Piperaquine
Piperaquine (PPQ) is a bisquinoline antimalarial drug with unknown mechanism of action. It has been used in combination with an artemisinin derivative, dihydroartemisinin (DHA), as artemisinin-based combination therapies (ACTs). Reduced susceptibility to piperaquine in Plasmodium falciparum has been associated with multiple copies of pfplasmepsin 2 and pfplasmepsin 3 genes.
- Multiple copies of pfplasmepsin 2-3 genes are associated with increased in piperaquine IC50 (Amato, et al, 2017, Lancet Infect Dis) and recrudescence at day 42 following DHA-PPQ treatment (Witkowski B, et al, 2017, Lancet Infect Dis).
- Recently, the parasites with a particular combination between pfplasmepsin 2 gene amplification and pfKelch13 mutation C580Y have emerged and spread rapidly across the Greater Mekong subregion. DHA-PPQ treatment failure has been associated with these parasites (Imwong, et al, 2017, Lancet Infect Dis; Amato R, et al, 2018, Lancet Infect Dis).
- Amplification of PF3D7_1408000 (plasmepsin 2) and PF3D7_1408100 (plasmepsin 3)
- Field utilized : geno_plasmepsin23_amp
| Amino acid change | Coding | Interpretation | Phenotype |
|---|---|---|---|
| Single | geno_plasmepsin23_amp == "WT" | Wild-type | Sensitive |
| Multiple | geno_plasmepsin23_amp == "Amplified" | Mutant | Resistant |
| Missing | geno_plasmepsin23_amp == "-" | Missing | Undetermined |
| Reference | Method | Location/Sample size/Genetic background | Finding summary |
|---|---|---|---|
| Amato R, Lim P, Miotto O, Amaratunga C, Dek D, Pearson RD, et al. Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study. Lancet Infect Dis. 2017;17(2):164-73. | - Genome-wide association study (GWAS) of P. falciparum isolates was performed to investigate the association between SNPs/CNVs and the piperaquine IC50 (ex vivo or after short term culture in vitro). - Whole-genome sequencing of the parasites was performed using Illumina HiSeq platform. - Piperaquine IC50 was determined by using a standard 72-h SYBR Green I-based staining method. - Piperaquine survival assay was performed by using a flow cytometry-based method. - The relationship between piperaquine susceptibility and the presence of either exo-E415G or plasmepsin 2-3 gene amplification was determined. |
- 297 P. falciparum isolates from Cambodia (Ratannakiri, Preah Vihear and Pursat) during 2010-2013. | - Genome-wide analysis of SNPs revealed that mutation in exonuclease-encoding gene (exo-E415G) on chromosome 13 associates with raised piperaquine IC50. - Genome-wide analysis of CNVs identified that amplifications of the plasmepsin 2 and plasmepsin 3 genes on chromosome 14 associate with raised piperaquine IC50. - Both exo-E415G mutation and plasmepsin 2-3 amplification associated with reduced survival rate. - Piperaquine IC50 increased significantly from 2011 to 2013; 1.96-fold increase in Ratannakiri, 3.43-fold increase in Preah Vihea, 4.14-fold increase in Pursat. - Parasites that did not recrudesce after DHA-PPQ treatment had wild-type Kelch13 and exonuclease and they carried single copy of mdr1 and plasmepsin 2-3. - Parasites that recrudesced after DHA-PPQ carried single copy of mdr1, multiple copies of plasmepsin 2-3 genes, and mutations at both kelch13-C580Y and exo-E415G. |
| Witkowski B, Duru V, Khim N, Ross LS, Saintpierre B, Beghain J, et al. A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study. Lancet Infect Dis. 2017;17(2):174-83. | - Recrudescence of parasites following DHA-PPQ treatment was determined at day 42. - Ex-vivo piperaquine survival assay (PSA) and amplification of plasmepsin 2 gene were determined from blood sample of patients treated with DHA-PPQ. - In vitro piperaquine survival assay, WGS, and plasmepsin 2 copy number were determined from culture-adapted parasites collected from 23 recrudescent and 8 non-recrudescent patients. |
- 725 parasite isolates from patients in Cambodia during 2009-2015. | - Ex-vivo piperaquine survival assay profile of 134 isolates correlated with plasmepsin 2 gene copy number. - In 31 culture-adapted parasite lines, amplification of plasmepsin2-3 genes was associated with in-vitro piperaquine resistance. - Multiple copies of plasmepsin 2 gene were associated with adjusted hazard ratio for piperaquine treatment failures in 750 patients treated with DHA-PPQ. - DHA-PPQ efficacy at day 42 fell below 90% while the proportion of multiple copies of plasmepsin 2 exceeded 22%. |
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Imwong M, Suwannasin K, Kunasol C, Sutawong K, Mayxay M, Rekol H, et al. The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. Lancet Infect Dis. 2017;17(5):491-7.
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Amato R, Pearson RD, Almagro-Garcia J, Amaratunga C, Lim P, Suon S, et al. Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study. Lancet Infect Dis. 2018;18(3):337-45.