In vivo/ex vivo efficacy of artemether-lumefantrine and artesunate-amodiaquine as first-line treatment for uncomplicated falciparum malaria in children: an open label randomized controlled trial in Burkina Faso

Moussa Lingani, Léa Nadège Bonkian, Isidore Yerbanga, Adama Kazienga, Innocent Valéa, Hermann Sorgho, Jean Bosco Ouédraogo, Petronella Francisca Mens, Henk D F H Schallig, Raffaella Ravinetto, Umberto d'Alessandro, Halidou Tinto, Moussa Lingani, Léa Nadège Bonkian, Isidore Yerbanga, Adama Kazienga, Innocent Valéa, Hermann Sorgho, Jean Bosco Ouédraogo, Petronella Francisca Mens, Henk D F H Schallig, Raffaella Ravinetto, Umberto d'Alessandro, Halidou Tinto

Abstract

Background: Artemisinin-based combination therapy (ACT) is recommended to improve malaria treatment efficacy and limit drug-resistant parasites selection in malaria endemic areas. 5 years after they were adopted, the efficacy and safety of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ), the first-line treatments for uncomplicated malaria were assessed in Burkina Faso.

Methods: In total, 440 children with uncomplicated Plasmodium falciparum malaria were randomized to receive either AL or ASAQ for 3 days and were followed up weekly for 42 days. Blood samples were collected to investigate the ex vivo susceptibility of P. falciparum isolates to lumefantrine, dihydroartemisinin (the active metabolite of artemisinin derivatives) and monodesethylamodiaquine (the active metabolite of amodiaquine). The modified isotopic micro test technique was used to determine the 50% inhibitory concentration (IC50) values. Primary endpoints were the risks of treatment failure at days 42.

Results: Out of the 440 patients enrolled, 420 (95.5%) completed the 42 days follow up. The results showed a significantly higher PCR unadjusted cure rate in ASAQ arm (71.0%) than that in the AL arm (49.8%) on day 42, and this trend was similar after correction by PCR, with ASAQ performing better (98.1%) than AL (91.1%). Overall adverse events incidence was low and not significantly different between the two treatment arms. Ex vivo results showed that 6.4% P. falciparum isolates were resistant to monodesthylamodiaquine. The coupled in vivo/ex vivo analysis showed increased IC50 values for lumefantrine and monodesethylamodiaquine at day of recurrent parasitaemia compared to baseline values while for artesunate, IC50 values remained stable at baseline and after treatment failure (p > 0.05).

Conclusion: These findings provide substantial evidence that AL and ASAQ are highly efficacious for the treatment of uncomplicated malaria in children in Burkina Faso. However, the result of P. falciparum susceptibility to the partner drugs advocates the need to regularly replicate such surveillance studies. This would be particularly indicated when amodiaquine is associated in seasonal malaria chemoprophylaxis (SMC) mass drug administration in children under 5 years in Burkina Faso. Trial registration clinicaltrials, NCT00808951. Registered 05 December 2008,https://ichgcp.net/clinical-trials-registry/NCT00808951?cond=NCT00808951&rank=1.

Keywords: Artemisinin-based combination therapy; Burkina Faso; Efficacy; In vivo/ex vivo; Paediatric; Safety; Sub-Saharan Africa; Uncomplicated malaria.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Trial profile: 42-day follow-up of study participants by treatment arm at the Dafra health district medical centre, Burkina Faso 2008-10. AL artemether–lumefantrine, ASAQ artesunate–amodiaquine
Fig. 2
Fig. 2
Kaplan Meier curves showing the treatment failure cumulative proportion for each treatment arm by day 42 in the per protocol population (N = 420): a recrudescent infections, b new infection, c recurrent infections (Recrudescent plus new infection)
Fig. 3
Fig. 3
Mean geometric IC50 values at day 0 and treatment outcome in study participants at the Dafra health district medical centre, Burkina Faso 2008–2010: a artemether–lumefantrine arm, b artesunate amodiaquine arm. D0 day of inclusion before treatment administration, NI new infection, R recrudescent, ACPR adequate clinical and parasitological response, DHA dihydroartemisinin, Lum lumefantrine, MDA monodesethylamodiaquine, IC50 50% inhibitory concentration

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