ArticlesArtemether-lumefantrine versus amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Burkina Faso: a randomised non-inferiority trial
Introduction
Antimalarial drug resistance is a severe and growing problem in Africa.1 As older monotherapy regimens become less effective, a consensus has emerged for the use of combination treatments for malaria.2 Artemisinin-based combination treatments have proved very effective against malaria in Asia and Africa,2, 3 and most countries in Africa have now changed their national regimens to incorporate artemisinin-based combination regimens as first-line treatment for uncomplicated malaria.4
However, the implementation of artemisinin-based combination therapy has its difficulties. First, these regimens are much more expensive than previous treatments. Although funding for antimalarial treatment in Africa has been increased, available resources might not be adequate to fund all the necessary treatments. Second, supplies of artemisinin derivatives, although growing, remain inadequate for the estimated 1 billion malaria treatments given each year in Africa.5 Third, artemisinin-based combination treatments have not yet been widely studied in all epidemiological settings in Africa, and might not be as successful in high transmission regions as in other areas.
Antimalarial combination regimens that do not contain an artemisinin derivative remain of interest, since they can be much less expensive and they offer an alternative treatment if artemisinin use remains restricted by cost, supply, unexpected toxic effects, or a combination of such factors. The non-artemisinin combination treatment that has been best studied is amodiaquine with sulfadoxine-pyrimethamine. This regimen combines two inexpensive and readily available drugs, and has proved to be particularly effective in regions of Africa with low levels of resistance to each component, such as much of west Africa.6, 7
Amodiaquine plus sulfadoxine-pyrimethamine has been shown to lower the risk of new infections after treatment compared with artemisinin-based regimens, presumably because of the long half-lives of sulfadoxine-pyrimethamine and amodiaquine or its derivatives.8 However, the benefits of any long-acting drug might be offset if it is selected for parasites with mutations that confer resistance to important antimalarial agents.9, 10, 11, 12, 13
Several countries in west Africa, including Burkina Faso, have changed their recommended first-line treatment for uncomplicated malaria to the artemisinin-based combination regimen, artemether-lumefantrine.4 However, few studies from Africa,14 and none from west Africa, have compared artemether-lumefantrine with non-artemisinin combination treatment. Our aim was to assess the efficacy of artemether-lumefantrine compared with amodiaquine plus sulfadoxine-pyrimethamine for treatment of patients with uncomplicated malaria in Burkina Faso.
Section snippets
Participants
The study was based in Bobo-Dioulasso, a city of about 450 000 inhabitants in western Burkina Faso, where malaria is holoendemic and transmission peaks during the rainy season (May to October). Patients were recruited from three government health centres (Colsama, Sarfalao, and Ouezzinville).
All patients who presented between August, 2005, and December, 2005, with high temperature or history of recent fever were referred to health-centre laboratories for initial screening of a thick blood smear
Results
Figure 1 shows that of the patients randomly assigned to a treatment group, 27 (5%) were excluded from enrolment either because they vomited their first dose of treatment twice or they had parasitaemias with densities that were outside of the inclusion criteria. Therefore, 521 patients were enrolled in the study. After 28 days of follow-up, 478 enrolled patients (92%) completed the study (figure 1). Table 1 shows the baseline characteristics of these study participants.
Table 2 shows results for
Discussion
We have shown that both artemether-lumefantrine and amodiaquine plus sulfadoxine-pyrimethamine were effective for clearance of uncomplicated malaria infections. However, in high transmission settings characteristic of much of sub-Saharan Africa, effects of therapy on subsequent infections should also be considered. Indeed, recurrent illnesses due to recrudescence and those caused by new infections are generally clinically indistinguishable.8 Therefore, the effects of treatment on the overall
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2020, International Journal for Parasitology: Drugs and Drug ResistanceCitation Excerpt :While further investigations will be needed to clarify the drug response phenotypes of these other combinations, the linkage of PfMDR1 N86 to the less sensitive LUM and MEF phenotypes of 803 relative to GB4 is consistent with previous reports associating N86 with reduced susceptibility to these drugs (Duraisingh et al., 2000; Sisowath et al., 2005; Dokomajilar et al., 2006; Mwai et al., 2009; Lekana-Douki et al., 2011; Li et al., 2014; Wurtz et al., 2014). The effect of the PfMDR1 Y184F polymorphism on LUM response in association with N86 is less clear: PfMDR1 N86 and Y184 were selected in reinfections after AL treatment in studies in Burkina Faso (Zongo et al., 2007; Somé et al., 2010), but PfMDR1 N86 and 184F were more prevalent in new infections after AL treatment in a Zanzibar cohort (Sisowath et al., 2007). In coastal Kenya, a slight increase of PfMDR1 184F in association with N86 and D1246 was attributed to AL pressure between 2006 and 2013 (Okombo et al., 2014); however, PfMDR1 184F was not associated with LUM or MEF responses in a study in Senegal (Wurtz et al., 2014) and, in Western Kenya, prevalence of Y184 allele was found to be increased in parasite populations post-AL treatment compared to populations before treatment (Achieng et al., 2015).
Antimalarial drug resistance in Africa: the calm before the storm?
2019, The Lancet Infectious DiseasesCitation Excerpt :With careful attention to drug solubility, IC50 values were consistently less than 25 nM at two sites in Uganda from 2006 to 2016,36,68,92 with values similar to those reported in 1997 and 2003 in Cameroon.93 However, use of artemether-lumefantrine is accompanied by selection of wild-type sequences in putative drug transporters—namely pfcrt Lys76Thr and pfmdr1 Asn86Tyr and Asp1246Tyr in parasites that emerge soon after therapy.60,61,71,94–97 This wild-type sequence selection is opposite to the selective pressures of artesunate-amodiaquine and dihydroartemisinin-piperaquine, which select for mutant sequences at these alleles, as previously mentioned in this Review.
AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial
2017, The Lancet Infectious DiseasesCitation Excerpt :However, previous studies have found faster parasite clearance with artemether plus lumefantrine than with other antimalarial drugs,13 faster fever clearance with treatment regimens containing 4-AQ,22 and haemolysis after the treatment of severe malaria with artemisinins.23 The absence of serious, grade 2, grade 3, and grade 4 adverse events in either group is consistent with data indicating serious adverse events are uncommon with artemether plus lumefantrine13,21,24,25 and with AQ-13,9 although experience with AQ-13 is limited. As in the phase 1 study,9 several participants reported less serious (≤grade 1) adverse events with AQ-13, in particular for pruritus.
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