head studies were conducted to examine the bioequivalence of the 20 mg and the 100 mg formulation of bedaquiline. Indirect bioequivalence testing showed that both tablets have the same bioavailability and can be used interchangeably at the same total dose. Findings from the bedaquiline crush study(85)also showed that bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole.
GDG considerations:The GDG discussed the desirable effects that were previously reported and noted that including bedaquiline in all-oral regimens for children will allow the construction of regimens that are more child- and family-friendly, with shorter durations (as shown by the IPD analysis, where bedaquiline-containing regimens were usually shorter than those not including bedaquiline). The GDG rated the desirable effects as moderate. The main concern noted by the panel was the lack of data on long-term safety and adverse events. However, the GDG noted that clinical experience with using bedaquiline in young children showed that the drug is tolerated well and often better than in the adult population. Therefore, the GDG agreed that the undesirable effects were small. Overall, the GDG determined that the balance between desirable and undesirable effects probably favours the use of bedaquiline in children aged below 6 years. The GDG highlighted that the benefits may vary depending on specific contexts and population characteristics, such as by nutritional status. The GDG also noted that the potential higher cost of bedaquiline in an MDR/RR-TB treatment regimen should be considered in the context of the benefits of shorter injectable free regimens (i.e. less travel, reduced time spent in clinics and fewer adverse events). In addition, they judged that equity might increase when bedaquiline becomes available to younger children, as its use would be acceptable to the majority of stakeholders, and that one of the main feasibility aspects would be related to the need for safety monitoring (i.e. access to ECG monitoring, as well as staff capacity for monitoring). However, the panel judged that the use of bedaquiline in young children was probably feasible to implement.
Children living with HIV:While trial TMC207-C211 has not yet enrolled children living with HIV, the IMPAACT study P1108 study enrols HIV-infected and HIV-uninfected infants, children and adolescents with MDR-TB disease (of the nine children aged below 6 years enrolled and with PK data at the time of the GDG report, one was HIV-infected). In the paediatric IPD, 12 of the 40 children (30%) aged below 6 years treated with a bedaquiline-containing regimen were HIV positive, as compared to 364 out of 1992 (20%) treated with DR-TB regimens not including bedaquiline.
The composition of treatment regimens for MDR/RR-TB does not usually differ substantially for people living with HIV; bedaquiline may be used in all children, irrespective of HIV status. Known drug-drug interactions, such as between bedaquiline and efavirenz, need to be avoided.
Extrapulmonary TB:The shorter, all oral bedaquiline-containing regimen is contraindicated in children with extrapulmonary forms of TB other than TB lymphadenopathy (see implementation considerations for the full eligibility criteria). Children with these forms of EPTB should be treated with longer regimens, composed of medicines from groups A, B and C(9).Data on the penetration of bedaquiline across the blood-brain barrier are sparse.
Eligibility for the shorter, all-oral, bedaquiline containing regimen:The removal of the age restriction for the use of bedaquiline means that children of all ages with confirmed MDR/RR-TB and without fluoroquinolone resistance may be offered the shorter, all-oral regimen with bedaquiline,if they meet the eligibility criteria. This regimen is composed of bedaquiline (used for 6 months), in combination with levofloxacin/moxifloxacin, ethionamide, ethambutol, isoniazid (high-dose), pyrazinamide and clofazimine for four months (with the possibility of extending to 6 months if the patient remains sputum smear positive at the end of four months); followed by 5 months of treatment with levofloxacin/moxifloxacin, clofazimine, ethambutol and pyrazinamide. The eligibility criteria are:
- No extensive TB disease
- No severe EPTB (any forms other than TB lymphadenopathy)
- No resistance or suspected ineffectiveness of a medicine in the shorter regimen (except isoniazid resistance)
- No exposure to previous treatment with second-line medicines in the regimen for more than one month (unless susceptibility to these medicines is confirmed).
Extensive (or advanced) TB disease refers to the presence of bilateral cavitary disease or extensive parenchymal damage on CXR in adults. In children aged under 15 years, advanced disease is usually defined by the presence of cavities or bilateral disease on CXR. Severe EPTB refers to the presence of miliary TB or TBM (i.e. disseminated disease)(61).In children aged under 15 years, extrapulmonary forms of disease other than lymphadenopathy (peripheral nodes or isolated mediastinal mass without compression) are considered as severe(86).The shorter regimen should not be used in the presence of mutations in both the inhA promoter and katG on first-line LPA (MTBDRplus) in the child as this suggests that both isoniazid at high dose and thioamides are not effective(87).
