Declining responsiveness of childhood Plasmodium falciparum infections to artemisinin-based combination treatments ten years following deployment as first-line antimalarials in Nigeria

Abstract

Background: The development and spread of artemisinin-resistant Plasmodium falciparum malaria in Greater Mekong Subregion has created impetus for continuing global monitoring of efficacy of artemisinin-based combination therapies (ACTs). This post analyses is aimed to evaluate changes in early treatment response markers 10 years after the adoption of ACTs as first-line treatments of uncomplicated falciparum malaria in Nigeria.

Methods: At 14 sentinel sites in six geographical areas of Nigeria, we evaluated treatment responses in 1341 children under 5 years and in additional 360 children under 16 years with uncomplicated malaria enrolled in randomized trials of artemether-lumefantrine versus artesunate-amodiaquine at 5-year interval in 2009-2010 and 2014-2015 and at 2-year interval in 2009-2010 and 2012-2015, respectively after deployment in 2005.

Results: Asexual parasite positivity 1 day after treatment initiation (APPD1) rose from 54 to 62% and 2 days after treatment initiation from 5 to 26% in 2009-2010 to 2014-2015 (P = 0.002 and P < 0.0001, respectively). Parasite clearance time increased significantly from 1.6 days (95% confidence interval [CI]: 1.55-1.64) to 1.9 days (95% CI, 1.9-2.0) and geometric mean parasite reduction ratio 2 days after treatment initiation decreased significantly from 11 000 to 4700 within the same time period (P < 0.0001 for each). Enrolment parasitaemia > 75 000 μl^{- 1}, haematocrit > 27% 1 day post-treatment initiation, treatment with artemether-lumefantrine and enrolment in 2014-2015 independently predicted APPD1. In parallel, Kaplan-Meier estimated risk of recurrent infections by day 28 rose from 8 to 14% (P = 0.005) and from 9 to 15% (P = 0.02) with artemether-lumefantrine and artesunate-amodiaquine, respectively. Mean asexual parasitaemia half-life increased significantly from 1.1 h to 1.3 h within 2 years (P < 0.0001).

Conclusions: These data indicate declining parasitological responses through time to the two ACTs may be due to emergence of parasites with reduced susceptibility or decrease in immunity to the infections in these children.

Trial registration: Pan African Clinical Trial Registration PACTR201508001188143 , 3 July 2015; PACTR201508001191898 , 7 July 2015 and PACTR201508001193368 , 8 July 2015 PACTR201510001189370 , 3 July 2015; PACTR201709002064150 , 1 March 2017; https://www.pactr.samrca.ac.za.

Keywords: Artemisinin-based combination treatment; Children; Declining responsiveness; Falciparum malaria; Nigeria.

Fig. 1

Map of Nigeria showing study sites

Fig. 2

Study profile of children randomised in efficacy study

Fig. 3

Kaplan-Meier survival estimates of reappearance of asexual parasitaemia after initial clearance following artemisinin-based combination treatments in 2009–2010 (blue line) and 2014–2015 (green line). Log-rank statistic = 14.12, P = 0.0002. Pooled analysis of artemether-lumefantrine and artesunate-amodiaquine treatments

Fig. 4

Study profile of children enrolled in parasitaemia half-life study. AA: Artesunate-amodiaquine; AL: Artemether-lumefantrine

Fig. 5

Frequency distribution of parasite clearance time (a) in 2009–2010 (green plots) and 2012–2015 (red plots), semilogarithmic plots of asexual parasitaemia versus time following treatment with artemether-lumefantrine or artesunate-amodiaquine (b), and frequency distribution of parasitaemia elimination half-life (c) in 2009–2010 (green plots) and in 2012–2015 (red plots)