Introduction

Vectorial transmission of Chagas disease mainly occurs during childhood in endemic areas. However, transmission can also occur through blood transfusion, organ transplantation, consumption of contaminated food or beverages, and from mother to fetus [1,2]. Maternal health and the risk of infection to newborns are an important but often ignored aspect of neglected tropical diseases (NTDs) in general and Chagas disease in particular. Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, endemic to the Americas, with the main vectors for transmission being triatomine bugs [3]. Mother-to-child transmission is the main route of new T. cruzi infection; around 1.7 million women of childbearing age worldwide are estimated to have T. cruzi infection, resulting in 9,000 babies born with Chagas disease every year [4]. Congenital infection can occur in non-endemic areas, which is a major challenge for Chagas disease control in areas with no vector transmission [5]. Fortunately, treatment of women before they conceive (e.g., in adolescence) has been demonstrated to prevent congenital Chagas disease transmission [6–10]. However, the risk of infection in children through both vectorial and congenital transmission remains high. While acute T. cruzi infection is usually mild or symptom-free, approximately 30% of chronic cases will develop serious complications many years later, that besides being associated with a variable morbidity, in some cases limiting the life of the person, potentially resulting in early mortality [11]. Treatment in the acute phase is required to clear T. cruzi infection [12].

There are currently only two drugs available to treat T. cruzi infection, benznidazole and nifurtimox [13]. However, both drugs were developed over 50 years ago and have limitations to their use, especially during the chronic stage of the infection [14–16], mainly due to the incidence of related adverse drug reactions (ADRs) (most of them mild, but in 20% of cases these prevent completion of treatment), and due to their variable efficacy depending on the stage of the disease. Although efforts have been made to produce and provide pediatric formulations, some barriers persist that may justify exploring new formulations [1,17]. Innovation for new and better drugs should be a priority in order to promote early treatment and universal access [13].

Target product profiles (TPPs) define the required product attributes of new drugs [18]. They can help as a planning tool to place patients, such as pediatric populations, at the center of drug discovery. TPPs are intended to guide all interested parties (pharmaceutical companies, academia, research institutions, product development partnerships, non-governmental and civil society organizations, and donors) to achieve better organized and more successful drug development programs [19], helping pinpoint the clinical and economic benefits of new drugs and formulations [20]. TPPs are available for Chagas disease and highlight areas where diagnostics or treatment are needed, such as point-of-care diagnosis and assessment of response to treatment [21], and to define biomarkers for early assessment of treatment efficacy [22]. There is also a TPP for Chagas disease treatment [23], however, given the particular needs of children, it was considered important to develop a specific TPP for the pediatric population infected with T. cruzi to help guide the development of appropriately adapted new medicines and therapeutic approaches. In this article, we present a TPP developed by an expert panel.

Methods

The starting point for this TPP was a review of relevant literature on the treatment of children with T. cruzi infection, including the work published on pharmacology related to T. cruzi infection treatment. We conducted a narrative review of the literature; the search was conducted in PubMed and incorporated search terms including Chagas disease, target product profile, pediatric, Trypanosoma cruzi, pharmacokinetics, and treatment, without time limitations. We excluded sources not related to Chagas disease or not directly applicable to treatment or to target product profiles (e.g., studies of the vector).

Recognized leaders in the field were then invited to contribute to the TPP working group based on their proven expertise (see authors/acknowledgements for a full list). The panel was selected among experts in the Chagas Clinical Research Platform, which is a global network of over 400 experts and other stakeholders dedicated to Chagas disease research and treatment access. Researchers included on the panel were experts from a wide range of geographical regions and backgrounds, including representatives of people at risk of having T. cruzi infection, pediatricians with experience in managing patients with T. cruzi (caregivers), researchers from different backgrounds (e.g., clinicians and pharmacologists) experts in pediatric clinical studies, healthcare personnel with expertise in in access and implementation of care models, medical anthropologists and epidemiologists, and experts in communication and advocacy linked to the T. cruzi infection community. After the literature review, a first TPP draft was then prepared and based on the feedback in the first round, another draft was prepared and circulated among the participants of the working group. This was then repeated over several rounds, which allowed all contributors to provide critical input and suggest points for review. Additionally, the draft Target Product Profile was made available and feedback was invited via the Chagas Clinical Research Platform (both at its annual plenary meeting and via its web forum) before being finalized. A final draft was prepared after consideration of all feedback and discussion points in advance of a consensus meeting with experts and relevant stakeholders (representatives of, or people at risk of, suffering from T. cruzi infection/ Chagas disease). The final consensus TPP was then established after unanimous agreement by the group.

