The BENEFIT Kids Project
Children affected by multi-drug-resistant tuberculosis (MDR-TB) are the most underserved and vulnerable population with tuberculosis globally.
There are currently an estimated two million children newly infected with MDR-TB strains globally each year. An estimated 30,000 children develop MDR-TB disease each year, but less than 10-15% are actually treated for this disease. For children who are able to access treatment, current regimens are still too long, complex, toxic, poorly tolerated and are not acceptable to children and families. However, children with MDR-TB have excellent treatment outcomes once they have accessed appropriate treatment. Effective safe and more child-friendly shorter treatments and strategies to prevent MDR-TB in children is therefore a priority. The current lack of high-quality evidence on the treatment and prevention of MDR-TB in children needs to be addressed urgently.
Lack of access to better MDR-TB treatment and prevention results in substantial preventable morbidity and mortality in children.
Better Evidence and Formulations for Improved MDR-TB Treatment for Children (BENEFIT Kids) is designed to address critical gaps in research and products in order to improve the treatment and prevention for children affected by MDR-TB. The project was made possible with support and funding from Unitaid, a leading international organisation that invests in innovations to prevent, diagnose, and treat major global health problems, including HIV/AIDS, malaria and tuberculosis and other disease, more quickly, affordably and effectively. The project started in 2019 and will be completed by the end of 2024.
The overall goal of our project is to reduce morbidity and mortality of children affected by MDR-TB through better access to improved MDR-TB prevention and treatment options. In order to do this, BENEFIT Kids is conducting the following work:
- Evaluate and synthesize existing evidence on the treatment of MDR-TB: Conduct two systematic reviews and individual patient data meta-analysis, to pool all available data on MDR-TB medications and treatment outcomes in children. The goal is to generate evidence on improved paediatric dosing and treatment strategies and inform WHO and national treatment guidelines.
- Generate new evidence: Conduct several pivotal clinical trials on the prevention and treatment of children affected by MDR-TB to generate urgently needed new data on the pharmacokinetics, safety, acceptability and efficacy of prevention and treatment strategies. The project is also addressing highly vulnerable neglected children affected by HIV, by conducting clinical trials of the pharmacokinetics and safety of new formulations of novel antiretroviral medications in newborn babies.
- Develop new formulations: In partnership with TB Alliance, the project is optimizing multiple child-friendly formulations of effective MDR-TB medications. In addition, we are supporting training, supporting market shaping and creation of demand to ensure that these treatments reach children in the field to ensure the desired impact.
Working in close collaboration with the World Health Organisation (WHO), the project continuously submits all synthesized and all newly generated evidence to inform international guideline development and tools to improve the delivery of treatment in the field. The BENEFIT Kids project is assisting in sensitizing key partners including civil society, affected communities, national treatment programmes, funders and industry to ensure the rapid adoption of new evidence and products.
The BENEFIT Kids Project focus countries are South Africa, India and the Philippines for the implementation of novel trials, but with broad global reach and collaboration for overall project implementation, evidence synthesis and dissemination.
Our key partners are TB Alliance (United States), University of California San Francisco (United States), Johns Hopkins University (United States), De La Salle University Medical Centre (Philippines), Byramjee Jeejeebhoy Medical College (India), Uppsala University (Sweden) and Chiang Mai University (Thailand) and the University of Wisconsin-Madison (USA).
Children deserve better care and treatment. Through BENEFIT Kids, Stellenbosch University and its global partners are catalysing better prevention and treatment globally for children affected by MDR-TB and also by HIV.
Overview of the different outputs forming part of the BENEFIT Kids Project
Output 1: Systematic reviews
The existing data on second-line TB drugs in children have not been optimally analysed and synthesized to produce evidence to best inform policy and clinical practice. As part of the BENEFIT Kids Project, two systematic reviews are being conducted. The systematic reviews rigorously synthesize existing data and use innovative analytic approaches to generate novel evidence with the potential to improve dosing guidance for medications and better treatment approaches for children with MDR-TB. The approach of using existing data is highly efficient and does not pose additional risk to children. These innovative analyses, involve pooling of data and use of advanced modelling techniques, will not only address current evidence gaps now, but will establish a foundation of data that can be built on in future, including supporting global data curation in collaboration with WHO. This work is charting a new approach to developing the best evidence for informing paediatric TB treatment recommendations by using existing data optimally. In addition to close coordination with WHO for this output, the BENEFIT Kids Project will continue to engage with a broad range of stakeholders for dissemination of results and to prepare for adoption of new evidence and scale up of these improved treatment approaches.
