Abstract
BackgroundArtemisinin-based combination therapy is the first-line anti-malarial treatment for uncomplicated Plasmodium falciparum infection in Angola. To date, the prevalence of polymorphisms in the pfk13 gene, associated with artemisinin resistance, and pfmdr1, associated with lumefantrine resistance, have not been systematically studied in Angola.MethodsDNA was isolated from pretreatment and late treatment failure dried blood spots collected during the 2015 round of therapeutic efficacy studies in Benguela, Lunda Sul, and Zaire Provinces in Angola. The pfk13 propeller domain and pfmdr1 gene were sequenced and analysed for polymorphisms. Pfmdr1 copy number variation was assessed using a real-time PCR method. The association between pfmdr1 and pfk13 mutations and treatment failure was investigated.ResultsThe majority of pretreatment (99%, 466/469) and all late treatment failure (100%, 50/50) samples were wild type for pfk13. Three of the pretreatment samples (1%) carried the A578S mutation commonly observed in Africa and not associated with artemisinin resistance. All 543 pretreatment and day of late treatment failure samples successfully analysed for pfmdr1 copy number variation carried one copy of pfmdr1. The NYD haplotype was the predominant pfmdr1 haplotype, present in 63% (308/491) of pretreatment samples, followed by NFD, which was present in 32% (157/491) of pretreatment samples. The pfmdr1 N86 allele was overrepresented in day of late treatment failure samples from participants receiving artemether–lumefantrine (p value 0.03).ConclusionsThe pretreatment parasites in patients participating in therapeutic efficacy studies in 2015 in Angola’s three sentinel sites showed genetic evidence of susceptibility to artemisinins, consistent with clinical outcome data showing greater than 99% day 3 clearance rates. The lack of increased pfmdr1 copy number is consistent with previous reports from sub-Saharan Africa. Although pfmdr1 NYD and NFD haplotypes were overrepresented in artemether–lumefantrine late treatment failure samples, their role as markers of resistance was unclear given that these haplotypes were also present in the majority of successfully treated patients in the artemether–lumefantrine treatment arms.
Highlights
Artemisinin-based combination therapy is the first-line anti-malarial treatment for uncomplicated Plasmodium falciparum infection in Angola
Ljolje et al Malar J (2018) 17:84 these haplotypes were present in the majority of successfully treated patients in the artemether–lumefantrine treatment arms
The samples analysed here included 506 pretreatment samples collected at enrollment and the 50 samples collected on any other days when enrolled patients returned with a recurrent malaria infection
Summary
Artemisinin-based combination therapy is the first-line anti-malarial treatment for uncomplicated Plasmodium falciparum infection in Angola. Artemisinin-based combination therapy (ACT) is among the last effective treatments against Plasmodium falciparum malaria in areas where older anti-malarials, such as chloroquine, sulfadoxine–pyrimethamine and mefloquine, have become ineffective due to parasite resistance [1]. The fast-acting artemisinin derivative, with a half-life on the order of hours, is responsible for the majority of parasite clearing, but is combined with a longer-lasting partner drug with a half-life on the order of days or weeks to clear remaining parasites and result in a lasting clinical cure. Partner drug resistance manifests as a late treatment failure, where a patient who initially cleared parasites develops recurrent parasitaemia within 4–6 weeks following anti-malarial therapy
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