Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine.

Jesmin Permala,Joel Tarning,Martin Bergstrand,Nicholas J White,François Nosten,Mats O Karlsson

doi:10.1128/aac.02491-16

Abstract

ABSTRACTIntermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ∼4% malaria incidence per year compared to ∼8% for dosing regimen of two tablets weekly and ∼10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.

Highlights

Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women
DISCUSSION a monthly DHA-PQ dosing regimen has proved effective and well tolerated in malaria prevention and elimination efforts, we suggest that the regimen can be improved further with more frequent dosing
Our results are in line with another recently published study advocating weekly dosing of DHA-PQ based on simulated PQ plasma concentration profiles in a pediatric population [11]

Summary

Introduction

Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. The three tablets weekly dosing regimen was more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ϳ4% malaria incidence per year compared to ϳ8% for dosing regimen of two tablets weekly and ϳ10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). Compromised by worsening drug resistance in many parts of Africa [4, 5], and so dihydroartemisinin-piperaquine (DHA-PQ) has been evaluated as an alternative [6] This artemisinin-based combination therapy (ACT) is widely used in South East Asia and exhibits excellent efficacy and tolerability [2]. The effects of nonadherence were investigated since this is a major cause of poor treatment responses [10]

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