Abstract
BackgroundPlasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). However resistance is spreading to the different ACT compounds; the artemisinin derivative and the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance.MethodsThe role of P. falciparum molecular markers in selection of reinfections was assessed in an efficacy trial comparing artesunate–amodiaquine fixed-dose combination with artemether–lumefantrine to treat malaria in Nimba County, Liberia 2008–2009. P. falciparum polymorphisms in pfcrt 76, pfmdr1 86, 184 and 1246, and pfmrp1 876 and 1466 were analysed by PCR-RFLP and pyrosequencing.ResultsHigh baseline prevalence of pfmdr1 1246Y was found in Nimba county (38 %). Pfmdr1 1246Y and pfmdr1 86+184+1246 haplotypes NYY and YYY were selected in reinfections in the artesunate–amodiaquine arm and pfcrt K76, pfmdr1 N86 and pfmdr1 haplotype NFD were selected in artemether–lumefantrine reinfections. Parasites harbouring pfmdr1 1246Y could reinfect earlier after treatment with artesunate–amodiaquine and parasites carrying pfmdr1 N86 could reinfect at higher lumefantrine concentrations in patients treated with artemether–lumefantrine.ConclusionsAlthough treatment is highly efficacious, selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored. Since individual drug levels and the day of reinfection were demonstrated to be key determinants for selection of reinfections, this data needs to be collected and taken into account for accurate evaluation of molecular markers for anti-malarial treatments.The protocols for the clinical trial was registered with Current Controlled Trials, under the Identifier Number ISRCTN51688713 on 9 October 2008
Highlights
Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT)
Selection of polymorphisms after treatment After treatment pfmdr1 1246Y was selected in the ASAQ-FDC arm, which was found in 55/294 (18.7 %) patients at baseline and in 24/60 (40.0 %) reinfections (Fisher, two-tailed, p < 0.001) (Table 1)
In the AL arm, a selection of pfcrt K76 and pfmdr1 N86 was identified, that increased in prevalence from 19/294 (6.5 %) and 90/294 (30.6 %) at baseline to 12/38 [31.6 % (p < 0.0001)] and 28/40 [70.0 % (p < 0.0001)], respectively, in reinfections (Table 1)
Summary
Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy (ACT). Resistance is spreading to the different ACT compounds; the artemisinin deriva‐ tive and the partner drug. The uncomplicated form of P. falciparum infection can be and successfully treated with an artemisinin-based combination therapy (ACT); there is always the threat of resistance development to the different ACT compounds; the artemisinin derivative and/or the partner drug. Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth understanding of the development and spread of resistance. An increased risk of recrudescence after AL treatment was demonstrated when pfmdr N86 was present [4]
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