Given the lack of published data on the topic, the minimum and optimal requirements for each attribute were defined through consensus as “essential requirements”. These represent target characteristics of a candidate regimen that are the same as or better than the current standard-of-care and are considered an acceptable minimum for global health impact; they provide the basis for making critical decisions throughout the development and assessment process. In addition, the “ideal requirements” were defined for a product, which, if met, would broaden and accelerate the global health impact. Any future regimen should have at least all the essential requirements and as many of the ideal requirements as possible.

Results

The TPP for the treatment of children with T. cruzi infection is summarized in Table 1 and includes 15 different attributes. The working group identified both essential and ideal indications for the development of pediatric formulations. The essential indication is for children with acute/congenital and chronic T. cruzi infection; however, the ideal indication would include children with chronic indeterminate, congenital, and/or acute vector-borne T. cruzi infection, immunosuppressed people, and pregnant women. The target population was defined as newborns to adolescents (age 0–18 years).

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Table 1. TPP for the development of pediatric formulations of new drugs for the treatment of Chagas disease.

https://doi.org/10.1371/journal.pntd.0013597.t001

Discussion

This TPP was developed to present the essential and ideal characteristics of pediatric formulations of new drugs for the treatment of Chagas disease. The expert working group identified 15 attributes that need to be considered by anyone developing Chagas disease formulations for children, including the target population, safety, efficacy, formulation, palatability, and administration.

Even if in 2017 DNDi and collaborators developed a TPP for Chagas disease treatment with a more general approach, and even if key attributes overlap partially with the ones described at that time, this TPP adds more details to the definition of the essential and ideal attributes for the development of medicines for paediatric use. Besides, the paediatric TPP prioritizes congenital and acute infection, and also includes the cases of pregnant adolescents and women. It also stresses the relevance of including aspects linked to access (taking also into consideration attributes like stability and storage) and costs, as well as global regulatory expectations for a new medicine under development to be registered and adopted.

Without accurate treatment, children are at risk of developing Chagas disease, which, later in life, may cause serious disease and early mortality. There is strong evidence to support the recommendation to treat infants with T. cruzi infection within the first year of life [24,25]. Given the efficacy of the two drugs that are available, there are no medical reasons to avoid treating children with Chagas disease. However, new drugs for Chagas disease therapy should be developed in order to eliminate any barriers related to their use [13,14,26]. If new drugs for Chagas disease are going to be suitable for children, their formulations need to be carefully considered.

Current treatments with benznidazole and nifurtimox are generally well tolerated, with up to 90% cure rates in infants [27–30]. Unfortunately, there is limited data on the safety of the current treatments in terms of their genotoxicity and teratogenic risk, and for this reason they are commonly avoided in pregnant women. Thus, screening to identify women with the infection, ideally before pregnancy, and diagnosis, monitoring, and treatment of infants with the infection is strongly recommended [31]. Factors limiting the use of adult-focused formulations (i.e., tablets) in children have been overcome through clinical programs that were set up to develop pediatric formulations of benznidazole and nifurtimox [32,33]. However, in some countries, the pediatric formulations of these drugs have not been registered by the pharmaceutical companies who developed them, and children must receive treatment off-label. Moreover, currently less than 1% of people with T. cruzi infection receive a treatment regimen regardless of their age [17,26,34,35]. It is important to note that the process of registering a drug is very arduous, as is maintaining it: if there is only a small number of patients in each country ready to receive such a treatment, industry will be discouraged from engaging, making alternative solutions, such as PAHO-mediated donation, a more realistic approach today. The reasons for the low treatment rate are complex, but include ambiguous messaging about treatment benefits, scarce knowledge of the disease, and limited and inconsistent access to drugs for different and context specific reasons [17,35]. Patients may have difficulty getting medication even in areas where the drugs have been approved, such as in the USA [1,36]. In endemic areas, particularly poor rural regions, access to healthcare providers can be difficult, and the availability of medications is low and unpredictable, which is particularly pertinent because Chagas disease treatment requires 30–60 days of dosing. Barriers into access related to economics have been mitigated by donation to countries and free delivery by health authorities that buy the drug. Without these measures, costs could be a barrier for people with low income [37]. The gap between the demand for etiologic treatment and the estimates of disease prevalence in endemic areas of Latin America demonstrates that access to treatment is lacking [35]. Up to 2012 there were disruptions in the supply of benznidazole and nifurtimox due to insufficient levels of production and disruption in the supply chain [17]. From 2012 to the present, production has been assured. Children have further hurdles to overcome, such as misinformation about the availability, use, and safety of pediatric formulations.