Promoting the use of bedaquiline in all-oral regimens for children will allow the construction of regimens that are more child- and family-friendly and shorter, which may reduce the use of second-line drugs with potentially more severe adverse events compared to bedaquiline (including, but not limited to injectables). Implementation of shorter, all-oral regimens may also facilitate the implementation of DR-TB treatment at peripheral levels of the health care system. NTPs and clinicians are therefore discouraged from using injectable agents as part of treatment regimens for MDR/RR-TB in children of all ages.
Regimen building for children not eligible for the shorter all-oral bedaquiline-containing regimen:Children who do not have bacteriological confirmation of TB and/or resistance patterns but who have a high likelihood of MDR/RR-TB (based on clinical signs and symptoms of TB, in combination with a history of contact with a patient with confirmed MDR/RR-TB) are eligible to receive bedaquiline as part of their treatment regimen. However, they do not meet the eligibility criteria for the shorter all-oral bedaquiline-containing regimen, as this regimen may only be used in people with TB with at least confirmation of rifampicin resistance in whom resistance to fluoroquinolones has been ruled out(84).These children will benefit from an individualized longer treatment regimen, taking into account the drug susceptibility (and/or mutation) pattern of the most likely source case, if this information is available. Treatment duration will depend on the extent and severity of disease, as well as the response to treatment. Shortening the total treatment duration to less than 18 months may be considered in children without extensive disease(61).Children with a diagnosis of rifampicin resistance only without further DST (such as a child diagnosed with Xpert MTB/RIF or Xpert Ultra testing on a stool sample but no further DST on respiratory samples) could be treated with available bedaquiline-containing regimens at the discretion of the treating clinician.
Guidance on how to construct optimal all-oral treatment regimens in children with MDR/RR-TB who are not eligible for the shorter, all-oral bedaquiline-containing regimen is provided in the operational handbook, considering their age, resistance patterns in the child or most likely source case and extent of TB disease. The construction of these treatment regimens is aligned to theWHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment,the priority drug groupings in groups A, B and C as well as the minimum number of effective drugs required(61).
Duration of bedaquiline use:Evidence assessed by a GDG in November 2019 supported the safe use of bedaquiline beyond 6 months in people with TB who received appropriate schedulesof baseline and follow-up monitoring. However, at that time the GDG was not able to assess the relative effectiveness of prolonged bedaquiline use, owing to limited evidence and potential residual confounding in the data. The regimen needs to have at least three effective agents if bedaquiline is stopped at six months; thus, if after 6 months, one of the three remaining agents needs to be stopped because of toxicity, then it needs to be replaced. The replacement medicine would be chosen from either group B (unless both clofazimine and cycloserine or terizidone are already included) or group C. The choice from group C is determined by the order in which the medicines are ranked, and the individual circumstances of the patient and setting (9).
Concurrent use of bedaquiline and delamanid:The GDG held in November 2019 found insufficient evidence to allow for 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, i.e. for those with an insufficient number of other effective drugs included in their regimen, such as 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 people with TB, including ECG and electrolyte monitoring, and clinicians should be cognizant of other medicines in the regimen that can either prolong the QT interval or cause other potential adverse events(9).
MDR/RR-TB case detection in children:Efforts to implement child-friendly DR-TB regimens including bedaquiline should be implemented in parallel with increased efforts at the country level to close the case detection gap. Evidence-based, integrated treatment decision algorithms (seechapter 4) that are specific for different settings with varying access to diagnostic tests and CXR, apply to children with presumptive MDR/RR-TB as well, and need to be widely implemented to ensure that MDR/RR-TB is detected and effectively treated among children.
Administration of bedaquiline:Dosing guidance for the use of bedaquiline in children below 6 years of age is provided in the operational handbook, based on an expert consultation on dosing that was conducted as a follow up to the GDG meeting. The guidance takes into account the child-friendly formulation of bedaquiline that was approved by the US FDA in May 2020 and has been available from the Stop TB Partnership GDF since June 2020, namely a 20 mg scored tablet which can be taken whole or dispersed in water for patients who have difficulty swallowing intact tablets. This formulation of bedaquiline has been included in the 8th WHO Essential Medicine List for Children (EMLc), released in October 2021(88).To aid with administration, the dispersed mixture in water can be further mixed with a beverage or soft food or crushed and mixed with soft food immediately prior to its use and administered (see below for more details). It should also be noted that the findings from the bedaquiline crush study showed that bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole(85).Therefore, if the 20 mg formulation of bedaquiline is not available, the crushed 100 mg formulation dissolved in water can be used to dose younger children without compromising bioavailability.
