Temporal trends in prevalence of Plasmodium falciparum drug resistance alleles over two decades of changing antimalarial policy in coastal Kenya

Okombo, John; Kamau, Alice; Marsh, Kevin; Sutherland, Colin J.; Ochola‐Oyier, Lynette Isabella

doi:10.1016/j.ijpddr.2014.07.003

Cited by 38 publications

(67 citation statements)

References 60 publications

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“…However, in other Indian states this haplotype is very rarely found (Mishra et al, 2006; Mixson-Hayden et al, 2010). Similarly, the C 72 V 73 I 74 E 75 T 76 haplotype is highly prevalent, and the frequency of the S 72 V 73 M 74 N 75 T 76 haplotype is comparatively low (Table 2), reconfirming previous observations from Odisha (Okombo et al, 2014; Ramani et al, 2016; Sutar et al, 2013; Sutar et al, 2011). The skewed distributional prevalence of the C 72 V 73 I 74 E 75 T 76 haplotype is reflected by the observation of statistically significant χ² value (Table 2).…”

Section: Discussionsupporting

confidence: 86%

“…For the Pfdhfr gene, although we have sequenced a larger DNA fragment in comparison to the Pfcrt gene, occurrence of mutations other than the ones conferring to SP resistance is reported to be minimal (Sharma, D. et al, 2015) For the Pfmdr1 gene, three amino acid substitutions (other than the mutations associated with drug resistance) could be found; one common in isolates from both the HF and RP ecotypes, and two only confined to RP (Table 3). While the common one (C 228 T) and the T 317 C (confined to RP) are entirely novel, the A 269 G (confined to RP) has been reported earlier in Kenya (Okombo et al, 2014). For the Pfdhps gene, as many as 11 nucleotide substitutions (resulting in two synonymous substitutions and nine non-synonymous, including three stop codons) could be found.…”

Section: Discussionmentioning

confidence: 67%

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Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

Kar

Chauhan

Nanda

et al. 2016

Infection, Genetics and Evolution

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Considering malaria as a local and focal disease, epidemiological understanding of different ecotypes of malaria can help in devising novel control measures. One of the major hurdles in malaria control lies on the evolution and dispersal of the drug-resistant malaria parasite, Plasmodium falciparum. We herewith present data on genetic variation at the Single Nucleotide Polymorphism (SNP) level in four different genes of P. falciparum (Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps) that confer resistance to different antimalarials in two different eco-epidemiological settings, i.e. Hilly-Forest (HF) and Riverine-Plain (RP), in a high malaria endemic district of Odisha state, India. Greater frequency of antimalarial resistance conferring SNPs and haplotypes was observed in all four genes in P. falciparum, and Pfdhps was the most variable gene among the four. No significant genetic differentiation could be observed in isolates from HF and RP ecotypes. Twelve novel, hitherto unreported nucleotide mutations could be observed in the Pfmdr1 and Pfdhps genes. While the Pfdhps gene presented highest haplotype diversity, the Pfcrt gene displayed the highest nucleotide diversity. When the data on all the four genes were complied, the isolates from HF ecotype were found to harbour higher average nucleotide diversity than those from RP ecotype. High and positive Tajima’s D values were obtained for the Pfcrt and Pfdhfr genes in isolates from both the HF and RP ecotypes, with statistically significant deviation from neutrality in the RP ecotype. Different pattern of Linkage Disequilibrium (LD) among SNPs located in different drug-resistant genes was found in the isolates collected from HF and RP ecotypes. Whereas in the HF ecotype, SNPs in the Pfmdr1 and Pfdhfr were significantly associated, in the RP ecotype, SNPs located in Pfcrt were associated with Pfmdr1, Pfdhfr and Pfdhps. These findings provide a baseline understanding on how different micro eco-epidemiological settings influence evolution and spread of different drug resistance alleles. Our findings further suggest that drug resistance to chloroquine and sulfadoxine-pyrimethamine is approaching fixation level, which requires urgent attention of malaria control program in India.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 67%

Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

Kar

Chauhan

Nanda

et al. 2016

Infection, Genetics and Evolution

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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: 60%

“…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.…”

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confidence: 54%

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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“…In agreement, a field study showed that the susceptibility rate of the parasites to chloroquine increased from 50% in 1993 to 99% in 2005 [30]. Similar reductions in the prevalence of the pfcrt 76T genotype have also been reported from Kenya, Senegal, and other countries that are mainly located in Africa, although their remission rates were less drastic than that in Malawi [12, 14, 31]. Based on these studies, it is suggested that the mutants are fitter than the wild type under the selective pressure of chloroquine.…”

Section: Resultssupporting

confidence: 56%

Genetic polymorphisms in Plasmodium falciparum chloroquine resistance genes, pfcrt and pfmdr1, in North Sulawesi, Indonesia

et al. 2017

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BackgroundMalaria still poses one of the major threats to human health. Development of effective antimalarial drugs has decreased this threat; however, the emergence of drug-resistant Plasmodium falciparum, a cause of Malaria, is disconcerting. The antimalarial drug chloroquine has been effectively used, but resistant parasites have spread worldwide. Interestingly, the withdrawal of the drug reportedly leads to an increased population of susceptible parasites in some cases. We examined the prevalence of genomic polymorphisms in a malaria parasite P. falciparum, associated with resistance to an antimalarial drug chloroquine, after the withdrawal of the drug from Indonesia.ResultsBlood samples were collected from 95 malaria patients in North Sulawesi, Indonesia, in 2010. Parasite DNA was extracted and analyzed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) for pfcrt and pfmdr1. In parallel, multiplex amplicon sequencing for the same genes was carried out with Illumina MiSeq. Of the 59 cases diagnosed as P. falciparum infection by microscopy, PCR–RFLP analysis clearly identified the genotype 76T in pfcrt in 44 cases. Sequencing analysis validated the identified genotypes in the 44 cases and demonstrated that the haplotype in the surrounding genomic region was exclusively SVMNT. Results of pfmdr1 were successfully obtained for 51 samples, where the genotyping results obtained by the two methods were completely consistent. In pfmdr1, the 86Y mutant genotype was observed in 45 cases (88.2%).ConclusionsOur results suggest that the prevalence of the mutated genotypes remained dominant even 6 years after the withdrawal of chloroquine from this region. Diversified haplotype of the resistance-related locus, potentially involved in fitness costs, unauthorized usage of chloroquine, and/or a short post-withdrawal period may account for the observed high persistence of prevalence.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-017-2468-1) contains supplementary material, which is available to authorized users.

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Temporal trends in prevalence of Plasmodium falciparum drug resistance alleles over two decades of changing antimalarial policy in coastal Kenya

Abstract: Graphical abstract

Cited by 38 publications

References 60 publications

Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

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

Genetic polymorphisms in Plasmodium falciparum chloroquine resistance genes, pfcrt and pfmdr1, in North Sulawesi, Indonesia

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