Abstract
BackgroundArtemisinin-based combination therapy (ACT) partner drugs, currently used in Ghana are lumefantrine, amodiaquine and piperaquine. Plasmodium falciparum isolates with reduced susceptibility to these partner drugs may affect treatment outcome. Mutations in pfmdr1 gene is linked to reduced parasite susceptibility to amodiaquine and lumefantrine. In addition, the potency of the partner drugs in vivo depends on the metabolism by the cytochrome P450 (CYP) enzyme in the host. Mutations in the CYP2C8 and CYP3A4 genes are linked to reduced metabolism of amodiaquine and lumefantrine in vitro, respectively. This study investigated the host and parasite genetic factors affecting the susceptibility of the malaria parasite to ACT partner drugs.MethodsArchived samples from 240 patients age ≤ 9 years participating in anti-malarial drug resistance survey in Ghana, and given artemether with lumefantrine (AL) or artesunate with amodiaquine (AA), were selected and analysed. Polymerase chain reaction (PCR) followed by Sanger sequencing was used to determine the polymorphisms in CYP2C8, CYP3A4 and pfmdr1 genes.ResultsFor CYP3A4, all had wild type alleles, suggesting that the hosts are good metabolizers of lumefantrine. For CYP2C8 60% had wild type alleles, 35% heterozygous and 5% homozygous recessive alleles suggesting efficient metabolism of amodiaquine by the hosts. For pfmdr1 gene, at codon 86, 95% were wild type (N86) and 5% mutant (Y86). For codon 184, 36% were wild type (Y184) and 64% mutant (F184) while for codons 1034, 1042 and 1246, 100% (all) were wild type. The high prevalence of N86-F184-D1246 haplotype (NFD) suggest presence of parasites with reduced susceptibility to lumefantrine and not amodiaquine. Delayed clearance was observed in individuals with mutations in the pfmdr1 gene and not cytochrome 450 gene. Both synonymous and non-synonymous mutations were observed in the pfmdr1 at low prevalence.ConclusionThe outcome of this study indicates that the parasite's genetic factors rather than the host’s are likely to drive resistance to ACT in Ghana.
Highlights
Artemisinin-based combination therapy (ACT) partner drugs, currently used in Ghana are lumefantrine, amodiaquine and piperaquine
Reduced susceptibility of parasites to partner drugs in ACT can potentially result in resistance to artemisinin in future as parasites that escape the fast action of artemisinin or its derivatives will not be cleared by the partner drug and this could allow for growth and expansion of a drug-resistant parasite population [4]
Ninety-four individuals were successfully genotyped for CYP2C8 of which 60% (56/94) had wild-type alleles, 35% (33/94) heterozygous and 5% (5/94) homozygous recessive alleles (Fig. 2)
Summary
Artemisinin-based combination therapy (ACT) partner drugs, currently used in Ghana are lumefantrine, amodiaquine and piperaquine. Plasmodium falciparum isolates with reduced susceptibility to these partner drugs may affect treatment outcome. Malaria caused by an infection of Plasmodium falciparum is one of the major causes of morbidity and mortality in sub-Saharan Africa, especially in children under 5 years old and pregnant women [1] The World Health Organization (WHO) recommends the use of a combination of a fast-acting artemisinin derivative and a Hodoameda et al Malar J (2020) 19:255 relatively slow-acting partner drug, for the treatment of uncomplicated malaria in disease-endemic areas [2]. The recommended first-line artemisinin combination therapy (ACT) in Ghana for treating uncomplicated malaria is artesunate with amodiaquine (AA), artemether with lumefantrine (AL) or a combination of dihydroartemisinin with piperaquine [3]. Reduced susceptibility of parasites to partner drugs in ACT can potentially result in resistance to artemisinin in future as parasites that escape the fast action of artemisinin or its derivatives will not be cleared by the partner drug and this could allow for growth and expansion of a drug-resistant parasite population [4]
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