The Roll-out of Child-friendly Fixed-dose Combination TB Formulations in High-TB-Burden Countries: A Case Study of STEP-TB

Abstract

A B S T R A C TChildhood tuberculosis (TB) has hitherto been treated through estimation of pediatric doses through the crushing of adult pills, but the bitter taste of the pills and the inaccuracy of this dosing method presents a challenge for both patients and healthcare providers, leading to poor treatment outcomes. The TB Alliance therefore launched the Speeding Treatments to End Pediatric-Tuberculosis (STEP-TB) project to incentivize the introduction of pediatric Fixed-Dose Combinations (FDCs) of TB drugs. This case study describes the elements of this project, evaluates its impact, and highlights future challenges for pediatric TB treatment. The impact assessment incorporates both market impact as well as projected public health impact, evaluating the availability, affordability, and quality of the FDCs, and lastly providing a projection of lives saved as a result of scale-up of the FDCs to near-universal availability and utilization, based on a publicly available pediatric TB-specific model. STEP-TB resulted in the development of two child-friendly FDCs that were successfully brought to market and made available in 20 of the project's 22 high-burden countries. On the basis of a country-specific projection of pediatric TB mortality in Kenya, scale-up to nearuniversal availability and utilization of the new FDCs could reduce pediatric TB-associated mortality by 2660 cases over the next 5 years. Future challenges include maintaining affordable prices for the FDCs and considering mechanisms to incentivize their introduction among high-risk groups in low-burden countries.

Availability of fixed-dose, child-friendly formulations of first-line tuberculosis drugs in Europe

“…Countries can access these new preparations through the Global Drug Facility (GDF). Up to 116 countries from many regions in the world are already routinely treating children with the new pFDCs [5,6]. However, these medicines are not licensed by the European Medicines Agency (EMA) for distribution in Europe, where pFDCs could be evaluated through a centralised authorisation process, or at a national level, to be later authorised in other European Union member states.We aimed to assess the availability of licensed first-line oral paediatric TB drug formulations in Europe, to investigate current practices regarding the choice and method of delivery of TB drugs and to assess knowledge and experience of the pFDCs in Europe.We conducted a web-based survey among the members of the Paediatric Tuberculosis Network European Trials Group ( ptbnet; http://www.tb-net.org/index.php/ptbnet) over a 2-month period (November to December 2019).…”

Modern approaches to pharmacotherapy of tuberculosis infection in children

“…Fixed-dose combined anti-TB drugs have been developed. An increase in adherence to treatment has been proven in the case of the use of such drugs (Faust et al 2019;Tsiligiannis et al 2019;Wademan et al 2019). In addition, the combination of anti-TB drugs makes it possible to sum up their therapeutic effect.…”

“…In addition, the combination of anti-TB drugs makes it possible to sum up their therapeutic effect. The destruction of MBT occurs faster, and the likelihood of drug resistance formation decreases (Faust et al 2019). A recent Russian multicenter observational study demonstrated that the use of fixed-dose combined anti-TB drugs in patients with newly diagnosed tuberculosis or its recurrence with preserved MBT sensitivity to Isoniazid and Rifampicin in chemotherapy regimens I and III was effective and was characterized by sufficient safety and tolerability (Tyulkova et al 2020).…”

Tuberculosis medicines for children in Europe: an unmet medical need

“…In addition, publications and sporadic reports suggested that suspensions or weight-adapted powder mixes are prepared ad hoc by pharmacies from capsules, and that breaking tablets (halved or cut, crushed or chewed directly) or mixing them with food or water are common off-label workarounds [ 13 , 15 ]. In the context of the recommended multidrug regimen, these practices translate into unreliable dosing [ 16 ] and further palatability problems [ 10 , 17 ]. Apart from the unknown effects on toxicity, the main concern is poor compliance [ 17 , 18 ].…”

“…In the context of the recommended multidrug regimen, these practices translate into unreliable dosing [ 16 ] and further palatability problems [ 10 , 17 ]. Apart from the unknown effects on toxicity, the main concern is poor compliance [ 17 , 18 ]. In turn, this may lead to insufficient dosages [ 10 ], potentially resulting in treatment failure, induction of microbial resistance, or both, after first-line treatment [ 2 , 10 ].…”