Abstract:
Background: 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. 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 amo‑
diaquine 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.
Methods: Archived 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 ana‑
lysed. Polymerase chain reaction (PCR) followed by Sanger sequencing was used to determine the polymorphisms in
CYP2C8, CYP3A4 and pfmdr1 genes.
Results: For 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.
Conclusion: The 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