Alongside access to the drugs, awareness of the disease among patients and healthcare providers remains below optimal, despite efforts at publicizing Chagas disease, meaning that many people are unaware of their risk of infection. Early detection and treatment of infection in children are vital to prevent disease development. Difficulties with the treatment regimen are also a factor. Adverse drug reactions, absence of treatment algorithms to address these, and long courses of therapy are usually mentioned as barriers for treatment. Since other drugs with more ADRs are commonly used, it is clear there is a complex network of different barriers surrounding the treatment of Chagas disease [37]. The need for novel drugs, repurposed drugs, or combination therapies that are safer and more effective in chronic infection is evident [26], but in the meantime the current therapies are still needed.

Discovery of new drugs is often challenging, with high attrition rates even in areas with high pharmaceutical investment and where a significant return on investment is expected. In an environment where the number of clinical trials involving children is already limited, drug development for pediatric populations with NTDs can be particularly challenging [38]. However, this approach is changing, and pediatric drug development is becoming increasingly important, and in some jurisdictions, mandatory or strongly encouraged. Several regulatory incentives and resources are now aimed at addressing these needs and promoting the development of formulations for children [39].

To guide research efforts towards the development of new therapeutic options to treat T. cruzi infection in children, we present a TPP for Chagas disease that aims to develop an oral, age-adapted shorter-course treatment that is safer and more effective than current options, for use in all regions and in both chronic and acute patients, including during pregnancy [23]. However, it is important to acknowledge that the pediatric population has some distinct needs that merit a standalone TPP, and guidance for this goal has been published [40]. Several addition to the previous TPP, built for a more general population, were highlighted above, but it is important to note that additional pharmaceutical specificities, such as more detailed formulation criteria for medicines to be used for children were added to this new TPP. Different patient populations have different pharmacological profiles, such as the lower plasma concentration of benznidazole in children [27]. While the tendency to exclude young children, adolescents, and pregnant and lactating women from clinical trials is changing, the numbers of these patients in recent studies are still low, so there is an inevitable delay in the approval process [41]. Pediatric populations may be considered a neglected population, so it is important to prioritize the affordability, availability, and adaptability of drugs to suit them [41].

Many points in this TPP for children are similar to those suggested in a previous TPP [23], reflecting similarities between the needs of children and more general populations. However, the current pediatric TPP highlights the treatment of acute/congenital infection as essential, while the previous TPP was more focused on chronic aspects of the infection. This distinction is important because of the large number of neonates who contract T. cruzi infection through mother-to-child transmission every year [4].

Important at this point to highlight another of the differences that the paediatric TPP added to the TPP developed in 2017: the new TPP introduces defined efficacy thresholds, in contrast to the previous relative-to-standard approach. It is essential that the efficacy of any new drug is greater than 75% (similar to current treatments), while efficacy greater than 90% would be ideal. Due to low and intermittent parasitemia, negative serological results are still the gold standard of cure [42]. However, achieving negative serological results (defined as the gold standard of cure) in adults and in adolescents in the chronic stage of the infection is quite difficult because of the prolonged persistence (potentially for decades) of antibodies to T. cruzi and limitations in the sensitivity of parasitological tests [6]. Molecular techniques generally involving polymerase chain reaction (PCR) can now identify low levels of parasitemia, but their use in the chronic phase of T. cruzi infection remains debatable because of variability in results, and because they have been a marker of therapeutic failure rather than a test for cure. These test results depend on the degree of parasitemia, sample volume, DNA purification method, target region, patient characteristics, and parasite genetic variability [43]. In children the scenario is different. For congenital transmission, the diagnosis is based on direct observation or PCR test during the first month of the newborn’s life [44]. If parasitemia is negative, due to low parasite level, diagnosis is based on a serological test after maternal T. cruzi antibodies have disappeared, after 9–12 months of age [43]. There is also evidence of decreased or serological negativity shortly after treatment in children, so serology is a useful marker of response to treatment in this group [13,45,46].

Another added attribute included in the paediatric TPP is the in vitro activity and clinical evaluation characteristics. Response to evaluation by clinical trials in at least T. cruzi-discrete type unit 1 (DTU1) and DTU2 was determined as an essential characteristic. This reflects the infection risk in children beyond endemic areas through infection routes other than vector transmission, such as congenital infection. An ideal characteristic would be to evaluate the new drug against various DTUs in different geographical areas, thus widely assessing its usefulness.

