The challenge

Schistosomiasis, a debilitating neglected infectious disease caused by parasitic flatworms, affects around 250,000 people a year, most of them in Africa. The disease is commonly associated with poor sanitation and no access to drinking water. Schistosomiasis can be treated with a drug known as praziquantel. However, the currently available pills are difficult for young children. They are large and hard to swallow, cannot be crushed, and have an unpleasant bitter taste which can lead to gagging and vomiting. “This is a serious problem,” says Dr Remco de Vrueh, the coordinator of the PZQ4PSAC study, “as schistosomiasis affects a large proportion of children under 14 years of age, including an estimated 28 million preschool-age children.”

The Pediatric Praziquantel Consortium, funded primarily by the Japan-based Global Health Innovative Technology Fund (GHIT), brings together researchers from Astellas Pharma Inc. (Japan), Farmanguinhos Fiocruz Foundation (Brazil), the Kenya Medical Research Institute (Kenya), Lygature (Netherlands), Merck KGaA (Germany), the Schistosomiasis Control Initiative (UK), the Swiss Tropical and Public Health Institute (Switzerland), and the Université Félix Houphouët Boigny (Côte d’Ivoire). SimCyp (UK) which was also part of the consortium, left in 2017 after completion of its pharmacokinetic modelling and simulation activities.

The consortium has developed in parallel two child-friendly 150-mg praziquantel tablets which dissolve in the mouth. The so-called L-praziquantel formulation, a tablet containing only the biologically active R(-)-praziquantel enantiomer, and a racemic (rac-)praziquantel formulation, a tablet containing the racemic mixture of R(-)- and S(+)-praziquantel enantiomers.

Both orodispersible formulations have been shown to be palatable to African children. The new tablets can be placed directly on the tongue or dispersed in a small volume of water. They also offer options for flexible dosing according to the weight of the child.

Dr Remco de Vrueh
the Netherlands

Impact

The new formulation will help many young children to gain the benefits of praziquantel – potentially both for treatment and, in mass drug administration campaigns, for prevention.

More generally, the project is the first outcome of an ongoing partnership between EDCTP and GHIT, organisations with common interests in HIV/AIDS, malaria, TB and poverty-related infectious diseases. The success of the consortium could serve as a model for future initiatives for global health research in neglected tropical diseases.

The project

In partnership with EDCTP, the consortium conducts a clinical trial to determine the safety and efficacy of this new formulation in young children in Cote d’Ivoire and Kenya.

Dr De Vrueh: “The ongoing phase III clinical trial in Cote d’Ivoire and Kenya will serve as confirmatory trial and provide the necessary corroborative evidence to be included in the registration file of the L-praziquantel orodispersible tablet. It will be submitted to the European Medicines Agency (EMA Article 58 procedure). Hopefully, this will be followed by WHO prequalification listing and registration in the first African countries. We have also planned for implementation research to understand how to effectively implement this future intervention and to promote its uptake”.

Dr de Vrueh: “The Pediatric Praziquantel Consortium has become an effective collaboration platform to which public research institutes, small- and medium-sized enterprises, pharma companies and external funders from the European Union, the United States and Japan have contributed resources and expertise. Since 2012, they have jointly progressed the project through the pre-clinical and clinical phases I and II. The consortium has already started to share its operational experience, as front-line experience in conducting high-quality clinical trials in children in low-income countries is highly valuable. Medications appropriate to millions of infected children are often lacking.”

Photo: Pediatric Praziquantel Consortium Team & Board visiting Homa Bay District hospital, phase III clinical trial site in Kenya.

Dr Elly Kourany-Lefoll
Germany

Video: Pediatric Praziquantel for Schistosomiasis (credit: The GHIT Fund)

The challenge

The World Health Organisation now recommends that all pregnant and breastfeeding women infected with HIV should be offered antiretroviral therapy and all infants at risk of contracting HIV should be given antiretrovirals for six weeks. This so-called option B+ strategy has been implemented across most of sub-Saharan Africa. However, significant numbers of infants are falling through the net. In 2015, residual transmission rates were still about 14% at one year old, which is well above the WHO target of 5%.

Women starting ART for prevention of transmission from mother to child (PMTCT) are five times more likely to default than women initiating ART for their own health (Tenthani, 2014). Secondly, there is a high risk of transmission of HIV-1 via breast milk when mothers interrupt ART while breastfeeding, due to viral rebound in breast milk. Finally, some women may get infected with HIV after ANC screening, during the last part of pregnancy or during breastfeeding. In that case of acute maternal infection occurring during breastfeeding, there is a very high risk (approximately 30%) of transmission of HIV to the infant from a mother not knowing her HIV status.

