Therapeutic efficacy and effects of artemisinin-based combination treatments on uncomplicated Plasmodium falciparum malaria -associated anaemia in Nigerian children during seven years of adoption as first-line treatments

Abstract

Background: Artemisinin-based combination treatments (ACTs) are the first-line treatments of uncomplicated Plasmodium falciparum malaria in many endemic areas but there are few evaluation of their efficacy in anaemic malarious children.

Methods: Therapeutic efficacy of 3-day regimens of artesunate-amodiaquine and artemether-lumefantrine was evaluated in 437 anaemic and 909 non-anaemic malarious children following treatment during a seven-year period (2008-2014). Patterns of temporal changes in haematocrit were classified based on haematocrit values <30% and ≥30%. Kinetics of the disposition of the deficit in haematocrit from 30% following treatment were evaluated using a non-compartment model.

Results: PCR-corrected parasitological efficacy 28 days after start of treatment was significantly higher in artesunate-amodiaquine- compared to artemether-lumefantrine-treated children [97% (95%CI: 92.8-100) versus 96.4% (95%CI: 91.3-99.4), P = 0.02], but it was similar in non-anaemic and anaemic children. Fall in haematocrit/1 000 asexual parasites cleared from peripheral blood was significantly greater at lower compared to higher parasitaemias (P < 0.0001), and in non-anaemic compared to anaemic children (P = 0.007). In anaemic children at presentation, mean anaemia recovery time (AnRT) was 15.4 days (95%CI: 13.3-17.4) and it did not change over the years. Declines in haematocrit deficits from 30% were monoexponential with mean estimated half-time of 1.4 days (95%CI: 1.2-1.6). Anaemia half-time (t_½anaemia) correlated positively with AnRT in the same patients (r = 0.69, P < 0.0001). Bland-Altman analysis of 10 multiples of t_½anaemia and AnRT showed narrow limit of agreement with insignificant bias (P = 0.07) suggesting both can be used interchangeably in the same patients.

Conclusions: Artesunate-amodiaquine and artemether-lumefantrine remain efficacious treatments of uncomplicated P. falciparum infections in non-anaemic and anaemic Nigerian children in the last 7 years of adoption as first-line treatments. These ACTs may also conserve haematocrit at high parasitaemias and in anaemic children.

Trials registration: Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201510001189370 , 3 July 2015; PACTR201508001191898 , 7 July 2015 and PACTR201508001193368 , 8 July 2015.

Keywords: Artemisinin-based combination treatments; Children; Malaria-associated anaemia; Nigeria; “Haematocrit conservation”.

Fig. 1

Map of Nigeria showing study locations in seven states

Fig. 2

Study profile. AA, artesunate-amodiaquine; AL, artemether-lumefantrine, * follow-up was for 42 days, ** follow-up was for 28 days, *** randomization at a ratio of 2:1 for artesunate-amodiaquine and artemether-lumefantrine, # number of children that completed follow-up period, ^ children are <5 years old.

Fig. 3

Profile of investigations carried out. PRR_D1, parasite reduction ratio 1 day after treatment began; PRR_D2, parasite reduction ratio 2 days after treatment began; PCT, parasite clearance time; FCT, fever clearance time; FIH, fall in haematocrit per 1 000 asexual parasites cleared from peripheral blood; PD, pharmacodynamic measure of recovery (anaemia recovery time); PK, pharmacokinetic measure of recovery (anaemia half-time); AA, artesunate-amodiaquine; AL, artemether-lumefantrine

Fig. 4

Kaplan-Meier survival estimates of asexual parasitaemia, (a) after treatment with AA (blue line) or AL (green line); [log-rank statistic = 7.37; P = 0.007], and (b) in children with (green line) or without (blue line) anaemia at presentation [log-rank statistic = 1.04; P = 0.31]. AA, artesunate-amodiaquine; AL, artemether-lumefantrine

Fig. 5

Scatter plots of day 1 parasite reduction ratios (PRR_D1) in children with uncomplicated P. falciparum malaria following treatment with artesunate-amodiaquine (AA) or artemether-lumefantrine (AL): (a) all children treated with AA or AL during the period 2008–2014, (b) all children treated with AA during the period 2008–2010 and 2011–2014 and (c) all children treated with AL between 2008–2010 and 2011–2014

Fig. 6

Semilog plots of deficit in haematocrit from 30% versus time in all children treated with artesunate-amodiaquine or artemether-lumefantrine (black line) and in children treated with artesunate-amodiaquine (green line) or artemether-lumefantrine (blue line)

Fig. 7

Bland-Altman plots of anaemia recovery times and multiples [9 (a) and 10 (b)] of anaemia half-times. Biases were 3.0, and 1.6 for plots A and B; P = 0.0005 and 0.07; respectively. The mean values ± 1.96 standard deviation (SD) of the differences are shown. AnRT; Anaemia recovery time, t_½; half-time