Research Article: Dihydroartemisinin-Piperaquine and Artemether-Lumefantrine for Treating Uncomplicated Malaria in African Children: A Randomised, Non-Inferiority Trial

Date Published: November 17, 2009

Publisher: Public Library of Science

Author(s): Quique Bassat, Modest Mulenga, Halidou Tinto, Patrice Piola, Steffen Borrmann, Clara Menéndez, Michael Nambozi, Innocent Valéa, Carolyn Nabasumba, Philip Sasi, Antonella Bacchieri, Marco Corsi, David Ubben, Ambrose Talisuna, Umberto D’Alessandro, Karen I. Barnes.

Abstract: Artemisinin combination therapies (ACTs) are currently the preferred option for treating uncomplicated malaria. Dihydroartemisinin-piperaquine (DHA-PQP) is a promising fixed-dose ACT with limited information on its safety and efficacy in African children.

Partial Text: Artemisinin-based combination therapies (ACTs) are highly efficacious and fast acting antimalarial medicines. The World Health Organization (WHO) recommends their use for treating uncomplicated malaria [1]. In Africa, their introduction on a wide scale began in 2003 and currently most African countries have adopted or are using ACTs as first or second line treatments, either artesunate-amodiaquine or artemether-lumefantrine (AL) [2], available as co-formulations produced under GMP, though the former is also used as a co-blistered or non-co-formulated product. The co-formulation of dihydroartemisinin (DHA), the active metabolite of artemisinin derivatives, with piperaquine (PQP), a bisquinoline structurally close to chloroquine, seems to be a promising combination and a good alternative to AL, whose optimal use in the public health system is challenged by the twice-daily dosing scheme and the need for co-administration with fatty food [3], necessary for improving the absorption of lumefantrine. DHA-PQP provides a simpler dosage scheme (a single daily dose over 3 days) than AL and is generally administered without specific food instructions, though recent data indicate that co-administration with fat (milk, biscuit, or other food) increases bio-availability of piperaquine and possibly efficacy [4].

The protocol for this trial and supporting non-inferiority adapted [14] CONSORT checklist are available and annexed as supporting information; see Protocol S1 and Checklist S1.

The fulfilment of the non-inferiority criterion on all analysis populations and the confirmation that in this study the comparator treatment had the expected efficacy [12], [21] proved that DHA-PQP is non inferior to AL in treating African children aged 6–59 months with uncomplicated malaria. The two treatments had similar safety profiles. Our study confirms the results of previous trials in Asia [8] and Africa [10]–[13] that found DHA-PQP to be as effective as other ACTs, including AL. A recent study in Papua New Guinea (PNG) reported a significantly higher cure rate (adequate clinical and parasitological response) in children treated with AL as compared to DHA-PQP [7]. The reasons for such discordant results are unclear though the authors mention the cross-resistance between chloroquine and PQP. However, PQP, though structurally related to chloroquine, has been shown to be effective in vitro against chloroquine-resistant strains [8], [22]. In addition, it has been suggested that the lower-than-expected DHA-PQP efficacy reported in PNG may be due to administration of the treatment without any food [4]. Indeed, PQP is highly lipid-soluble and its oral bioavailability is enhanced when given with food [23], [24], though an additional study in Vietnamese healthy volunteers reports no influence of food intake (standardised Vietnamese meal) on PQP pharmacokinetics [25]. The issue on whether to recommend the administration of DHA-PQP with a biscuit or a glass of milk remains unanswered. Though co-administration with food may improve the drug’s bioavailability, it is unclear whether this will translate in a higher efficacy. In our study, DHA-PQP was given without specific instructions regarding co-administration with food but its efficacy at day 42 was over 90%, similar to that reported in a study carried out in Uganda [10] but lower than in two other African studies [12], [13]. Moreover, no clinically relevant heterogeneity was shown across the five African countries despite the high chloroquine resistance previously reported from most study sites [26]. When taking into account all recurrent infections observed during the follow up period, i.e., without the PCR correction, the cure rates for DHA-PQP were significantly better than AL, indicating a better post-treatment prophylaxis (PTP) than AL [27] and confirming that chloroquine resistance did not interfere with DHA-PQP efficacy. The significantly higher Hb change from baseline to the last available data in the DHA-PQP group is in line with this observation. Therefore, the longer PQP’s elimination half-life (about 20 days) as compared to lumefantrine (4–10 days), provides a longer PTP, prevents the emergence of new infections and improves the patient’s haematological recovery, despite a significant chloroquine resistance background. While this is clearly an advantage for the individual, at the population level, it may increase the risk of selecting resistant parasites among the new infection [28] and stress the need of matching the large scale deployment of DHA-PQP with the careful monitoring of resistance [29].



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