We are collaborating with global partners who are contributing data and key expertise and with our methodological partners at the University of California San Francisco (UCSF, Rada Savic), and the Medical Research Council of South Africa (MRC SA, Tamara Kredo)
Systematic review 1: paediatric pharmacokinetics (PK) data for 2nd-line TB drugs
As part of this systematic review, we will synthesize available data on the pharmacokinetics of second-line drugs for tuberculosis. Using state-of-the-art methods, this data will contribute to optimal dosing recommendations for MDR-TB prevention and treatment in children. Results will be disseminated during 2023 and 2024.
Systematic review 2: paediatric MDR-TB treatment
As part of this systematic review, we synthesize the available data on available treatment and outcomes in children treated for drug-resistant tuberculosis. This evidence is proactively shared with the WHO for consideration for uptake into paediatric dosing and treatment guidelines and initial results have already informed WHO guidelines on the use of bedaquiline and delamanid in children in 2022. Additional results will be disseminated during 2023. Going forward, the project will continue to support global data curation on MDR-TB treatment in children, adolescents and pregnant women.
Output 2: Clinical trials to create novel evidence for improved paediatric MDR-TB treatment
The Project is undertaking several distinct and complementary clinical trials of the pharmacokinetics and safety of key TB drugs, selected and designed to address key remaining knowledge gaps and strategies to prevent TB in young child MDR-TB household contacts, and the optimal dosing of new antiretroviral drugs in newborn babies.
Pharmacokinetics of lEvofloxacin FORmulations in children with MDR-TB exposure study is evaluating the pharmacokinetics and acceptability of generic levofloxacin adult tablets (crushed/dissolved) compared to novel paediatric dispersible tablets (Macleods Pharmaceuticals, Mumbai, India) in 24 children at a single site in Cape Town, South Africa. PERFORM will inform improved and evidence-based guidance on using both commercially available formulations of levofloxacin tablets in children, facilitating access to levofloxacin in young children at safe and effective doses. The lead investigator for this study is Dr Louvina van der Laan, Desmond Tutu TB Centre. This trial was completed in 2022 and results will be disseminated during 2023.
The Clofazimine and moxifloxacin PK, safety and AccepTAbiLitY for paediatric TB treatment (CATALYST) study is a trial of the pharmacokinetics, safety, tolerability and acceptability of new generic formulations of clofazimine and moxifloxacin in children treated for drug-resistant tuberculosis. It is a multi-country study newly available generic child-friendly formulations (moxifloxacin dispersible tablets, Micro Labs Ltd, Bangalore, India and clofazimine solid tablets, Macleods Pharmaceuticals, Mumbai, India). As of December 2022, the study was fully enrolled: 37 children with DR-TB were enrolled from 3 sites (Cape Town in South Africa, Pune in India (JHU, BJMC) and Manila in the Philippines (De La Salle University Medical Centre). In addition to the pharmacokinetic and acceptability analyses, the costs of routine paediatric MDR-TB treatment will be assessed in these three diverse settings and will inform cost-effectiveness analysis. We are coordinating closely with WHO and other stakeholders to share this new evidence to inform guideline development. We will engage with a broad range of stakeholders to disseminate results and plan for adoption and scale-up of the new treatment light of the findings. Trial follow-up will be completed during 2023 with dissemination of results to follow. The lead investigator for this study is Dr Megan Palmer, Desmond Tutu TB Centre.
TB CHAMP is a cluster-randomized, community-based, double-blind controlled trial to assess the efficacy and safety of levofloxacin vs. placebo in children below 5 years of age exposed to MDR-TB in the household. In this trial, almost 1000 children with recent household exposure to an MDR-TB source case were enrolled across 5 sites and randomized by household to receive either daily levofloxacin (15-20 mg/kg) or matching placebo for 6 months and followed for a maximum of 18 months to characterize the efficacy (incident TB disease), safety and tolerability of the treatment. The trial opened in South Africa in Quarter 4, 2017 and completed accrual in 2022. Trial results will be disseminated during 2023. Evidence for the efficacy and safety of levofloxacin in preventing MDR-TB in exposed children is expected to result in international recommendations for its use for this indication. This has the potential for substantial public health impact, as implementation would help prevent the development of MDR-TB in at-risk children. The lead investigator for this study is Anneke Hesseling (Co-principal investigators: James Seddon and Simon Schaaf), in collaboration with the MRC CTU at UCL (PI:Dr. Trinh Duong).
The Delamanid Crush study characterized the pharmacokinetics and the acceptability of crushed or dissolved delamanid 50 mg solid tablets in 24 healthy adult volunteers to inform their use for children affected by MDR-TB. The lead investigator for this study is Dr Veronique de Jager, and the trial was implemented at TASK Applied Science in Cape Town. Results have been disseminated to WHO during 2022 and have informed delamanid dosing guidelines in children, and final data has been published.
