Tuberculosis remains a global health crisis, disproportionately affecting children in high-burden countries. For young patients battling drug-resistant strains of the disease, the arduous treatment regimens often feel as traumatic as the illness itself. But a groundbreaking study is offering a glimmer of hope. Dr. Graeme Hoddinott, a socio-behavioral scientist at Stellenbosch University and a fellow of the African Research Initiative for Scientific Excellence (ARISE), led a project that put children’s taste buds at the forefront of drug development, potentially revolutionizing pediatric TB care. Capital’s Groum Abate spoke with Dr. Hoddinott about the ChilPref ML study, its surprising findings, and its implications for improving treatment adherence and reducing suffering for young TB patients worldwide. Excerpts;
Capital: Can you explain the significance of the ChilPref ML study in the context of pediatric TB treatment?
Dr Graeme Hoddinott: The ChilPref ML study was about two of the drugs (Moxifloxacin and Linezolid) that are priority treatments for drug resistant TB. Typically, treatment of drug resistant TB, including among children, uses a combination of more than five drugs, combined in a regimen and taken daily for at least 6 months, though often for longer. Moxifloxacin and Linezolid are two important drugs used in many of these regimens. Unfortunately, available formulations of both drugs are often highly unpalatable. Imagine, trying to administer handfuls of drugs to young children (often younger than 5-years-old or 2-years-old), every day for many months. And the available formulations of those drugs taste disgusting. They are not designed to be portioned (cut up), even though they have to be for children who need smaller doses, and they do not dissolve. Just think about what that is like for a child and their caregivers. In ChilPref ML, worked with two pharmaceutical manufacturers (MacLeods and Microlabs respectively). Both company were in the process of creating generic formulations of Moxifloxacin and Linezolid. We worked with them to select three versions of each drug that they had tried to make as palatable as possible for children. We then asked children to taste these and select which of the formulations they preferred.
Capital: What motivated the researchers to focus on the taste of moxifloxacin for children?
Hoddinott: To clarify, the study was about moxifloxacin and linezolid. Both drugs were reported in small qualitative studies and anecdotally to be especially bad tasting. Poor palatability (taste) of drugs – when it is as bad as these are – is itself a trauma for children and their caregivers. For example, in previous studies, TB survivors have reported that the experience of treatment is worse than the experience of disease. So, improving acceptability of TB treatments for children is an important goal in its own right – to reduce treatment-associated morbidity. In addition, poor acceptability also compromises administration and adherence. For example, the child may spit up some of the dose, and therefore be under-dosed. If the caregiver attempts to then administer more, then they may be over-dosed. And there are other similar challenges, e.g., treatment fatigue – after months of physically restraining your 2-year-old and forcing these awful medicines into them, its understandable that sometimes caregivers may start skipping some doses, especially as the child recovers. In turn, these challenges to administration / adherence negatively impact the child’s outcomes, increasing their risk of death and long-term negative health consequences.
Capital: What were the key methodologies used in the study to evaluate children’s taste preferences?
Hoddinott: This was a ‘swish-and-spit’ taste panel evaluation. Imagine like a wine or cheese-tasting experience, but with different taste blends of the drugs. The panel included (a) a relative ranking (i.e., putting the formulation versions in order of preference), (b) five-point Likert-scale questionnaires about the experience of each blend, and (c) nested qualitative data.
Capital: How did the researchers ensure the safety and feasibility of the study design involving children?
Hoddinott: The participants are healthy volunteers. I.e., they did not have TB at the time of the study. Both the drugs (moxifloxacin and linezolid) are safe and used routinely in the treatment of children with MDR-TB in South Africa (and many other countries). And, as a swish-and-spit approach, the children did not ingest any of the drugs – they spit them out after swirling in their mouth for a few seconds. All caregivers of participants completed informed consent, and all the child participants also completed informed assent.
Capital: Can you describe the process of selecting the flavor blends that were tested?
Hoddinott: Both manufacturers started with a flavour blend that they believed would be child friendly. Each of the manufacturers independently used their routine internal processes for developing flavour blends in their labs. The project team provided general advice from parallel research on what types of flavours children with TB tend to prefer. And then each manufacturer then developed two more flavour blends of each of the drugs.
Capital: What were the main findings regarding the taste preferences of children for the different formulations of moxifloxacin?
Hoddinott: For both manufacturers, for moxifloxacin, the children demonstrated a significant preference for the novel flavour blends over the blend that the manufacturer had originally proposed as child friendly. I.e., that both manufacturers should change from the blend that they would have proposed and instead propose one of the novel blends. We also found that for linezolid, there was no improvement in preference for any of the novel blends, and the manufacturers could proceed with the blend that they had originally proposed. Secondarily, we described the palatability of the preferred blends in absolute terms and noted still needing to further improving even the most preferred formulations to be genuinely ‘acceptable’.
Capital: How do you anticipate these new formulations will impact adherence to TB treatment among children?
Hoddinott: Firstly, making the drugs taste better is good in and of itself, regardless of any benefits for adherence. We did not assess adherence in this project. But given how much more preferred the blends were, we can only assume that they would be easier to administer and therefore adherence will also be easier. From the qualitative data, some children did indicate that the preferred blends weren’t that bad and they could take this medicine.
Capital: What role does taste play in the overall treatment experience for children with drug-resistant TB?
Hoddinott: Taste is one component of palatability, which also includes other attributes such as mouth-feel, smell, etc. And palatability is one component of acceptability. Taste is disproportionally important, especially to the younger children.
Capital: How has collaboration with pharmaceutical manufacturers contributed to the outcomes of this study?
Hoddinott: This was a close collaboration with the manufacturers (MacLeods and MicroLabs), and the TB Alliance. The project could not have been completed without their engaged participation.
Capital: What are the next steps for implementing the findings from this research into clinical practice?
Hoddinott: The manufacturers have submitted their generic formulations (with the flavour blends identified here) for oversight by regulatory bodies. Once approved, these will then become available to the global procurement processes and the supply-chain of country programmes.
Capital: What does this study suggest about the importance of involving patients, especially children, in the development of medical treatments?
Hoddinott: We already know that this is essential. And that especially children are often excluded from such involvement. The study demonstrates that we can have high-impact from listening to affected communities, including young children, and that this can be done with limited additional investment and rapidly.
Capital: How can this research be a model for improving treatments for other pediatric diseases?
Hoddinott: There is no reason why this same approach cannot be applied to the drug development pipelines for all drugs used for children. And wherever poor palatability might be an important driver of treatment associated morbidity and negative adherence / outcomes, we advocate that it should always be included.
Capital: What challenges did you face during the study, and how did you overcome them?
Hoddinott: Honestly, there were very few challenges. Recruitment for participants went very fast – affected communities understood the importance of the project because they had personal or vicarious experiences of how awful TB treatments can be, especially for children, and they wanted to help. The findings have also been received positively, and we genuinely hope that this model will be adopted widely.
Capital: What message do you hope to convey to healthcare providers and policymakers based on the results of this study?
Hoddinott: We do not have to accept the suffering imposed by sub-optimal palatability on children. It is not good enough to only inform decisions based on safety and efficacy. This is a relatively simple, inexpensive process that can make a big difference. Let’s do it.
