“
test the safety and efficacy of this new formulation in young children

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Bringing antiretroviral drugs to children

The CHAPAS trials have ensured that many more children with HIV have benefited
from life-saving antiretrovirals.

The challenge

P. falciparum malaria is still an important cause of mortality and morbidity. Over half a million malaria deaths were reported in 2015 particularly in children, and malaria was associated with 795 per 100,000 disability-adjusted life years in 2016.

Severe malaria causes neurobehavioural impairments (behavioural disorders, seizures and cognitive and language impairments. The effect of chronic parasitisation and repeated episodes of mild malaria on neurobehavioural outcomes is not well documented. Young children (< 2 years) are particularly susceptible since this is the period of maximum brain growth postnatally.

Phase III, RTS,S/AS01 vaccine showed efficacy of up to 55% against all episodes of malaria, and 45% against cases of severe malaria. Insecticide-treated bednets (ITBN) prevented severe malaria morbidity in 44% of children under 5 years in Kilifi, Kenya. Therefore, by preventing malaria, RTS,S/AS01 and ITBN may have prevented neurobehavioural impairments attributable to malaria, and may also improve school participation and performance especially because the vaccine and the ITBN were given in the first two years of life.

Dr Kariuki proposes to follow up Kenyan children vaccinated with RTS,S/AS01 during the first two years of life and who used ITBN during the first five years of life. Those who were not vaccinated are to be examined for neurobehavioural impairments and school participation approximately nine years after initial vaccination and eleven years after ITBN intervention.

Dr Kariuki will perform the primary study on the Kenyan coast on a sample of 600 children in a phase II RTS,S/AS01 trial undergoing active surveillance for malaria, and in a random sample of 1052 children who participated in the ITBN intervention in Kilifi, Kenya. The phase II RTS,S/AS01 findings in Kilifi will be used to conduct an external validation study using children in a phase III RTS,S/AS01 trial from areas with passive surveillance in Western Kenya. Trained clinicians will take clinical history to diagnose seizure disorders and to document medical history. Behavioural disorders, cognitive impairments and school participation will be examined using assessment tools adapted to the local populations and these will be administered by trained neuropsychological assessors.

The project

The later CHAPAS-3 trial compared the efficacy and safety of three fixed-dose combinations including two without stavudine (found to have some long-term side effects in adults, leading to a recommendation that its use be discontinued in children). The trial the first of its kind in Africa studied nearly 500 children at four sites in two African countries.

Dr Kariuki aims to provide evidence of possible extended benefits of the malaria vaccine RS,S/AS01 for the prevention of neurobehavioural impairment in young children.

ratios forfixed-dose combinations and on appropriatedosage according to weight. 

The CHAPAS-3 trial confirmed the effectiveness of fixed-dose combinations, providing further impetus to the rollout of antiretrovirals to children. Its evidence on abacavir informed the WHO recommendation of abacavir-containing combinations for first-line therapy in children. Trial data have also been used to support applications for regulatory approval for new scored efavirenz tablets.

Impact