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

Abstract

BackgroundPlasmodium 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.MethodsDNA 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.ResultsSeven 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 (χ2 = 2.37; p = 0.795). The K76 allelic prevalence was between 85.7 and 93% in regions (χ2 = 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%.ConclusionsCQ 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.

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

“…In South America, the prevalence of the CQR marker K76T in the drug efflux transmembrane protein PfCRT has remained high, despite CQ having been abandoned for the treatment of P. falciparum infections (7)(8)(9). This situation contrasts with multiple settings in Africa, where the majority of molecular studies (10)(11)(12)(13) have documented an increase in the prevalence of WT pfcrt after CQ withdrawal. An analysis of the diversity of microsatellites flanking pfcrt in Malawi showed that the return to CQ susceptibility was caused by a reexpansion of the WT PfCRT haplotype (11).…”

High prevalence of Plasmodium falciparum pfcrt K76T mutation in children with sickle cell disease at a tertiary hospital in north-western Tanzania

“…These two studies included parasites from all patients and not a special group of patients with sickle cell disease. Similarly, higher prevalence of these mutants at pfcrt have been reported recently from elsewhere Tanzania (Ngasala et al, 2011;Malmberg et al, 2013;Mohamed et al, 2013). However, in these other Tanzanian studies the prevalence of patients with SCD was not stated.…”

“…After discontinuation of CQ use, several studies in African countries have reported different prevalence of pfcrt K76T mutation. In some countries there is clear re-emergence of wild type strains coupled with CQ sensitivity (Kublin et al, 2003;Lauffer et al, 2006;Ginsburg et al, 2006;Frosch et al, 2011;Kamugisha et al, 2012;Mohamed et al, 2013;Malmberg et al, 2013). In other countries the level of CQ resistance is going down very slowly or is fixed (Frosch et al, 2011).…”

Incomplete reversal of genotypic resistance of Plasmodium falciparum to chloroquine after a decade of change in malaria treatment policy in Uganda

“…In addition, other factors such as the variation in the intensity of malaria transmission in different geographical locations coupled with the introduction of closely related antimalarial agents such as amodiaquine may further explain the observed variation. 42 The current study provides evidence of a slow progressive decline in the prevalence of genotypic (Pfcr K76T and Pfmdr N86Y) CQ resistance among P. falciparum parasites in Uganda. This is indicative of the persistent possibility of unfavorable clinical outcomes if CQ is introduced in malaria treatment in the country.…”

“…In Ghana, for example, the prevalence of Pfcrt T76 declined from 80% to ∼60% between 2005 and 2011. 41 A study by Mohammed et al 42 in Tanzania found a CQ susceptibility rate of more than 90% among P. falciparum parasite isolates following 12 years after the change in policy. In Kenya, when CQ use in malaria treatment was stopped from 1993 to 2006, CQ susceptibility rose from 5% to 40%.…”