Prof. Philippe van de Perre
France

Impact

For more than a decade, the PROMISE consortium, set up with EDCTP funding, has developed a portfolio of studies addressing mother-to-child transmission of HIV in Africa. These have generated vital evidence on the importance of pre-emptively treating infants to prevent transmission of HIV. Three large trials conducted by the PROMISE Consortium have been supported by EDCTP: PROMISE-PEP, PROMISE-TB and now, PROMISE-EPI. In addition, several ancillary projects have been conducted as satellites of these three trials. PROMISE-EPI could identify a readily implementable strategy to identify infants who nonetheless have been infected, and thus reduce still further infant infection rates.

Prof. Van de Perre: “The PROMISE consortium was created in 2004 by researchers from Burkina Faso, Uganda, South Africa, Zambia, France, Norway and Sweden, all sharing a common passion for the health of mothers and their infants, and appropriate infant feeding in the context of the HIV epidemic. The PROMISE consortium’s remarkable dynamic would have never been possible without the support of EDCTP. It is now a recognised, stable, innovative and productive group of researchers. Fifteen years after it was born, the consortium is still very creative and active. We have many more hypotheses to be validated to improve women and infant health in Africa!”

Photo: The PROMISE-EPI group.

“The current prevention strategy is based on identifying HIV-infected women during the process of antenatal care (ANC),” says Professor Philippe Van de Perre of the Institut national de la santé et de la recherche médicale (INSERM). “Programmes to prevent mother-to-child transmission which are centered on antenatal care, face many difficulties in testing, treating and retaining women who initiated antiretroviral therapy.”

He gives the example of Malawi, where one out of five HIV-infected women diagnosed during pregnancy or lactation never initiate antiretroviral therapy (ART; Tenthani, 2014).

The project

The PROMISE-EPI study is assessing whether a ‘rescue’ package can be integrated into routine immunisation services, an approach which is known as the expanded programme on immunisation or EPI. Its goal is to identify and treat the hidden infant HIV cases and to prevent transmission from undiagnosed HIV-infected mothers.

In Burkina Faso and Zambia, nearly all newborns receive vaccinations through the EPI at 4–6 weeks. The PROMISE-EPI study will assess whether it is possible to use the EPI platform to examine the mother’s experience of prevention services at birth; to detect missed HIV infections through point-of-care testing, so antiretroviral therapy can be started; and to measure virus levels in mothers, to identify infants at risk of infection, so mothers can be treated and preventive measures initiated.

Prof. Van de Perre coordinates the PROMISE-EPI project. “The principle of PMTCT rescue strategies is based on maternal HIV retesting during the late stages of pregnancy or during breastfeeding. We have chosen to initiate this strategy during the immunisation visit when the baby is 6 to 8 weeks old (the second EPI visit) because we know that this EPI visit is attended by almost all of the babies across Africa. Therefore, this strategy enhances our chances to prevent HIV acquisition in all babies exposed to HIV”.

The existence of highly performant point-of-care HIV tests (Technau, 2019) renders possible the rapid diagnosis of infant HIV infection. By means of these tests, it is also possible to identify breastfeeding women whose HIV infection is not controlled by ART, which poses a threat to her baby.

This situation requires urgent care of the mother through initiation or reinforcement of ART. It also indicates that the infant is exposed to HIV. Daily administration of an antiretroviral drug to the infant until the end of breastfeeding is a safe intervention to protect the infant against becoming infected with HIV during breastfeeding.

The challenge

The antimalarial dihydroartemisinin-piperaquine (DP) is highly efficacious against uncomplicated malaria. It is considered the most promising antimalarial to reduce malaria transmission. However, the widespread use of an antimalarial among unselected populations (as in mass drug administration campaigns) requires a drug with a wide therapeutic range and an excellent safety profile. This posed a challenge for the use of DP as it has a relatively narrow therapeutic range. Safety concerns regarded especially children who would possibly be under-dosed and certain groups at risk for cardiac problems, for which the safe concentration threshold was uncertain.

Dr Anja Terlouw
United Kingdom

Impact

When the World Health Organization decided to adjust the dose recommendation for young children in its 2015 Guidelines for the Treatment of Malaria, the ADJusT data was the only clinical data at that dose available. In 2016, data from the ADjusT study contributed to the decision of the WHO Malaria Policy Advisory Committee to establish a formal WHO Evidence Review Group on cardiac safety of malaria drugs. The ADAPT and ADJusT studies both contributed data to this review. Additionally, members of the IMPACT project team contributed to the identification of global evidence gaps and research priorities and highlighted the importance of developing conventions that optimise the quality and consistency of cardiac safety data in antimalarial trials.