Concomitant food intake is an important factor to consider when evaluating bioavailability. Bedaquiline bioavailability was optimized in the trials when co-administered with a high-fat meal. In practice, feeding frequency needs to be considered. In infants, feeding frequency is higher and favours the administration with high-fat meals, but it should also be considered that buffering capacity increases with increased feeding frequency. The paediatric bedaquiline formulation can be prepared and administered with a variety of foodstuffs (including water, milk products, apple juice, orange juice, cranberry juice, carbonated beverages, yoghurt, apple sauce, mashed banana and porridge) to improve palatability. The formulation is also stable for eight hours if the preparation is stored in a syringe. It should ideally be taken with a high-fat meal, and administration on an empty stomach should be avoided as bedaquiline drug exposures are reduced.
Clinical monitoring:The risk of emergence of bedaquiline resistance should be a key consideration when the drug is being used. Due to the difficulties in obtaining a suitable specimen from children aged below 6 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 gastric aspirate, sputum induction or NPA (stool is not a suitable sample for conducting DST).
In the IMPAACT P1108 study, none of the children aged below 6 years had QT prolongation in any of the categories of 60 milliseconds and above. Almost all children also received clofazimine. Three children (of 11; 27%) experienced QT prolongation of 30-60 milliseconds, which was described as mild and insignificant. In general, the use of bedaquiline in populations with underlying cardiac conduction abnormalities and concomitant medications that prolong QTc needs to be carefully considered. A major implementation consideration includes the need for safety monitoring, as well as the need to build staff capacity (training, capacity building) to ensure that appropriate safety monitoring is put in place. Additional costs associated with wider implementation of bedaquiline (in addition to the higher cost of the drug), include availability of ECG machines, appropriate monitoring and trained staff to perform these activities. However, the GDG felt that savings related to potential shorter treatment duration as well as the avoidance of additional resource requirements related to injectable use (such as for monitoring with audiometry and implications for child development), outweigh the costs of bedaquiline introduction and implementation.
Adaptation of the recommendation to the local context will require staff capacity building and training, followed by supportive supervision and mentoring. Implementing all-oral treatment regimens will facilitate decentralization of MDR-TB treatment services and may therefore improve access to patient-centred care.
Monitoring and evaluation
People with TB, including children who receive a shorter or longer MDR-TB treatment regimen need to be monitored for response to treatment and for safety during treatment using schedules of relevant clinical and laboratory testing. This has been successfully applied in previous studies of shorter regimens under field conditions and in the programmatic setting in South Africa.
The WHO framework for active drug safety monitoring(89)needs to be applied to people with TB on any type of MDR-TB regimen, to ensure appropriate action and an acceptable level of monitoring for and prompt response to adverse events - alongside monitoring for treatment outcomes. Electrocardiography is indicated for children on regimens with two or three agents that are expected to prolong the QT interval. Specific biochemical tests should also be made available according to the agents included in the regimens.
In children, smear and culture monitoring of the response to treatment may be challenging, due to difficulties in obtaining appropriate specimens for testing. However, 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.
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 to monitor the programmatic implementation of newly recommended regimens as well as efforts to improve case finding of children with DR-TB. Data from national programmes on the use of bedaquiline in children of all ages is important to increase the evidence base.
³² Pharmacokinetic study to evaluate anti-mycobacterial activity of TMC207 in combination with background regimen (BR) of multidrug resistant tuberculosis (MDR-TB) medications for treatment of children/adolescents pulmonary MDR-TB (https://clinicaltrials.gov/ct2/ show/NCT02354014, accessed 21 January 2022).
³³ P1108. A Phase I/II, open-label, single arm study to evaluate the pharmacokinetics, safety and tolerability of bedaquiline (BDQ) in combination with optimized individualized multidrug-resistant tuberculosis (MDR-TB) therapy in HIV-infected and HIV-uninfected infants, children and adolescents with MDR-TB disease (https://www.impaactnetwork.org/studies/p1108, accessed 21 January 2022).