In vitro piperaquine susceptibility is not associated with the Plasmodium falciparum chloroquine resistance transporter gene

Abstract

BackgroundDihydroartemisinin-piperaquine is a new ACT that is administered as single daily dose for three days and has been demonstrated to be tolerated and highly effective for the treatment of uncomplicated Plasmodium falciparum malaria. Piperaquine was used alone to replace chloroquine as the first-line treatment for uncomplicated malaria in China in response to increasing chloroquine resistance in the 1970s. However, the rapid emergence of piperaquine-resistant strains that resulted in the cessation of its use in China in the 1980s, suggests that there is cross-resistance between piperaquine and chloroquine. Very few data are available on cross-resistance between piperaquine and chloroquine, and the data that do exist are often contradictory.MethodsIn total, 280 P. falciparum isolates, collected between April 2008 and June 2012 from patients hospitalized in France with imported malaria from a malaria-endemic country, were assessed ex vivo for piperaquine and chloroquine susceptibilities by using the standard 42-hour 3H-hypoxanthine uptake inhibition method. The chloroquine resistance-associated mutation K76T in pfcrt was also investigated for the 280 isolates.ResultsThe IC50 for piperaquine ranged from 9.8 nM to 217.3 nM (mean = 81.3 nM. The IC50 for chloroquine ranged from 5.0 nM to 1,918 nM (mean = 83.6 nM. A significant but low correlation was observed between the Log IC50 values for piperaquine and chloroquine (r = 0.145, p < 0.001). However, the coefficient of determination of 0.021 indicates that only 2.1% of the variation in the response to piperaquine is explained by the variation in the response to chloroquine. The mean value for piperaquine was 74.0 nM in the Pfcrt K76 wild-type group (no = 125) and 87.7 nM in the 76 T mutant group (no = 155). This difference was not significant (p = 0.875, Mann Whitney U test).ConclusionsThe present work demonstrates that there was no cross-resistance between piperaquine and chloroquine among 280 P. falciparum isolates and that piperaquine susceptibility is not associated with pfcrt, the gene involved in chloroquine resistance. These results confirm the efficacy of piperaquine in association with dihydroartemisinin and support its use in areas in which parasites are resistant to chloroquine.

Changing Antimalarial Drug Sensitivities in Uganda

“…3) (36). Interestingly, consistent with prior reports (7,37), the associations seen for other aminoquinolines were not seen for piperaquine. Associations with other polymorphisms and for other drugs were mostly not significant.…”

“…Third, we Associations of ex vivo drug sensitivity with transporter polymorphisms. We and others have previously shown that polymorphisms in the putative transporters pfcrt and pfmdr1 are associated with altered ex vivo drug sensitivity (7,12,(34)(35)(36)(37)(38). We tested for associations between pfcrt K76T and pfmdr1 N86Y, Y184F, and D1246Y polymorphisms, and the ex vivo drug sensitivities were determined for samples collected in 2016 (Fig.…”

Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance

“…Similarly, China-Myanmar border isolates with a single Pfmdr1 copy and the Pfcrt K76T genotype were reported to have reduced CQ and PPQ susceptibility (38). While there appears to be a link between PPQ and CQ resistance, PPQ may have additional resistance mechanisms suggested by preserved activity against CQ-resistant isolates from Africa (41,42) and lack of correlation between Pfcrt polymorphisms and reduced PPQ susceptibility in isolates from various regions (43,44). Our findings support the notion that until definitive molecular markers of PPQ clinical resistance are identified, the combination of Pfmdr1 deamplification and PPQ IC 50 s is useful for tracking what appears to be rapidly emerging PPQ resistance.…”

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

“…Structurally, PPQ comprises two CQ-like 4-aminoquinoline moieties with a central linker. This drug is generally effective against parasites that evolved resistance to CQ through specific sets of point mutations in the P. falciparum CQ resistance transporter (PfCRT), which is also present on the digestive vacuole membrane 34,35 (Fig. 2 and Box 1).…”