No Evidence of Plasmodium falciparum
            <i>k13</i>
            Artemisinin Resistance-Conferring Mutations over a 24-Year Analysis in Coastal Kenya but a Near Complete Reversion to Chloroquine-Sensitive Parasites

Wamae, Kevin; Okanda, Dorcas A; Ndwiga, Leonard; Osoti, Victor; Kimenyi, Kelvin M.; Abdi, Abdirahman; Bejon, Philip; Sutherland, Colin J.; Ochola‐Oyier, Lynette Isabella

doi:10.1128/aac.01067-19

Cited by 39 publications

(42 citation statements)

References 64 publications

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“…In this study, no Pfk13 propeller region mutations previously validated to be correlated with artemisinin resistance were detected. These findings are consistent with previous studies conducted in western Kenya [29,48] and coastal Kenya [49], which did not report any Pfk13 propeller region mutations that have been associated with artemisinin resistance. The absence of these Pfk13 mutations associated with artemisinin resistance in this study, as well as in other African countries [50], suggests that artemisinin resistance may not have emerged on the continent or spread from Southeast Asia.…”

Section: Discussionsupporting

confidence: 93%

“…This may be a result of the withdrawal of chloroquine and the introduction of ACT in 2006 in Kenya, which may have promoted the re-emergence of chloroquine-sensitive isolates. This is consistent with other studies conducted in Kenya [49,58], Malawi [59], Côte d'Ivoire [60], and Tanzania [8], which have reported re-emergence of chloroquine-susceptible parasites following years of discontinuation of chloroquine use. A small proportion of parasites (< 5%) contained a mixed (N75D) or mutated (75E) nucleotide at codon 75, yielding haplotypes CVIDT, CVMDT, and CVIET.…”

Section: Discussionsupporting

confidence: 92%

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Assessment of molecular markers of anti-malarial drug resistance among children participating in a therapeutic efficacy study in western Kenya

Chebore

Zhou

Westercamp

et al. 2020

Malar J

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Background: Anti-malarial drug resistance remains a major threat to global malaria control efforts. In Africa, Plasmodium falciparum remains susceptible to artemisinin-based combination therapy (ACT), but the emergence of resistant parasites in multiple countries in Southeast Asia and concerns over emergence and/or spread of resistant parasites in Africa warrants continuous monitoring. The World Health Organization recommends that surveillance for molecular markers of resistance be included within therapeutic efficacy studies (TES). The current study assessed molecular markers associated with resistance to Artemether−lumefantrine (AL) and Dihydroartemisinin−piperaquine (DP) from samples collected from children aged 6-59 months enrolled in a TES conducted in Siaya County, western Kenya from 2016 to 2017. Methods: Three hundred and twenty-three samples collected pre-treatment (day-0) and 110 samples collected at the day of recurrent parasitaemia (up to day 42) were tested for the presence of drug resistance markers in the Pfk13 propeller domain, and the Pfmdr1 and Pfcrt genes by Sanger sequencing. Additionally, the Pfpm2 gene copy number was assessed by real-time polymerase chain reaction. Results: No mutations previously associated with artemisinin resistance were detected in the Pfk13 propeller region. However, other non-synonymous mutations in the Pfk13 propeller region were detected. The most common mutation found on day-0 and at day of recurrence in the Pfmdr1 multidrug resistance marker was at codon 184F. Very few mutations were found in the Pfcrt marker (< 5%). Within the DP arm, all recrudescent cases (8 sample pairs) that were tested for Pfpm2 gene copy number had a single gene copy. None of the associations between observed mutations and treatment outcomes were statistically significant. Conclusion: The results indicate absence of Pfk13 mutations associated with parasite resistance to artemisinin in this area and a very high proportion of wild-type parasites for Pfcrt. Although the frequency of Pfmdr1 184F mutations was high in these samples, the association with treatment failure did not reach statistical significance. As the spread of

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Assessment of molecular markers of anti-malarial drug resistance among children participating in a therapeutic efficacy study in western Kenya

Chebore

Zhou

Westercamp

et al. 2020

Malar J

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“…The most common quintuple haplotypes identified in Pfcrt gene were CVMNK and CVIET. This concords with previously published studies in other regions [ 101 , 102 ]. It is important to note that one study reported the presence of Pfcrt SVMNT haplotype with a prevalence of 4.4% [ 59 ], which is lower than the 19.0% [ 15 ] and 56.9% [ 14 ] reported in the Korogwe District, Tanzania and Luanda, Angola, respectively.…”

Section: Discussionsupporting

confidence: 90%

Drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon: a systematic review and meta-analysis (1998–2020)

