Compassionate use of new drugs in children and adolescents with multidrug-resistant and extensively drug-resistant tuberculosis: early experiences and challenges

Tadolini, Marina; Garcia-Prats, Anthony J.; D’Ambrosio, Lia; Hewison, Catherine; Schaaf, H. Simon; Marais, Ben J.; Ferreira, Héverson Batista; Caminero, José A.; Jonckheere, Sylvie; Sinha, Animesh A.; Herboczek, Krzysztof; Khaidarkhanova, Zarema; Hayrapetyan, Armen; Khachatryan, Naira; Urtkmelidze, I; Loreti, Carolina; Esposito, Susanna; Matteelli, Alberto; Furin, Jennifer; Varaine, Francis; Migliori, Giovanni Battista

doi:10.1183/13993003.00705-2016

Cited by 72 publications

(59 citation statements)

References 15 publications

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“…68 There is growing data to support the efficacy and safety of delamanid in children above the age of 6, Otsuka Trial 233 is on-going with 6 month pharmacokinetic (PK)/safety in all paediatric weight groups with results in 2020, following Trial 232 with 18day PK/safety in same weight groups, results due out in 2018. 64,69,70 Delamanid is also being tested in a number of new trials, most notably endTB ( Table 2). The MDR-END trial (Seoul National University hospital), which is evaluating a regimen containing delamanid, linezolid, levofloxacin, and pyrazinamide for 9 or 12 months.…”

Section: Updates On Bedaquiline and Delamanidmentioning

confidence: 99%

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Tiberi

Plessis

Walzl

et al. 2018

The Lancet Infectious Diseases

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313

275

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Tuberculosis (TB) remains the top killer from an infectious globally causing an estimated 1.674.000 million deaths worldwide. In 2016, WHO estimates 600.000 cases of rifampicin-resistant TB of which 490.000 had multidrug-resistant (MDR) and less than half of them survive after receiving currently recommended WHO treatment regimens, illustrating weaknesses in current treatment approaches. We review progress and advances in the development of new and repurposed TB drugs, treatment trials and host-directed therapies. Updates are provided on phase 3 trials of the new compounds bedaquiline, delamanid, pretomanid; phase 2 trials of sutezolid, SQ-109, LCB01-0371, PBTZ-169; and five new drugs in phase 1 development. Approved or repurposed drugs undergoing further testing are rifampicin, rifapentine, clofazimine, and linezolid. Update on ongoing clinical trials, which aim to shorten TB treatment and improve treatment outcome is given. Several new or repurposed antimicrobial drugs are in advanced trial stages for MDR-TB, and five antimicrobial drug candidates are in phase 1 (Q203, TBI-166, OPC-167832, GSK 070, TBA-7371) and 5 in pre-clinical studies. Specific issues of safety and toxicity; drug-drug interactions; Therapeutic Drug Monitoring are reviewed. A wide range of candidate host-directed therapies (HDTs) and immune-based treatments are being investigated to accelerate the eradication of M.tb infection and for use as adjunctive therapy in shortening duration of treatment, preventing permanent lung injury and improving treatment outcomes of MDR-TB. Ongoing clinical trials of HDTs for TB treatment, the current HDT development pipeline and translational research efforts for advancing further HDT options are presented. Ongoing clinical trials of HDTs for TB treatment, the current HDT development pipeline and translational research efforts for advancing further HDT options are presented.5

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Section: Updates On Bedaquiline and Delamanidmentioning

confidence: 99%

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Tiberi

Plessis

Walzl

et al. 2018

The Lancet Infectious Diseases

Self Cite

313

275

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“…A case series published in 2016, describes 19 children administered delamanid on compassionate basis, 5 from India; interim outcome in the form of culture conversion was favorable in all children. Serious adverse event requiring stopping of delamanid was reported in one child [72]. The WHO interim policy recommendations (2016) states that delamanid may be added to background regimen for MDR-TB/RR-TB in children ≥6 years of age with>20 kg body weight under the following conditions [73]:

When the core regimen for MDR-TB with pyrazinamide and at least four 2nd line drugs deemed to be still effective cannot be completed either due to intolerance to drugs or resistance.

When there is resistance to fluoroquinolones and/or SLI.

Failing MDR-TB regimen with extensive disease (bilateral pulmonary involvement, cavities) – delamanid should not be the only agent added to a failing regimen.

Proper adherence can be ensured and monitored.

Proper pharmacovigilance for adverse events and drug–drug interaction is in place.

Informed consent has been taken from the parent/legal guardian of the concerned child.

…”

Section: New Drugsmentioning

confidence: 99%

Current therapies for the treatment of multidrug-resistant tuberculosis in children in India

Mukherjee

Lodha

Kabra

2017

Expert Opinion on Pharmacotherapy

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Introduction: Multidrug-resistant tuberculosis (MDR-TB) is a serious life threatening condition affecting children as well as adults worldwide. Timely diagnosis and effective treatment, both of which are complex in children, are the prerogatives for a favorable outcome.Areas covered: This review covers epidemiology, treatment regimen and duration, newer drugs and adverse events in children with MDR-TB. Special note has been made of epidemiology and principles of treatment followed in Indian children.Expert opinion: High index of suspicion is essential for diagnosing childhood MDR-TB. If there is high probability, a child can be diagnosed as presumptive MDR-TB and started on empiric treatment in consultation with experts. However, every effort should be made to confirm the diagnosis. Backbone of an effective MDR-TB regimen consists of four 2nd line anti-TB drugs plus pyrazinamide; duration being 18–24 months. The newer drugs delamanid and bedaquiline can be used in younger children if no other alternatives are available after consultation with experts. Wider availability of these drugs should be ensured for benefit to all concerned. More research is required for development of new and repurposed drugs to combat MDR-TB. Children need to be included in clinical trials for such life-saving drugs, so that nobody is denied the benefits.

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“…Improved regimens are urgently needed and the new drugs, bedaquiline and delamanid, could play a more prominent role in paediatric MDR-TB treatment [15,16]. In spite of this, however, treatment success was achieved in most children with a proactive approach to contact tracing, early treatment based on clinical diagnosis, structured approach to the construction of drug regimens based on the international recommendations, and the active management of adverse reactions.…”

mentioning

confidence: 97%

Multidrug-resistant tuberculosis in children in northwest Russia: an observational cohort study

et al. 2016

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Compassionate use of new drugs in children and adolescents with multidrug-resistant and extensively drug-resistant tuberculosis: early experiences and challenges

Cited by 72 publications

References 15 publications

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Current therapies for the treatment of multidrug-resistant tuberculosis in children in India

Multidrug-resistant tuberculosis in children in northwest Russia: an observational cohort study

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