An IMPACT member and the company Cardiabase (Banook Group) developed such conventions, which were published on the WARRN website as WWARN Guidance document: Collection of ECG data in antimalarial clinical trials.

The project

The IMPACT project aimed to determine the frequency and severity of DP cardio-toxicity, and its correlation with dose and drug concentration. The analyses made use of two pioneering data-sharing platforms on antimalarial efficacy and safety, developed by WWARN (the Worldwide Antimalarial Resistance Network) and the Liverpool School of Tropical Medicine.

The IMPACT project built on data from two studies funded under the first EDCTP programme, ADJust and ADAPT, which evaluated drug concentration profiles and safety of antimalarials in two groups at higher risk of malaria: young children and HIV-infected adults on antiretroviral treatment, respectively.

“The objective of the IMPACT project was to effectively share and help translate the findings of these projects into policy and practice. IMPACT particularly aimed to raise awareness of the importance of antimalarial dose optimisation among researchers and control programmes, with a focus on cardiac safety findings,” says Dr Anja Terlouw of the Liverpool School of Tropical Medicine in the United Kingdom, the coordinator of the project.

“The ADAPT and ADJusT studies both contributed to addressing global evidence gaps but the ADJusT study particularly focused on assessing the cardiac safety concerns about DP. Temporary significant QT interval prolongation in participants was observed. The IMPACT study, however, found no evidence of clinically significant cardiotoxicity. Peak piperaquine concentrations were similar to those in older children and adults and we did not find a dose-response effect. We concluded that in young children, the predicted benefits in improved cure rates would not happen at the expense of increased risk. Our findings, therefore, supported the change in dose recommendation in the 2015 WHO guidelines.”

WWARN team
United Kingdom

The challenge

Pneumonia is the leading cause of death in children under the age of five. Current hospital care is still associated with relatively high mortality (9–16%). Moreover, children are still at risk of dying after they are discharged from the hospital, particularly if they are malnourished.

“Children who survive severe pneumonia have a 2.5-fold higher risk to die after hospital discharge than children admitted without severe pneumonia, and an increased risk of readmission,” says Professor Kathryn Maitland of the Imperial College of Science Technology and Medicine (ICL), United Kingdom.

There is considerable scope to improve the treatment of young children with pneumonia. Key questions include when oxygen therapy should be used, and the most effective way it could be delivered, particularly in settings that lack equipment for mechanical ventilation. In addition, there is no formal evidence that supplementary feeding improves survival in undernourished children.

Prof. Maitland: “The major risk factor for the poor long-term outcomes (including readmission and death) from severe pneumonia is undernutrition. In patients with a severe infection such as pneumonia, the body’s usual stress response includes the release of hormones in order to rapidly mobilise energy. This is done mainly via protein breakdown, resulting in rapid skeletal muscle breakdown leading to muscle ‘wasting’. The standard approach to prevent such wasting is to supply extra nutrition to a patient with a critical illness. The integrated Global Action Plan for Pneumonia and Diarrhoea developed by WHO and UNICEF recommends ‘continued’ feeding for both these conditions. However, it does not give any specific recommendations for this nutritional support. We, therefore, have proposed to provide Ready-to-Use Therapeutic Food (RUTF) as a supplement for children recovering from severe pneumonia.”

Professor Kathryn Maitland
United Kingdom

Impact

The COAST-Nutrition trial will reveal whether extending the use of food supplements beyond the group of the most severely under-nourished children improves longer-term survival after hospitalisation for pneumonia. Ready-to-use therapeutic food is safe and widely available, so it could be relatively straightforward to implement this intervention if evidence suggests that it reduces mortality.

Prof. Maitland: “We integrated an economic evaluation in the study to establish whether the additional costs of the nutritional feeds are proportionate to the health benefits, and to inform future decision-making on value for money regarding possible widespread implementation.”

Photo: The COAST-Nutrition team.

The project

The COAST-Nutrition team is already conducting a clinical trial, funded by the Wellcome Trust and the UK Medical Research Council, which evaluates different ways to deliver oxygen therapy to children hospitalised with pneumonia. EDCTP funding is used to take advantage of this platform to assess the benefits of wider use of supplemental feeding, which is currently only given to the most severely under-nourished children.

Children that survive to 48 hours will be enrolled in a further trial to see if supplemental feeding to day 28 improves survival at 90 days. The team will also carry out other studies to see if simple measures or diagnostics are predictive of viral or bacterial pneumonia, to provide tools for improved care of children and targeted antibiotic therapy in hospitals without microbiology services.

Photo: Ready‐to‐use therapeutic food (RUTF) training.