Niba

Nji

Evehe

et al. 2021

Malar J

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Background Malaria remains highly endemic in Cameroon. The rapid emergence and spread of drug resistance was responsible for the change from monotherapies to artemisinin-based combinations. This systematic review and meta-analysis aimed to determine the prevalence and distribution of Plasmodium falciparum drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon from January 1998 to August 2020. Methods The PRISMA-P and PRISMA statements were adopted in the inclusion of studies on single nucleotide polymorphisms (SNPs) of P. falciparum anti-malarial drug resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, Pfatp6, Pfcytb and Pfk13). The heterogeneity of the included studies was evaluated using the Cochran’s Q and I2 statistics. The random effects model was used as standard in the determination of heterogeneity between studies. Results Out of the 902 records screened, 48 studies were included in this aggregated meta-analysis of molecular data. A total of 18,706 SNPs of the anti-malarial drug resistance genes were genotyped from 47,382 samples which yielded a pooled prevalence of 35.4% (95% CI 29.1–42.3%). Between 1998 and 2020, there was significant decline (P < 0.0001 for all) in key mutants including Pfcrt 76 T (79.9%-43.0%), Pfmdr1 86Y (82.7%-30.5%), Pfdhfr 51I (72.2%-66.9%), Pfdhfr 59R (76.5%-67.8%), Pfdhfr 108 N (80.8%-67.6%). The only exception was Pfdhps 437G which increased over time (30.4%-46.9%, P < 0.0001) and Pfdhps 540E that remained largely unchanged (0.0%-0.4%, P = 0.201). Exploring mutant haplotypes, the study observed a significant increase in the prevalence of Pfcrt CVIET mixed quintuple haplotype from 57.1% in 1998 to 57.9% in 2020 (P < 0.0001). In addition, within the same study period, there was no significant change in the triple Pfdhfr IRN mutant haplotype (66.2% to 67.3%, P = 0.427). The Pfk13 amino acid polymorphisms associated with artemisinin resistance were not detected. Conclusions This review reported an overall decline in the prevalence of P. falciparum gene mutations conferring resistance to 4-aminoquinolines and amino alcohols for a period over two decades. Resistance to artemisinins measured by the presence of SNPs in the Pfk13 gene does not seem to be a problem in Cameroon. Systematic review registration PROSPERO CRD42020162620

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“…In the early 2000, the rapid development and spread of drug resistance markers compelled the Cameroon government to effect malaria treatment changes from monotherapies to artemisinin-based combination therapies in line with the WHO recommendations [2]. Since the ban on the use of chroroquine in many malaria endemic regions, trend analyses have showed the decline of the Pfcrt 76T mutant over the years, thus con rming the re-emergence of chloroquine sensitive parasites [35][36][37]. Moreover, different studies carried have also demonstrated an opposing effect in the selection of Pfmdr1 YYY triple haplotype for ASAQ and Pfmdr1 NFD triple haplotype for AL [15,38].…”

Section: Discussionmentioning

confidence: 99%

Drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon: a systematic review and meta-analysis protocol

Niba

Nji

Evehe

et al. 2020

Preprint

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Background: Cameroon remains a country faced with high malaria burden despite enormous efforts made in the control of the disease. The rapid development and dispersal of mutations associated with anti-malarial drug resistance influenced policy changes from the use of chloroquine, amodiaquine and sulphadoxine-pyrimethamine to the adoption of artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria. Different studies have identified the frequency of key markers in Plasmodium falciparum associated with drug resistance without a clear picture on the localisation of potential hotspots that may drive the emergence of resistance to the currently used ACTs. This systematic review and meta-analysis aims to determine the prevalence and distribution of P. falciparum drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon from 1990 to present. Methods: The PRISMA, PRISMA-P and STREGA statements will be adopted in the quality assessments of studies to be included in this review. The electronic databases of Medline via Pubmed, EMBASE, Google Scholar and Science Direct will be searched by two independent researchers using different MeSH terms and Boolean operators (AND, OR). More so, unpublished data that will be sourced from academic libraries will also be extracted. Quantitative syntheses will be done using the “metaphor” and “meta” commands in the R statistical software package version 3.5.2. Heterogeneity will be assessed using the Cochrane Q and I2 statistics. The random effects model will be used as benchmark in the determination of heterogeneity between studies. Discussion: The primary outcome of this review is to identify and describe molecular markers conferring drug resistance in Plasmodium falciparum parasites that have been circulating for a period of over 30 years in Cameroon. This review will be able to pool data from previously published and unpublished studies on anti-malarial drug resistance gene mutations. This will provide evidence to support the continuous use of ACTs in the treatment of uncomplicated P. falciparum malaria. Moreover, it is also hoped that potential hotspots driving the emergence and spread of anti-malarial resistance markers will be identified. Systematic review registration: PROSPERO CRD42020162620

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No Evidence of Plasmodium falciparum k13 Artemisinin Resistance-Conferring Mutations over a 24-Year Analysis in Coastal Kenya but a Near Complete Reversion to Chloroquine-Sensitive Parasites

Cited by 39 publications

References 64 publications

Assessment of molecular markers of anti-malarial drug resistance among children participating in a therapeutic efficacy study in western Kenya

Assessment of molecular markers of anti-malarial drug resistance among children participating in a therapeutic efficacy study in western Kenya

Drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon: a systematic review and meta-analysis (1998–2020)

Drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon: a systematic review and meta-analysis protocol

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