Plasmodium falciparum genetic factors rather than the hosts' are likely to drive resistance to acts in ghana.

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Abstract Background: Artemisinin-based Combination Therapy (ACT), a combination of a fast-acting artemisinin derivative and a relatively slow-acting partner drug, is used for malaria treatment in disease-endemic areas. The 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 the parasite multidrug-resistant 1 (Pfmdr1) gene is linked to reduced 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 gene are linked to reduced metabolism of amodiaquine in vitro while mutations in CYP3A4 may be linked to reduced metabolism to lumefantrine in vitro. Methods: This study investigated the host and parasite genetic factors affecting the susceptibility of the malaria parasite to ACT partner drugs. Archived samples from 240 patients (120 given AL and the other half given AA) aged ≤9years participating in antimalarial drug resistance survey in sites representing the three ecological areas of Ghana were used. Polymerase chain reaction (PCR) followed by Sanger sequencing was used to determine the polymorphisms in CYP2C8, CYP3A4, and Pfmdr1 genes. Results: Of the 93 samples successfully genotyped for CYP3A4, all had wild type alleles which suggest that the hosts are good metabolizers of lumefantrine. Ninety-four samples were successfully genotyped for CYP2C8 of which 60% had wild type alleles, 35% heterozygous and 5% homozygous recessive alleles. The high percentage of wild type alleles observed also suggests that amodiaquine was metabolized efficiently by the hosts. Ninety-five samples were successfully genotyped for the Pfmdr1 gene. At codon 86, 95% were wild type (N86), 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, and D1246 (NFD) suggest the presence of strains of the 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. There were both synonymous and nonsynonymous mutations observed in the Pfmdr1 at low prevalence. Conclusion: The outcome of this study indicates that parasite's genetic factors rather than the hosts' are likely to drive resistance to ACTs in Ghana.

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