Parasite reduction ratio one day after initiation of artemisinin-based combination therapies and its relationship with parasite clearance time in acutely malarious children

Kazeem Akano,Nma Jiya,Grace O Gbotosho,Nnenna Ezeigwe,Joy C Ebenebe,J P Ambe ,Sikiru Amoo,Bayo Fatunmbi,Olugbenga A Mokuolu ,Oluwabunmi K Basorun,Finomo Finomo,Christian T Happi,Onikepe A Folarin,Olubunmi A Wewe,Chimere Agomo,Robinson D Wammanda ,Go Emechebe ,Stephen Oguche,Godwin Ntadom,A Sowunmi

doi:10.1186/s40249-018-0503-7

Abstract

BackgroundIn acute falciparum malaria, asexual parasite reduction ratio two days post-treatment initiation (PRRD2) ≥ 10 000 per cycle has been used as a measure of the rapid clearance of parasitaemia and efficacy of artemisinin derivatives. However, there is little evaluation of alternative measures; for example, parasite reduction ratio one day after treatment initiation (PRRD1) and its relationship with parasite clearance time (PCT) or PRRD2. This study evaluated the use of PRRD1 as a measure of responsiveness to antimalarial drugs.MethodsIn acutely malarious children treated with artesunate-amodiaquine (AA), artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHP), the relationships between PRRD1 or PRRD2 and PCT, and between PRRD1 and PRRD2 were evaluated using linear regression. Agreement between estimates of PCT using PRRD1 and PRRD2 linear regression equations was evaluated using the Bland-Altman analysis. Predictors of PRRD1 > 5000 per half cycle and PRRD2 ≥ 10 000 per cycle were evaluated using stepwise multiple logistic regression models. Using the linear regression equation of the relationship between PRRD1 and PCT previously generated in half of the DHP-treated children during the early study phase, PCT estimates were compared in a prospective blinded manner with PCTs determined by microscopy during the later study phase in the remaining half.ResultsIn 919 malarious children, PRRD1 was significantly higher in DHP- and AA-treated compared with AL-treated children (P < 0.0001). PRRD1 or PRRD2 values correlated significantly negatively with PCT values (P < 0.0001 for each) and significantly positively with each other (P < 0.0001). PCT estimates from linear regression equations for PRRD1 and PRRD2 showed insignificant bias on the Bland-Altman plot (P = 0.7) indicating the estimates can be used interchangeably. At presentation, age > 15 months, parasitaemia > 10 000/μl and DHP treatment independently predicted PRRD1 > 5000 per half cycle, while age > 30 months, haematocrit ≥31%, body temperature > 37.4 °C, parasitaemia > 100 000/μl, PRRD1 value > 1000 and no gametocytaemia independently predicted PRRD2 ≥ 10 000 per cycle. Using the linear regression equation generated during the early phase in 166 DHP-treated children, PCT estimates and PCTs determined by microscopy in the 155 children in the later phase were similar in the same patients.ConclusionsPRRD1 and estimates of PCT using PRRD1 linear regression equation of PRRD1 and PCT can be used in therapeutic efficacy studies.Trial registrationPan African Clinical Trial Registration PACTR201709002064150, 1 March 2017, http://www.pactr.org

Highlights

In acute falciparum malaria, asexual parasite reduction ratio two days post-treatment initiation (PRRD2) ≥ 10 000 per cycle has been used as a measure of the rapid clearance of parasitaemia and efficacy of artemisinin derivatives
parasite clearance time (PCT) estimates from linear regression equations for Parasite reduction ratio one day post-treatment initiation (PRRD1) and Parasite reduction ratio two days post-treatment initiation (PRRD2) showed insignificant bias on the Bland-Altman plot (P = 0.7) indicating the estimates can be used interchangeably
Using the linear regression equation generated during the early phase in 166 DHP-treated children, PCT estimates and PCTs determined by microscopy in the 155 children in the later phase were similar in the same patients

Summary

Introduction

Asexual parasite reduction ratio two days post-treatment initiation (PRRD2) ≥ 10 000 per cycle has been used as a measure of the rapid clearance of parasitaemia and efficacy of artemisinin derivatives. Given most human infections with P. falciparum are relatively synchronized and artemisinins have broad stage specificity [5, 6], alternative indices for evaluating rapid or delayed clearance of asexual parasitaemia within a day of commencing ACTs are needed for assessment in therapeutic efficacy studies. One such index with potential clinical application is asexual parasite reduction ratio one day after treatment initiation (PRRD1). The use of PRRD1 is plausible because parasite prevalence one day after initiation of ACTs is directly attributable to rapid clearance of asexual parasitaemia by artemisinin components of ACTs [2, 5, 6]

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Discussion

Conclusion