Delamanid and bedaquiline to treat multidrug-resistant and extensively drug-resistant tuberculosis in children: a systematic review
Review Article

Delamanid and bedaquiline to treat multidrug-resistant and extensively drug-resistant tuberculosis in children: a systematic review

Lia D’Ambrosio1,2, Rosella Centis1, Simon Tiberi3, Marina Tadolini4, Margareth Dalcolmo5, Adrian Rendon6, Susanna Esposito7, Giovanni Battista Migliori1

1World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Maugeri Care and Research Institute, IRCCS, Tradate, Italy;2Public Health Consulting Group, Lugano, Switzerland;3Division of Infection, Royal London Hospital, Barts Health NHS Trust, London, UK;4Unit of Infectious Diseases, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy;5Hélio Fraga Reference Center, Fiocruz/MoH, Rio de Janeiro, Brazil;6Center for Research, Prevention and Treatment of Respiratory Infections, University Hospital of Monterrey, Monterrey, Mexico;7Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Perugia, Italy

Contributions: (I) Conception and design: GB Migliori, R Centis, L D’Ambrosio, S Tiberi, S Esposito; (II) Administrative support: R Centis, L D’Ambrosio; (III) Provision of study materials or patients: R Centis, L D’Ambrosio, S Tiberi, M Tadolini, S Eposito, M Dalcolmo, A Rendon; (IV) Collection and assembly of data: R Centis, M Dalcolmo, A Rendon, L D’Ambrosio; (V) Data analysis and interpretation: GB Migliori, R Centis, L D’Ambrosio, S Tiberi, M Tadolini; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Prof. Giovanni Battista Migliori. World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Maugeri Care and Research Institute, IRCCS, Tradate, via Roncaccio 16, 21049 Tradate, Italy. Email: giovannibattista.migliori@icsmaugeri.it.

Abstract: The new drugs delamanid and bedaquiline are increasingly used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). As evidence is lacking, the World Health Organization recommends their use under specific conditions in adults, delamanid only being recommended in children ≥6 years of age. No systematic review has yet evaluated the efficacy, safety and tolerability of the new drugs in children. A search of peer-reviewed, scientific evidence was performed, to evaluate the efficacy/effectiveness, safety, and tolerability of delamanid or bedaquiline-containing regimens in children with confirmed M/XDR-TB. We used PubMed and Embase to identify any relevant manuscripts in English until 31 December 2016, excluding editorials and reviews. Three out of 96 manuscripts retrieved satisfied the inclusion criteria, while 93 were excluded because dealing exclusively with adults (12: 4 on delamanid and 8 on bedaquiline), being recommendations or guidelines (8 manuscripts), reviews (17 papers) or other studies (56 papers). One of the studies retrieved reported evidence on 19 M/XDR-TB children, 16 of them treated under compassionate use with delamanid (13 achieving consistent bacteriological conversion) and 3 candidates for the drug. Two studies reported details on the first paediatric case treated (and cured) with a delamanid-containing regimen. Eight trials including children were also retrieved (clinicaltrials.gov). Although the methodology used in the study was rigorous, the results are limited by the paucity of the studies available in the literature on the use of new anti-TB drugs in children. In conclusion, more evidence is needed on the use of delamanid and bedaquiline in paediatric patients.

Keywords: Multidrug-resistant tuberculosis (MDR-TB); extensively drug-resistant tuberculosis (XDR-TB); delamanid; bedaquiline; children

Submitted Mar 08, 2017. Accepted for publication May 19, 2017.

doi: 10.21037/jtd.2017.06.16

Introduction

With 10.4 million cases of tuberculosis (TB) estimated by the World Health Organization (WHO) to have occurred in 2015 [480,000 of whom affected by multidrug-resistant tuberculosis (MDR-TB)—10% meeting the criteria for extensively drug-resistant tuberculosis (XDR-TB) and 100,000 by rifampicin-resistant TB] and 190,000 deaths, the disease is a public health priority (1-4).

Treating MDR-/XDR- is extremely difficult, as the treatment is long and expensive, and outcomes remain sub-optimal, because of frequently observed adverse events, and high rates of treatment failure (3-10).

The WHO has recently issued new recommendations on how to design MDR-TB regimens, moving from the previous stepwise approach based on five groups of drugs in priority order (9,11) to a new approach and a new drugs classification (7,12,13).

The new drugs delamanid and bedaquiline are presently classified in group D2 (7), and their use is recommended in adults for a maximum of six months, at the recommended doses, added to an OBR (optimized background regimen), under an adequate clinical monitoring (particularly for the QT interval, e.g., measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle), and in the presence of pharmacovigilance and informed consent (14-16). Recently, the WHO has approved the use of delamanid for children above 6 years of age, given PK (pharmacokinetic) data having been made available (16,17).

