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

Date Published: February 6, 2019

Publisher: Public Library of Science

Author(s): Oriane Sottas, Monia Guidi, Benjamin Thieffry, Marie Schneider, Laurent Décosterd, Ivo Mueller, Blaise Genton, Chantal Csajka, Nicolas Senn, Luzia Helena Carvalho.


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.

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.

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.

Partial Text

In Papua New Guinea (PNG), malaria transmission is high and the disease is responsible for several thousands of deaths each year. The number of estimated cases in 2013 was between 800’000 and 2’000’000[1]. The major plasmodium species present in PNG are Plasmodium falciparum and Plasmodium vivax.

The IPTi randomized controlled trial was conducted in PNG in the Mugil area of the Sumkar District, Madang Province, between June 2006 and May 2010 and included 1125 children. Each study participant received four courses of treatment at 3, 6, 9 and 12 months. Each course consisted of three days of treatment and each time, nursing staff delivered SP (single dose) and the first dose of AQ or AS (day 0, D0) by initiation under directly observed treatment (DOT) and parents at home without supervision the others doses of AQ or AS (day 1 and 2). The tablets were given with sweet syrup after being crushed by the nurse or parents. The first drug dose (D0) was given a second time if the child vomited within 30 minutes. A community reporter living in the village was in charge of visiting the children to check that no adverse events occurred. He/she had no responsibility for giving drugs or supervising drug intake. All details concerning the trial and efficacy results have been published elsewhere[5]. The study was carried out in accordance with Good Clinical Practice (ICH GCP E6) guidelines and externally monitored by two independent monitors and the Data Safety Monitoring Board. The study (main protocol and present amendment) was approved by the PNG Medical Research Advisory Committee (MRAC number 05.20). The trial was registered on (number NCT00285662) and formed part of the IPTi Consortium ( In concordance with MRAC regulations, written informed consent was obtained from the parents both for the main IPTi study and the present work.

This study suggests that a majority of children did not receive the full IPTi treatment within the frame of the randomized trial, which could substantially decrease the optimal efficacy of the intervention. Our results indeed showed that only 39 to 50% of children, depending on the PK model used, received the three scheduled doses of AQ, while 33 to 37% received two doses and 17 to 24% received only the first dose, administered by the study nurse.

This study showed that less than half of the study participants in an IPTi randomized controlled clinical trial took the full three-day course of antimalarial preventive medication. This is very low considering that the first dose was directly administered by a study nurse and the study was closely monitored. These results seem to indicate that medication adherence is low in an ideal research setting and therefore might be even lower if implemented in day-to-day practice, questioning the impact that this intervention might really have. It also reinforces the hypothesis that AQ add little to the overall efficacy of the IPTi intervention, which relies mostly on the long lasting effect of a single dose of SP. Finally, these results question the self-administration approach for preventive malaria treatments in children. This is relevant information, not only for the specific IPTi intervention, but also more generally for drug trials of this kind. Indeed, researchers should consider using this approach when designing new studies and estimating effect sizes of short malaria treatment courses.




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