Changes in genotypes of Plasmodium falciparum human malaria parasite following withdrawal of chloroquine in Tiwi, Kenya

Mang’era, Clarence M.; Mbai, Fiona N.; Omedo, Irene; Mireji, Paul O.; Omar, Sabah A.

doi:10.1016/j.actatropica.2012.05.007

Cited by 23 publications

(17 citation statements)

References 38 publications

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“…The first report of a decline in the prevalence of CQ-resistant parasites in Africa was documented in Malawi, 10 years after CQ withdrawal (22,24). Similar trends were later reported in studies conducted in Malawi (24,25), in Tanzania (26), and along the coast of Kenya (28)(29)(30). In Kenya, this decline was first reported in Kilifi in 2006, 13 years after the discontinuation of CQ use (28), in which the prevalence of the Pfcrt K76T mutation was shown to decrease from ϳ95% in 1993 to ϳ60% in 2006.…”

Section: Discussionsupporting

confidence: 61%

“…For example, 10 years after the discontinuation of CQ for malaria treatment in Malawi, several studies demonstrated the return of CQ-sensitive parasites and an increase in the prevalence of parasites harboring the wild-type (WT) Pfcrt K76 codon (22,23). Similar trends were later reported from studies conducted in other parts of Malawi (24,25), Tanzania (26,27), and Kenya (28)(29)(30)(31), raising the possibility of the selected reintroduction of CQ for malaria treatment. In contrast, countries that delayed the withdrawal of CQ for malaria treatment demonstrated no significant decreases in the prevalence of CQ resistance parasites (reviewed in reference 32), implying that drug pressure plays a major role in the maintenance of drug-resistant parasites in a population.…”

supporting

confidence: 67%

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In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

Lucchi

Komino

Okoth

et al. 2015

Antimicrob Agents Chemother

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Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203 Plasmodium falciparum malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed in vitro for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in P. falciparum crt (Pfcrt), Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the Pfcrt wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P < 0.0001), and higher proportions of parasites with elevated sensitivity to CQ in vitro. The majority of isolates harbored the wild-type N allele in Pfmdr-1 codon 86 (93.5%), with only 7 (3.50%) samples with the N86Y mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type Pfmdr-1 D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Y mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the Pfmdr-1 gene (mean of 0.907 ؎ 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya.A ntimalarial drug resistance has hampered progress in malaria control and has led to several changes in drug policies over time. To minimize the potential emergence of drug resistance, the World Health Organization (WHO) recommends the use of artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative coformulated with another class of antimalarial (1). In Kenya, the use of chloroquine (CQ) as the first line of malaria treatment was discontinued in the late 1990s due to a high percentage of treatment failures. CQ was replaced by sulfadoxinepyrimethamine (SP) as the first line of treatment, with amodiaquine (AQ) as a second choice. However, the use of SP was shortlived, as the majority of circulating parasites rapidly developed resistance to SP (reviewed in reference 2). Therefore, in April 2004, the ACT artemether-lumefantrine (AL; Coartem) was recommended as the first-line therapy for the treatment of uncomplicated Plasmodium falciparum malaria in Kenya, although this was not fully implemented until late 2006, when the country was finally able to undertake delivery of large quantities of the drug. Thus, between 2004 and 2006, AQ was briefly used as the first-line treatment for malaria in Kenya. Dihydroartemisinin-piperaquine (DHAP) is the current second-line antimalarial drug treatment, while artesu...

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Section: Discussionsupporting

confidence: 61%

supporting

confidence: 67%

In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

Lucchi

Komino

Okoth

et al. 2015

Antimicrob Agents Chemother

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“…15 Since this study, studies in Tanzania, 16 Kenya, 17 Senegal, 18 and Mozambique 19 have shown similar trends of reemergence of CQ sensitivity, and it is tempting to consider reintroduction of CQ in combination with another antimalarial drug in areas where CQ resistance has decreased and possibly reserved for malaria treatment of targeted populations, such as pregnant women, as has been suggested by others. 20 Another marker of antimalarial drug resistance is the P. falciparum multidrug resistance gene-1 (Pfmdr-1) implicated in resistance/tolerance to almost all antimalarial drugs including CQ, amodiaquine (AQ) and most importantly, the artemisinins.…”

Section: Introductionmentioning

confidence: 98%

Rapid Selection of Plasmodium falciparum Chloroquine Resistance Transporter Gene and Multidrug Resistance Gene-1 Haplotypes Associated with Past Chloroquine and Present Artemether-Lumefantrine Use in Inhambane District, Southern Mozambique

Thomsen¹,

Madsen²,

Hansson³

et al. 2013

The American Society of Tropical Medicine and Hygiene

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Abstract. Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246 haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased use of CQ and large-scale use of AL. In the absence of a clear AL-resistance marker and the (almost) continent-wide use of AL in sub-Saharan Africa, and when considering CQ reintroduction, continued monitoring of these markers is needed.

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“…20,21 Changes have also been seen in the prevalence of key pfmdr1 genotypes in Kenya, Tanzania, and Zanzibar, with WT N86 and D1246 genotypes increasing over time. 11,[21][22][23] The SNPs in folate enzyme genes are associated with decreased sensitivity to antifolate antimalarials such as SP. 24 Antifolate resistance develops in a stepwise manner.…”

Section: Introductionmentioning

confidence: 99%

Temporal Changes in Prevalence of Molecular Markers Mediating Antimalarial Drug Resistance in a High Malaria Transmission Setting in Uganda

Mbogo¹,

Nankoberanyi²,

Tukwasibwe³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Abstract. Standard therapy for malaria in Uganda changed from chloroquine to chloroquine + sulfadoxine-pyrimethamine in 2000, and artemether-lumefantrine in 2004, although implementation of each change was slow. Plasmodium falciparum genetic polymorphisms are associated with alterations in drug sensitivity. We followed the prevalence of drug resistancemediating P. falciparum polymorphisms in 982 samples from Tororo, a region of high transmission intensity, collected from three successive treatment trials conducted during 2003-2012, excluding samples with known recent prior treatment. Considering transporter mutations, prevalence of the mutant pfcrt 76T, pfmdr1 86Y, and pfmdr1 1246Y alleles decreased over time. Considering antifolate mutations, the prevalence of pfdhfr 51I, 59R, and 108N, and pfdhps 437G and 540E were consistently high; pfdhfr 164L and pfdhps 581G were uncommon, but most prevalent during 2008-2010. Our data suggest sequential selective pressures as different treatments were implemented, and they highlight the importance of genetic surveillance as treatment policies change over time.

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Changes in genotypes of Plasmodium falciparum human malaria parasite following withdrawal of chloroquine in Tiwi, Kenya

Cited by 23 publications

References 38 publications

In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

Rapid Selection of Plasmodium falciparum Chloroquine Resistance Transporter Gene and Multidrug Resistance Gene-1 Haplotypes Associated with Past Chloroquine and Present Artemether-Lumefantrine Use in Inhambane District, Southern Mozambique

Temporal Changes in Prevalence of Molecular Markers Mediating Antimalarial Drug Resistance in a High Malaria Transmission Setting in Uganda

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