The PETITE study platform was established as part of the BENEFIT-Kids project to inform evidence-based guidance on the use of novel paediatric antiretroviral formulations in neonates who currently have few options for the prevention and treatment of HIV. Adrie Bekker, Stellenbosch University, and Tim R. Cressey, Chiang Mai University, are co-leading the series of PETITE studies.
The first PETITE study evaluated the pharmacokinetics and safety of a novel fixed-dose combination granule formulation of abacavir/ lamivudine/ lopinavir/ ritonavir (4-in-1) in 16 HIV-exposed neonates enrolled at Tygerberg Hospital, Cape Town, South Africa. The higher than standard doses of abacavir and lamivudine imposed by the FDC were well tolerated but the lopinavir/ritonavir exposures were very low, thus preventing the use of this paediatric formulation in neonates in future. Given these findings, a second study assessing two separate formulations of the same three drugs (a quarter dispersible tablet of abacavir/ lamivudine once a day and 2 sachets of lopinavir/ritonavir twice a day) was conducted in 24 neonates to allow for higher dosing of lopinavir/ritonavir. This study was completed and results from this second study will be disseminated during 2023.
A third pivotal study, the PETITE Dolutegravir study, recently started enrolling neonates exposed to HIV to assess the pharmacokinetics and safety of dolutegravir in addition to standard of care antiretroviral prophylaxis. To date, 16 neonates have enrolled and the study is expected be completed during 2023. Dolutegravir is being rolled out globally in children and data on its appropriate and safe dosing with appropriate formulations in newborn babies is urgently needed.
Output 3: Targeted formulation and market shaping work to improve the availability of child-friendly formulations of 2nd-line TB drugs
Led by TB Alliance and in partnership with Stellenbosch University, the BENEFIT Kids project is working closely with generic manufacturers to stimulate progress and ensure the development of two novel or optimized formulations of 2 key drugs, moxifloxacin and linezolid, to ensure that formulations are child-friendly and are palatable to children, the end-users. As part of this work, a study of the best tasting formulation blend of these drugs (ChilPref_ML) was successfully completed in healthy child volunteers in South Africa in 2022. The results, which will be disseminated during 2023, have informed the taste selection of these new formulations going forward. We will continue to build on this work in future and undertake more field work on more optimal and practical delivery methods of TB medications to children.
This video (courtesy TB Alliance) shows a representative procedure for preparation of compounded BDQ syrup suspension. This approach can make pills easier for patients to take.
BENEFIT Kids is also undertaking complementary laboratory-based work to inform the use of extemporaneous suspension formulations, prepared from widely available existing adult tablets, for treatment of children to bridge current gaps in access to paediatric formulations in the field. In addition, taste test evaluations have be conducted to understand children’s preferences of paediatric TB formulations. This will be an important bridge in some settings until child-friendly formulations are more widely available. This work is ongoing and several outputs have been disseminated and have already been shared with WHO during 2022, informing operational guidance for the practical use of these formulations in the field.
The BENEFIT Kids Project at the Union Conference 2022
The BENEFIT Kids Project, or Better Evidence and Formulations for Improved MDR-TB Treatment for Children, is a Unitaid-funded project aimed at contributing to reduced morbidity and mortality of children with MDR-TB through better access to improved prevention and treatment.
During 2022, we shared findings from studies at the virtual Union World Conference on Lung Health 2022 which took place from 8-11 November. The presentations were well received in the scientific and TB community.
Relative bioavailability of delamanid tablets dispersed in water in healthy adult volunteers
-Dispersed 50mg delamanid tablets have the same bioavailability as tablets swallowed whole and can therefore be used in children and other patients who cannot swallow whole tablets, improving access to treatment
Treatment outcomes in young children with RR-TB treated with regimens including bedaquiline and delamanid: a global individual patient data meta-analysis
-Bedaquiline and delamanid have been used infrequently in young children due to limited outcomes, dosing and safety data. In the subset of children aged <3-6 years in a systematic review and individual patient data meta-analysis of children with rifampicin-resistant tuberculosis, we evaluated the effect of bedaquiline and delamanid on outcome.
Predictors of treatment outcomes in children with rifampicin-resistant tuberculosis: a global individual patient data meta-analysis
-To inform approaches to treatment of paediatric rifampicin-resistant tuberculosis (RR-TB), we undertook a global systematic review and individual patient data meta-analysis. We evaluated and report on demographic, clinical and treatment predictors of outcome in 20395 children and adolescents (0-19 years) treated for RR-TB.
Pharmacokinetics and optimised dosing of novel dispersible and non-dispersible levofloxacin formulations in children
-A crossover study compared the pharmacokinetics of novel dispersible (paediatric) to routine non-dispersible (adult) levofloxacin formulation in children on routine preventive therapy for rifampicin-resistant tuberculosis.
-Differences in bioavailability, and hence exposures, were observed between the formulations and new optimized age- and weight-based dosing strategies are suggested based on globally available formulations.