Evidence in adults shows that delamanid and bedaquiline increase sputum smear and culture conversions, as well as success rates at the end of treatment, although much needs to be known on the potential drug-drug interactions-related cardio-toxicity. In fact, both delamanid and bedaquiline, as well as other core second-line drugs such as fluoroquinolones and clofazimine may increase the QT interval (18-26).

In adults with M/XDR-TB, as well as in children, it is often difficult to identify at least four active drugs which are necessary to design an effective regimen (2,7,10,13,27). While today some repurposed drugs are useful in designing these regimens [e.g., linezolid (28-34) and carbapenems (35-40)], there is urgent need to know how better to use the new drugs delamanid and bedaquiline (41-43). In children the problem is even more pressing, as less information is available and recruitment of paediatric cases in clinical trials is usually more challenging (17).

As of today, the information available on the use of new drugs in children is scanty.

Aim of the present manuscript is to perform a systematic review on the use of delamanid and bedaquiline in children.

Methods

A search of peer-reviewed, scientific evidence was performed, to evaluate the efficacy/effectiveness, safety, and tolerability of delamanid or bedaquiline-containing regimens in children with M/XDR-TB.

MDR-TB was defined as resistance to at least isoniazid and rifampicin, and XDR-TB as MDR with additional resistance to a fluoroquinolone plus at least one of the three second-line injectable drugs (amikacin, capreomycin and kanamycin).

We used PubMed and Embase to identify any relevant manuscripts published until December 31st, 2016, excluding editorials and reviews.

We decided to exclude conferences’ abstracts because, on the basis of the word count, the information provided is too limited when assessing the above described objectives, whilst including letters or case-series/report in case detailed clinical information. Only papers written in English were considered.

The key-words “tuberculosis and (delamanid or bedaquiline) and (child or adolescent or young)’’ were used.

The search exclusion criteria were the following: (I) experimental studies on animals with TB; (II) reviews and editorials on delamanid and bedaquiline; (III) M/XDR-TB cases not bacteriologically confirmed.

Two authors independently performed the search and evaluated the titles and abstracts of the records according to the selection criteria. Potentially interesting articles were downloaded and critically assessed; when they fulfilled the enrolment criteria, the needed information (e.g., sputum smear and culture conversion, treatment outcomes, adverse events and their grading, demographics, epidemiological data, drug resistance patterns of the collected Mycobacterium tuberculosis isolates, drug regimen prescribed and its duration) was retrieved and collected using a pre-designed electronic template. The entire process was carried out following the guidelines of the 2009 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement (44).

In addition, clinical trials involving children were looked for in the clinicaltrials.gov website using the following key words: ‘TB and (bedaquiline or delamanid) and child’ as of January1st, 2017 (45).

Results

A total of 96 records were obtained from the search (PRISMA flowchart, Figure 1); 93 were excluded because dealing with the new drugs in adults (12: 4 on delamanid and 8 on bedaquiline), being recommendations or guidelines (8 manuscripts), reviews (17 papers) or other studies (56 papers).

Figure 1 Selection process: PRISMA 2009 flow diagram.

Three studies only (20,21,46) satisfied the criteria for further analysis: all of them were published between 2014 and 2016, 2 being research letters, and reporting on a total of 19 cases. Two studies (21,46) (both from the same Authors) provided additional details on the first child treated with delamanid and being cured.

All the 19 cases described were part of the Compassionate Use Programme of the delamanid’s manufacturer; 16 of them received delamanid with a mean delay of 73.5 days (range, 14–153 days), while 3 were still waiting for the drug at the moment the article was accepted (20).

They were recruited in eight different countries in Africa, Asia and Europe. Based on limited treatment options, extensive resistance profile (from 4 to 15 drugs) or adverse events to core second line anti-TB drugs, an independent Consilium-like body supported the rationale use of delamanid, and the manufacturer provided it under compassionate use.

All 19 children had pulmonary TB, 2 additionally having extrapulmonary localizations. Their mean age was 14.4 years, ranging from 8 to 17 years. Three out of 19 were HIV co-infected. Out of 19 children, 14 met the XDR-TB defining criteria, 4 were pre-XDR (e.g., their disease was due to MDR-TB strains with additional resistance to one fluoroquinolone (3 cases) or one injectable second-line anti-TB drug (one case)) and one had MDR-TB. All cases were bacteriologically confirmed, 14 undergoing Xpert (13 being rifampicin-resistant and one indeterminate).

Delamanid was prescribed at the dose of 100 mg twice a day, with one single exception where the dose was reduced to 50 mg (as the body weight was 22 kg) (20).