In terms of safety, the essential characteristics identified were tolerance equal or better than standard treatments, and absence of long-term toxicity to bone metabolism, neurodevelopment, or reproductive toxicity, reflecting concerns about the long-term effects of medications on developing children, while the ideal characteristics were better tolerance than standard treatments, severe immunological non-toxicity, safety in pregnancy, and absence of chronic toxicity. The current treatments have some ADRs, including rash and pruritus, headache, myalgia, and gastrointestinal discomfort for benznidazole and anorexia and weight loss, irritability, sleepiness, and other nervous system signs and symptoms for nifurtimox [13,47]. These symptoms prevent patients from finishing the prescribed treatment regimen in around 20% of cases in adults and in 5% in children if they are not properly monitored by the health teams [13,47]. This is worth highlighting from the perspective of safety during pregnancy, because it will have an impact upon both the mother and newborn infant. The evidence shows that current treatments are safe for the baby during breastfeeding [48,49], however, extended information on the reproductive toxicity of benznidazole and nifurtimox is lacking. Given that effective treatment will prevent future congenital transmission, and that in some areas (e.g., rural impoverished areas) a young woman may only come in contact with the health system during pregnancy and delivery, providing treatment as soon as possible after delivery has the potential to prevent future infection of newborns, as would developing treatments that could be administered during pregnancy.

Drug-drug interactions are another safety-related aspect that must be characterized to ensure the product has no serious interactions with other medications, and in this TPP, in contrast to the TPP for general population developed in 2017, the definition of the essential and ideal characteristics is more accurate.

If the final goal is to expand the use of the new therapeutic options, other equally important characteristics must be taken into consideration. The formulation, palatability, and method of administration are particularly important to pediatric populations and impact the acceptability of treatment. Oral dosing is preferable for most children, and dosing needs to be simple with minimal or no need to break tablets [38]. Therefore, a liquid formulation may be considered, and this could be injectable for patients who cannot tolerate oral medications, such as premature newborns and immunosuppressed patients. However, the use of liquid may be limited in some locations due to storage and transportation issues. Liquid formulations are often less stable than tablets, weigh more, and can be difficult to transport, often requiring refrigeration in hot climates [50]. Dispersible tablets offer many benefits in terms of storage and can be easily swallowed in a liquid, while a grooved tablet allows for split dosing. An ideal formulation would be a slotted dispersible tablet with no need for formulation manipulation. In addition, there is a requirement for a pleasant taste to ensure the solution is palatable to infants and children [39].

Another important attribute adapted in this TPP for paediatric use (and another difference regarding the TPP for medicines of general use in Chagas) is the consensus to markedly shorten the ideal treatment duration (7 days) compared to the broader <30-day goal in the general one. Dosing frequency, included in this TPP and not in the previous one, was defined to be twice or ideally once daily, for a period of 8–30 days, and ideally 7 days, since long treatment durations can lead to discontinuation, which impacts efficacy and drug resistance [51]. Dose flexibility, with the ability to be adjusted and the requirement that the medicine should be easily measured is also requested as an attribute to be considered in drug development for children in Chagas context. Administration needs to be oral or injectable intravenously (IV), with no food interaction, as modified absorption can complicate dosing. Other attributes to take into consideration that were lacking in previous TPPs were: a) Stability and storage are also vital considerations in many low and middle-income countries (LMICs),and b) Packaging, which must also be childproof and provide information in a visual manner easy to understand, since those administering the treatment may not be able to read. A blister pack for the tablets, for example, would make them easy to store and administer.

Access and cost factors are particularly important considerations for a product targeting an NTD in a neglected population. In this case, it is essential that the cost of goods is aligned with the cost of production. The product should be widely available in the health system and out-of-hospital pharmacies. It would be ideal if the product were manageable in primary care centers and other health system centers. The current problems with access to treatment should not be repeated with new formulations, distribution and production must be guaranteed in the long term, and the use of future pediatric formulations promoted. Regarding regulatory expectations, an important difference with the previous TPP is the inclusion of a global regulatory ambition, setting the requirement that registration must be comprehensive to avoid the need for off-label use, including by Latin American and international agencies, such as the Food and Drug Administration of the United States of America (FDA) and the European Medicines Agency (EMA).

Conclusion

We present a new TPP for the development of pediatric formulations of new drugs for T. cruzi infection. Besides efficacy and safety requirements, the TPP highlights specific characteristics that are relevant for children, such as drug formulation, palatability, dose, administration, and accessibility. This tool is intended to assist in the development of novel therapeutic options to fight Chagas disease in this especially vulnerable population, in which timely treatment can cure the infection, preventing the development of future organ damage.

Acknowledgments

We would like to thank Melanie Colegrave, a consultant medical writer working for Morula Health, for her assistance in writing the manuscript.