Adherence to intermittent preventive treatment for malaria in Papua New Guinean infants: A pharmacological study alongside the randomized controlled trial.

BACKGROUND: The intermittent preventive treatment in infants (IPTi) trial that took place in Papua New Guinea showed an overall reduction of 29% of the risk of malaria when delivering single-dose sulfadoxine-pyrimethamine (SP) associated to 3 days of amodiaquine (AQ) every three months to children during the first year of life. The aim of the present study was to assess if the last two doses of AQ were truly administered as prescribed by the parents at home based on drug level measurement and PK modelling, which is a good proxy of medication adherence. It provides also important information to discuss the efficacy of the intervention and on feasibility of self-administered preventive malaria treatment. METHODS AND FINDINGS: During the three-arm randomized double-blinded IPTi trial, each child was prescribed one dose of SP (day 0) and 3 doses of either AQ or artesunate (AS) at day 0, 1 & 2 adjusted to weight or placebo. Treatments were given at 3, 6, 9 and 12 months of age. The first day of treatment was delivered by nursing staff (initiation under directly observed treatment (DOT)) and the two last doses of AQ or AS by parents at home without supervision. For this cross-sectional study, 206 consecutive children already involved in the IPTi trial were enrolled over a 2-month period. At the time of the survey, allocation of the children to one of the three arms was not known. Blood samples for drug level measurement were collected from finger pricks one day after the planned last third dose intake. Only children allocated to the SP-AQ arm were included in the present analysis. Indeed, the half-life of AS is too short to assess if drugs were given on not. Because of the short half-life of AQ, desethyl-AQ (metabolite of AQ (DAQ)) measurements were used to investigate AQ medication adherence. Two PK (PK) models from previously published studies in paediatric populations were applied to the dataset using non-linear mixed effect modelling (NONMEM) to estimate the number of doses really given by the parents. The study nurse reported the administration time for the first AQ dose while it was estimated by the parents for the remaining two doses. Out of 206 children, 64 were in the SP-AQ arm. The adjusted dosing history for each individual was identified as the one with the lowest difference between observed and individual predicted concentrations estimated by the two PK models for all the possible adherence schemes. The median (range) blood concentration AQ in AQ arm was 9.3 ng/mL (0-1427.8 ng/mL), (Quartiles 1-3: 2.4 ng/mL -22.2 ng/mL). The median (range) for DAQ was 162.0 ng/mL (0-712 ng/mL), (Quartiles 1-3: 80.4 ng/mL-267.7 ng/mL). Under the assumption of full adherence for all participants, a marked underprediction of concentrations was observed using both PK models. Our results suggest that only 39-50% of children received the three scheduled doses of AQ as prescribed, 33-37% two doses and 17-24% received only the first dose administered by the study nurse. Both models were highly congruent to classify adherence patterns. CONCLUSIONS: Considering the IPTi intervention, our results seem to indicate that medication adherence is low in the ideal trial research setting and is likely to be even lower if given in day-to-day practice, questioning the real impact that this intervention might have. More generally, the estimation of the number of doses truly administered, a proxy measure of adherence and an assessment of the feasibility of the mode of administration, should be more thoroughly studied when discussing the efficacy of the interventions in trials investigating self-administered malaria preventive treatments.