Out of the 16 children treated with delamanid, 6 completed 24 weeks of delamanid treatment while 10 were still completing it at the moment the paper was accepted. Thirteen out of 16 children achieved a consistent bacteriological conversion (1 being cured), the remaining 3 having just started their delamanid treatment. No adverse event was reported in fifteen children. A single child, treated with a combination of delamanid, capreomycin, ethionamide, cycloserine, clofazimine, imipenem, amoxicillin/clavulanate and pyrazinamide experienced vomiting, renal impairment, electrolyte disturbances and QTcF (QT interval in the electrocardiogram corrected according to Fredericia formula) ≥500 ms requiring temporary interruption of delamanid. After managing vomiting and the electrolyte imbalance, the child was able to complete delamanid treatment without further QtcF prolongation (20).

Details on the studies are reported in Tables 1-3.

Table 1
Table 1 Epidemiological characteristics of the selected studies
Full table
Table 2
Table 2 Clinical features of the selected studies
Full table
Table 3
Table 3 Effectiveness, safety and tolerability profiles of delamanid in the selected studies
Full table

A summary of the ongoing clinical trials on new drugs in children is available in Table 4.

Table 4
Table 4 Clinical trials on new drugs in children [modified from (45)]
Full table

Out of 8 trials, 2 are evaluating delamanid, 4 bedaquiline and 2 both of them.

The outcome measures are safety and tolerability in two trials, PK parameters in two trials, safety/tolerability/efficacy in three trials and drug-drug interaction between both delamanid/bedaquiline and antiretrovirals in one trial. The different trials (in all phases from 1 to 5) have a sample size ranging from 36 to 1,786 cases. Out of 8 trials, 6 are presently recruiting. No information on ‘ad-interim’ analyses is available as of today.

Discussion

Aim of the present study is to systematically review the available scientific evidence on the use of delamanid or bedaquiline in M/XDR-TB children.

Only three papers met the inclusion criteria (20,21,46), all focused on delamanid, while no study is unfortunately available on bedaquiline in children.

Although several reviews discussing the new anti-TB drugs were checked, none of them was systematic providing a methodology justifying the choice of the articles cited (thus preventing the reader from understanding if other articles were eventually available in the literature).

The core study (20) included information on 19 children treated with delamanid under compassionate use, while the two ancillary studies (21,46) provide details on the first case of the series. This case is rather emblematic, being the first child who accessed delamanid under compassionate use, the first who underwent delamanid for more than 6 months and, more importantly, the first child who was cured with the new drug (20,21,46).

The information identified is really scarce, due to the lack of studies on new drugs in children. In spite of the format used (Letter), the core details of the individual patients have been provided. Unfortunately, only a few cases (6) completed the 24 weeks of delamanid treatment, and a single case the whole treatment regimen (therefore having the treatment outcome available). In spite of its poverty, this piece of evidence is one of the few allowing WHO to revise its recommendations for the use of delamanid in children and adolescents (16).

The main conclusions which can be drawn from this systematic review are the following: (I) information on delamanid in children is increasingly available, while no published data on bedaquiline can be found yet. We need to wait for the results of the ongoing trials (45), although out of the 4 trials on bedaquiline and the 2 on both the new drugs, 2 have not yet started to recruit patients; (II) delamanid in children seems to be promising, as it was well tolerated (a single, reversible QT prolongation above 500 msec was described, which has been adequately managed) in the 16 children treated (20) and apparently effective, as all the 13 children undergoing treatment for more than a few days achieved smear and culture conversion. However, more information is necessary to draw consistent conclusions, and the results of the ongoing trials will be most welcome; (III) electrolytes (potassium and magnesium) as well as albumin should be monitored, as electrolytes disturbance and/or hypoalbuminemia and any problem need to be adequately managed to prevent QTc prolongation or other problems; (IV) no published information is presently available on the combined use of delamanid and bedaquiline in children.

Unfortunately, even the recent large study describing safety and effectiveness of bedaquiline used programmatically was performed on adults only (47).

Although the methodology used in the study was rigorous, the results are limited by the paucity of the studies available in the literature on the use of new anti-TB drugs in children.

In conclusion, more evidence is needed on the use of delamanid and bedaquiline in paediatric patients.

Acknowledgements

This article has been developed within the ERS/ALAT SinTB project and ERS/SBPT project.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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Cite this article as: D’Ambrosio L, Centis R, Tiberi S, Tadolini M, Dalcolmo M, Rendon A, Esposito S, Migliori GB. Delamanid and bedaquiline to treat multidrug-resistant and extensively drug-resistant tuberculosis in children: a systematic review. J Thorac Dis 2017;9(7):2093-2101. doi: 10.21037/jtd.2017.06.16

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