New advances in paediatric drug-resistant tuberculosis

¹Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

^&Corresponding author
Sheetal Harichander, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

Perspective    

A reflection

Tuberculosis (TB) is a preventable and typically curable disease caused by the bacterium Mycobacterium tuberculosis [1]. In 2022, TB was the world´s second leading cause of death from a single infectious agent, following the coronavirus disease (COVID-19), and accounted for nearly twice as many deaths as HIV/AIDS. That year, 7.5 million new TB cases were reported globally, the highest number since the World Health Organization (WHO) began tracking TB in 1995 [1]. This figure likely includes a backlog of cases from previous years, as the COVID-19 pandemic disrupted healthcare services and delayed diagnoses and treatments. According to the WHO´s Global TB Report, 12% of TB cases in 2022 occurred in children aged 0-14 years. Additionally, an estimated 410,000 people worldwide developed drug-resistant (DR) TB that same year [1].

Of the estimated 1.2 million children under the age of 15 who develop TB each year, only about one-third receive a diagnosis and are treated [2]. Even more concerning is that, of the 30,000 children believed to have multidrug-resistant (MDR) TB caused by organisms resistant to at least isoniazid and rifampicin, only around 5,000 receive treatment annually [2]. South Africa (SA) is listed as one of the high-burden countries for TB, human immunodeficiency virus HIV-associated TB, and Multi-drug Resistant MDR/ Rifampicin Resistant (RR) TB [1]. However, SA has increased efforts to locate individuals with undiagnosed disease and initiate treatment. Furthermore, the country has been instrumental in providing evidence and research in terms of HIV, TB, and DR-TB to the WHO.

Though children with DR-TB have better treatment outcomes than adults [3,4], many children struggle during treatment due to the limited availability of paediatric formulations of antitubercular medication [5]. Childhood TB and DR-TB have previously been treated through the estimation of paediatric doses by the crushing of adult tablets and opening of capsules [6]. This could result in incorrect dosing, which may lead to prolonged hospitalization and require significant staff time for preparing and administrating medication [6,7]. This impacts treatment adherence in the population, which leads to treatment failure [7-10]. Some of the factors that impact adherence in children include the lack of paediatric formulations, pill burden, palatability, length of therapy, and toxicity [7-10].

Several studies conducted in SA describe the unique challenges experienced by children, caregivers, and healthcare professionals in the manipulation of solid dosage forms for the treatment of DR-TB. Wademan et al. described the poor overall acceptability of DR-TB in children and the negative experiences of children and caregivers [11,12]. Misra et al. further explored that for a child diagnosed with DR-TB, there is a lived experience of stress that impacts their physical, mental, and social well-being [13].

Closing the gaps

Following decades of limited progress, the past ten years have seen significant breakthroughs in the treatment of DR-TB in children and adolescents. These advances mark a crucial turning point in TB care, offering new hope for more effective therapies. In March 2022, the WHO recommended the use of bedaquiline and delamanid for treating DR-TB in children of all age groups [14]. These new and repurposed drugs offer promising opportunities to shorten the traditionally lengthy treatment duration and reduce reliance on injectable drugs, as well as drugs associated with severe side effects and drug interactions.

The Stop TB Partnership's Global Drug Facility (GDF), acknowledged as the world´s largest supplier of quality-assured TB medications, has taken significant steps to include child-friendly formulations in its product portfolio. These formulations include second-line TB drugs such as bedaquiline, clofazimine, cycloserine/terizidone, ethambutol, ethionamide, levofloxacin, moxifloxacin, and pyrazinamide, aiming to improve the treatment experience for children [15-17]. A presentation done at the South African Association of Hospital and Institutional Pharmacists (SAAHIP) conference in 2023 detailed the “KwaZulu-Natal Experience” with the child-friendly formulations that were donated by the GDF and received in the province in 2020 [18]. KZN received dispersible tablets of ethambutol 100mg, pyrazinamide 150mg, levofloxacin, and dispersible clofazimine 50mg. Given that these formulations were not registered in SA, the route of Section 21 was followed. This process entailed obtaining informed consent and submitting progress reports that monitored outcomes and adverse drug reactions every 6 months and at the end of treatment [18]. According to the study, 24 children in the province benefitted from this initial donation. The child-friendly formulations were well-received and tolerated by both caregivers and children. Healthcare workers noted ease of administration, better tolerability, and more accurate dosing calculations with the dispersible formulations [18].

In a presentation conducted at the 8^th South African TB Conference held in June 2024, it was explained that the country received the second donation of dispersible tablets of delamanid 25mg, levofloxacin 100mg, clofazimine 100mg and linezolid 150mg in 2023 and access was expanded to the Eastern and Western Cape provinces. A third donation of bedaquiline 20mg, clofazimine 50mg, levofloxacin 100mg, and delamanid 25mg is expected this year (2024) to include two additional provinces i.e. Gauteng and Mpumalanga [19]. Table 1 provides a summary of the second-line drugs available for the treatment of DR-TB, including the dosage forms registered for use in SA and the availability of child-friendly formulations that can be procured from the STOP TB Partnership Global Drug Facility [15,17,20].

The future

Although the GDF has provided a catalogue for countries to request a donation of child-friendly formulations, access in several countries is still a challenge as indicated in a study by Buonsenso et al. [21] SA has received two donations from the GDF, however access has been restricted to three out of the nine provinces in the country [19]. According to the presented findings at the 8^th South African TB Conference held in June 2024, uptake with the child-friendly formulations remains low in SA [19]. The country is focused on finding the missing cases of children with DR-TB and initiating treatment. More research is required into the acceptability and tolerability of these child-friendly formulations to advocate for registration in the country. Although the donation of child-friendly formulations has temporarily closed the gaps, local manufacture and registration in countries should be encouraged to ensure a sustainable supply of these formulations.

To effectively address DR-TB in children, a coordinated global effort is essential, focusing on several key areas. First, investment in paediatric research must be prioritized, with increased emphasis on paediatric-specific clinical trials to develop evidence-based treatments tailored for children with DR-TB. This includes expanding access to trials for new drug regimens and assessing the safety and efficacy of existing treatments in paediatric populations. Second, access to child-friendly drug formulations must be scaled up through collaboration between pharmaceutical companies and global health organizations, alongside streamlined regulatory processes to fast-track approvals in high-burden countries. Third, strengthening health systems in regions with high DR-TB incidence is crucial, particularly through investments in diagnostic tools and treatment infrastructure. Ensuring the availability of rapid diagnostic tools at the primary care level can significantly reduce delays in diagnosis and treatment initiation. Finally, addressing adherence and treatment support is vital, with comprehensive systems needed to help children complete their treatment regimens. This includes providing counselling for caregivers, monitoring for adverse effects, and offering social support to help families navigate the challenges of long-term treatment.

Conclusion     

While the future of DR-TB in children holds promise due to medical advancements, the global response must prioritize the unique needs of pediatric patients. Addressing the existing gaps in drug formulations, access, research, and healthcare infrastructure is essential to achieving better health outcomes and reducing the global burden of DR-TB in children.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Sheetal Harichander, Varsha Bangalee, and Frasia Oosthuizen conceived the study design. Sheetal Harichander wrote the draft of the manuscript with Varsha Bangalee, and Frasia Oosthuizen assisted with further drafts and revisions. All authors reviewed and approved the final version of the manuscript.

Tables     

Table 1: available second-line antitubercular drugs for management of drug-resistant tuberculosis in children

References