☆ 4.4 Article

Trends in chloroquine resistance marker, Pfcrt-K76T mutation ten years after chloroquine withdrawal in Tanzania

MALARIA JOURNAL (2013)

Journal

MALARIA JOURNAL

Volume 12, Issue -, Pages -

Publisher

BMC

DOI: 10.1186/1475-2875-12-415

Keywords

Plasmodium falciparum; Chloroquine; Pfcrt; Tanzania; Drug resistance; Malaria; Mutations; Parasites; Polymorphisms

Funding

Training Health Researchers into Vocational Excellence in East Africa (THRiVE) consortium
Wellcome Trust [087540]

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Abstract

Background: Plasmodium falciparum resistance to anti-malarial drugs remains a major obstacle to the control of malaria. In 2001 Tanzania replaced chloroquine (CQ) with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2006. SP has however, continued to be used in intermittent preventive treatment of malaria in pregnancy (IPTp) despite reports of high levels of resistance to SP due to the lack of alternatives to SP for IPTp. Recent reports have indicated recovery of CQ-susceptibility in Malawi, Kenya, Mozambique, and Tanzania based on the prevalence of wild types at codon 76 of the Pfcrt gene in indigenous P. falciparum populations. The current prevalence of this Pfcrt-76 CQ resistance marker from six regions of Tanzania mainland is hereby reported. Methods: DNA extracted from filter-paper dried blood spots and rapid diagnostics kit strips collected from finger-prick blood were used to genotype the Pfcrt-76 resistance marker using PCR-RFLP. Data from previously published studies were used to generate CQ susceptibility recovery trends using logistic regression model. Results: Seven hundred and forty one (741) samples were genotyped. The current frequency of the CQ-susceptible Pfcrt-K76 was above 92% and did not differ between regions in Tanzania (chi 2 = 2.37; p = 0.795). The K76 allelic prevalence was between 85.7 and 93% in regions (chi 2 = 7.88, p = 0.163). The CQ resistance recovery trends showed regional variability that may be caused by differences in malaria transmission intensity, but overall the trends converge as the susceptibility levels in all regions approach >90%. Conclusions: CQ withdrawal in Tanzania has resulted into >90% recovery of susceptibility in ten years of withdrawal. These findings are in support of the search for CQ-based combination drugs as a possible future alternative to SP for IPTp in places where full recovery of CQ-susceptibility will be evident.

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Additional PfCRT mutations driven by selective pressure for improved fitness can result in the loss of piperaquine resistance and altered Plasmodium falciparum physiology

Laura M. Hagenah, Satish K. Dhingra, Jennifer L. Small-Saunders, Tarrick Qahash, Andreas Willems, Kyra A. Schindler, Gabriel W. Rangel, Eva Gil-Iturbe, Jonathan Kim, Emiliya Akhundova, Tomas Yeo, John Okombo, Filippo Mancia, Matthias Quick, Paul D. Roepe, Manuel Llinas, David A. Fidock

Summary: Efforts to eliminate malaria in Southeast Asia have been hampered by multidrug-resistant Plasmodium falciparum. A specific mutation in the PfCRT gene is associated with high-grade resistance to piperaquine, a commonly used antimalarial drug. This mutation not only causes resistance but also affects the growth of the parasite. Recent studies have found additional mutations that compensate for the growth defect caused by the original mutation. Removing drug pressure results in the loss of resistance, highlighting the transient nature of piperaquine resistance.

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