Mutation Profile of
            <i>pfdhfr</i>
            and
            <i>pfdhps</i>
            in Plasmodium falciparum among Returned Chinese Migrant Workers from Africa

Xu, Chun‐Fang; Sun, Hao; Wei, Quan; Li, Jin; Xiao, Ting; Kong, Xiangli; Wang, Yongbin; Zhao, Guihua; Wang, Longjiang; Liu, Gongzhen; Gao, Yan; Huang, Baoyu; Yin, Kun

doi:10.1128/aac.01927-18

Cited by 17 publications

(15 citation statements)

References 16 publications

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“…An evaluation of gene polymorphisms of the Pfdhfr revealed that the triple IRN mutant haplotype was the most reported in 18 studies with the minimum prevalence of 4.3% [ 79 ] and a maximum prevalence of 100.0% [ 54 , 58 ]. Only 10 studies reported the quadruple IRNG mutant haplotype involving Pfdhfr and Pfdhps with the highest prevalence of 95.9% [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…Only 10 studies reported the quadruple IRNG mutant haplotype involving Pfdhfr and Pfdhps with the highest prevalence of 95.9% [ 60 ]. Moreover, Pfdhfr / Pfdhps quintuple haplotype IRNGE was identified in 3 studies [ 58 , 60 , 79 ] with a maximum prevalence of 16.7% [ 58 ] (Additional file 7 ).…”

Section: Resultsmentioning

confidence: 99%

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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“…Over one third (37.5%) of P. falciparum isolates sampled here were “quintuple mutants” for five dhfr and dhps alleles that confer strong SP resistance ( IRN S GE A, Table 2 ). For comparison, this haplotype was not observed among 66 samples collected in Uíge in 2004 [ 36 ], and was present in only 11.6% of samples from migrant workers collected between 2013–2016 [ 37 ]. A different set of five markers ( IRNAG KA) was found in 15.6% of isolates in this study, while 43.7% contained four markers ( IRN S G KA or I C NAG KA).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to markers of CQ resistance, markers of SP resistance have been on the rise in several African countries [ 40 , 41 , 47 – 49 ] where SP is used for malaria treatment and prevention. In Angola, the available data suggest a rapid increase in the prevalence of SP-resistant “quintuple mutants” in dhfr/dhps between 2004 (0%) [ 36 ], 2013–2016 (11.6%) [ 37 ], and 2018 (Table 2 , 37.5%). This increase could be partially driven by the rise of one particular marker, dhfr 59R (Table 5 ), although dhfr/dhps genetic diversity may also vary among sites [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Historical trends and new surveillance of Plasmodium falciparum drug resistance markers in Angola

Ebel

Reis

Petrov

et al. 2021

Malar J

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Background Plasmodium falciparum resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) has historically posed a major threat to malaria control throughout the world. The country of Angola officially replaced CQ with artemisinin-based combination therapy (ACT) as a first-line treatment in 2006, but malaria cases and deaths have recently been rising. Many classic resistance mutations are relevant for the efficacy of currently available drugs, making it important to continue monitoring their frequency in Angola. Methods Plasmodium falciparum DNA was sampled from the blood of 50 hospital patients in Cabinda, Angola from October-December of 2018. Each infection was genotyped for 13 alleles in the genes crt, mdr1, dhps, dhfr, and kelch13, which are collectively involved in resistance to six common anti-malarials. To compare frequency patterns over time, P. falciparum genotype data were also collated from studies published from across Angola in the last two decades. Results The two most important alleles for CQ resistance, crt 76T and mdr1 86Y, were found at respective frequencies of 71.4% and 6.5%. Historical data suggest that mdr1 N86 has been steadily replacing 86Y throughout Angola in the last decade, while the frequency of crt 76T has been more variable across studies. Over a third of new samples from Cabinda were ‘quintuple mutants’ for SP resistance in dhfr/dhps, with a sixth mutation at dhps A581G present at 9.6% frequency. The markers dhfr 51I, dhfr 108N, and dhps 437G have been nearly fixed in Angola since the early 2000s, whereas dhfr 59R may have risen to high frequency more recently. Finally, no non-synonymous polymorphisms were detected in kelch13, which is involved in artemisinin resistance in Southeast Asia. Conclusions Genetic markers of P. falciparum resistance to CQ are likely declining in frequency in Angola, consistent with the official discontinuation of CQ in 2006. The high frequency of multiple genetic markers of SP resistance is consistent with the continued public and private use of SP. In the future, more complete haplotype data from mdr1, dhfr, and dhps will be critical for understanding the changing efficacy of multiple anti-malarial drugs. These data can be used to support effective drug policy decisions in Angola.

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“…Each point represents the total number of resistance allels in both genes from a single isolate. Solid points indicate new data from this study; historical data are from32,38,41 . Points are jittered horizontally and vertically for clarity.…”

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confidence: 99%

Shifts in antimalarial drug policy since 2006 have rapidly selectedP. falciparumresistance alleles in Angola

Ebel

Reis²,

Petrov

et al. 2020

Preprint

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BACKGROUNDPlasmodium falciparum resistance to chloroquine (CQ), the most widely used antimalarial drug, has historically posed a major threat to malaria control in Angola and throughout the world. Although Angola replaced CQ with artemisinin combination therapy (ACT) as a frontline treatment in 2006, malaria cases and deaths have recently been rising. CQ-resistance mutations may still be a contributing factor, given that (1) some also modulate resistance to ACT partner drugs and (2) ACT is not yet consistently implemented across Angola. It is important to continue monitoring all known resistance alleles in P. falciparum, but no studies have done so in Angola since 2012.METHODSWe sampled P. falciparum DNA from the blood of 50 hospital patients in Cabinda, Angola in 2018. Each infection was genotyped for 13 alleles in the genes crt, mdr1, dhps, dhfr, and kelch13, which collectively confer resistance to six common drugs. To analyze frequency trajectories over time, we also collated P. falciparum genotype data published from across Angola in the last two decades.RESULTSThe two most important alleles for CQ resistance, crt 72-76CVIET and mdr1 86Y, have both declined in frequency from respective highs of 98% in 1999 and 73% in 2003. However, the former remains at 71% frequency in this sample while the latter has dropped to just 7%. Of seven possible alleles for sulfadoxine-pyrimethamine (SP) resistance in dhps and dhfr, the average total number per isolate increased from 2.9 in 2004 to 4.4 in 2018. Finally, we detected no non-synonymous polymorphisms in kelch13, which is involved in artemisinin resistance in Southeast Asia.CONCLUSIONSChanges in drug policy in Angola since 2006 appear to have exerted strong selection on P. falciparum drug resistance alleles. Resistance to CQ is declining, but due to functional tradeoffs and novel selection at mdr1 loci, resistance to ACT partner drugs appears to be rising. More haplotype-based studies at mdr1 will be needed to understand the changing efficacy of multiple drugs. Finally, SP resistance has jumped rapidly since 2014, consistent with widespread use of intermittent SP treatment during pregnancy. These data can be used to support effective drug policy decisions in Angola.

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Mutation Profile of pfdhfr and pfdhps in Plasmodium falciparum among Returned Chinese Migrant Workers from Africa

Cited by 17 publications

References 16 publications

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 (1998–2020)

Historical trends and new surveillance of Plasmodium falciparum drug resistance markers in Angola

Shifts in antimalarial drug policy since 2006 have rapidly selectedP. falciparumresistance alleles in Angola

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