Longitudinal ex vivo and molecular trends of chloroquine and piperaquine activity against Plasmodium falciparum and P. vivax before and after introduction of artemisinin-based combination therapy in Papua, Indonesia

Jutta Marfurt, Grennady Wirjanata, Pak Prayoga, Ferryanto Chalfein, Leo Leonardo, Boni F. Sebayang, Dwi Apriyanti, Maic A.E.M. Sihombing, Leily Trianty, Rossarin Suwanarusk, Alan Brockman, Kim A. Piera, Irene Luo, Angela Rumaseb, Barbara MacHunter, Sarah Auburn, Nicholas M. Anstey, Enny Kenangalem, Rintis Noviyanti, Bruce RussellJeanne R. Poespoprodjo, Ric N. Price

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Abstract

Drug resistant Plasmodium parasites are a major threat to malaria control and elimination. After reports of high levels of multidrug resistant P. falciparum and P. vivax in Indonesia, in 2005, the national first-line treatment policy for uncomplicated malaria was changed in March 2006, to dihydroartemisinin-piperaquine against all species. This study assessed the temporal trends in ex vivo drug susceptibility to chloroquine (CQ) and piperaquine (PIP) for both P. falciparum and P. vivax clinical isolates collected between 2004 and 2018, by using schizont maturation assays, and genotyped a subset of isolates for known and putative molecular markers of CQ and PIP resistance by using Sanger and next generation whole genome sequencing. The median CQ IC50 values varied significantly between years in both Plasmodium species, but there was no significant trend over time. In contrast, there was a significant trend for increasing PIP IC50s in both Plasmodium species from 2010 onwards. Whereas the South American CQ resistant 7G8 pfcrt SVMNT isoform has been fixed since 2005 in the study area, the pfmdr1 86Y allele frequencies decreased and became fixed at the wild-type allele in 2015. In P. vivax isolates, putative markers of CQ resistance (no pvcrt-o AAG (K10) insertion and pvmdr1 Y967F and F1076L) were fixed at the mutant alleles since 2005. None of the putative PIP resistance markers were detected in P. falciparum. The ex vivo drug susceptibility and molecular analysis of CQ and PIP efficacy for P. falciparum and P. vivax after 12 years of intense drug pressure with DHP suggests that whilst the degree of CQ resistance appears to have been sustained, there has been a slight decline in PIP susceptibility, although this does not appear to have reached clinically significant levels. The observed decreasing trend in ex vivo PIP susceptibility highlights the importance of ongoing surveillance.

Original languageEnglish
Pages (from-to)46-56
Number of pages11
JournalInternational Journal for Parasitology: Drugs and Drug Resistance
Volume17
Early online date21 Jun 2021
DOIs
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
The study was funded by the Wellcome Trust (Senior Research Fellowship in Clinical Science 200909 to RNP), the National Health and Medical Research Council (1023438, 1037304, 1132975 and Fellowship 1135820 to NMA), and the Swiss National Science Foundation (Fellowship for Emerging Researchers: PBBSP3-125580, and Advanced Researchers: PA00P3_139723/1 to JM).

Publisher Copyright:
© 2021

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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