Effect of mass dihydroartemisinin–piperaquine administration in southern Mozambique on the carriage of molecular markers of antimalarial resistance

Gupta, Himanshu; Galatas, Beatriz; Chidimatembue, Arlindo; Huijben, Silvie; Cisteró, Pau; Matambisso, Glória; Nhamússua, Lídia; Simone, Wilson; Bassat, Quique; Ménard, Didier; Ringwald, Pascal; Rabinovich, N. Regina; Alonso, Pedro Luis Cano; Saúte, Francisco; Aíde, Pedro; Mayor, Alfredo

doi:10.1371/journal.pone.0240174

Cited by 17 publications

(19 citation statements)

References 52 publications

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“…However, long-term use of anti-malarial drugs particularly PPQ induced ADR [14]. Previous studies indicated that several mutations of pfcrt (93S, 97Y, 101F, 145I, 343L, 353 V, and 356 T) were related to reducing parasite sensitivity to PPQ [13,14,[36][37][38][39]. In this study, no mutations were detected at loci 93, 97, 101, 145, 343, 350, and 353.…”

Section: Discussionmentioning

confidence: 41%

Molecular surveillance of anti-malarial resistance pfcrt, pfmdr1, and pfk13 polymorphisms in African Plasmodium falciparum imported parasites to Wuhan, China

Cheng

Song

Tan

et al. 2021

Malar J

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Background Imported malaria parasites with anti-malarial drug resistance (ADR) from Africa is a serious public health challenge in non-malarial regions, including Wuhan, China. It is crucial to assess the ADR status in African Plasmodium falciparum isolates from imported malaria cases, as this will provide valuable information for rational medication and malaria control. Methods During 2017–2019, a cross-sectional study was carried out in Wuhan, China. Peripheral blood 3 ml of returned migrant workers from Africa was collected. The target fragments from pfcrt, pfmdr1, and k13 propeller (pfk13) genes were amplified, sequenced, and analysed. Results In total, 106 samples were collected. Subsequently, 98.11% (104/106), 100% (106/106), and 86.79% (92/106) of these samples were successfully amplified and sequenced for the pfcrt (72–76), pfmdr1, and pfk13 genes, respectively. The prevalence of the pfcrt 76 T, pfmdr1 86Y, and pfmdr1 184F mutations was 9.62, 4.72, and 47.17%, respectively. At codons 72–76, the pfcrt locus displayed three haplotypes, CVMNK (wild-type), CVIET (mutation type), CV M/I N/E K/T (mixed type), with 87.50%, 9.62%, and 2.88% prevalence, respectively. For the pfmdr1 gene, NY (wild type), NF and YF (mutant type), N Y/F, Y Y/F, and N/Y Y/F (mixed type) accounted for 34.91, 43.40, 3.77, 15.09, 0.94, and 1.89% of the haplotypes, respectively. A total of 83 isolates with six unique haplotypes were found in pfcrt and pfmdr1 combined haplotypes, of which NY-CVMNK and NF-CVMNK accounted for 40.96% (34/83) and 43.37% (36/83), respectively. Furthermore, 90 cases were successfully sequenced (84.91%, 90/106) at loci 93, 97, 101, and 145, and 78 cases were successfully sequenced (73.58%, 78/106) at loci 343, 353, and 356 for pfcrt. However, the mutation was observed only in locus 356 with 6.41%. For pfk13, mutations reported in Southeast Asia (at loci 474, 476, 493, 508, 527, 533, 537, 539, 543, 553, 568, 574, 578, and 580) and Africa (at loci 550, 561, 575, 579, and 589) were not observed. Conclusions The present data from pfcrt and pfmdr1 demonstrate that anti-malarial drugs including chloroquine, amodiaquine, and mefloquine, remain effective against malaria treatment in Africa. The new mutations in pfcrt related to piperaquine resistance remain at relatively low levels. Another source of concern is the artemether-lumefantrine resistance-related profiles of N86 and 184F of pfmdr1. Although no mutation in pfk13 is detected, molecular surveillance must continue.

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Section: Discussionmentioning

confidence: 41%

Molecular surveillance of anti-malarial resistance pfcrt, pfmdr1, and pfk13 polymorphisms in African Plasmodium falciparum imported parasites to Wuhan, China

Cheng

Song

Tan

et al. 2021

Malar J

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“…There is longstanding concern regarding the potential for MDA to introduce widespread drug resistance, such as observed with the use of table salt containing CQ starting in the 1950s ( von Seidlein and Greenwood, 2003 ). However, so far there remains an absence of evidence linking direct MDA using therapeutic doses of an artemisinin-based drug combination (ACT) such as DHAPQ, with emerging drug resistance ( Deng et al, 2018 ; Gupta et al, 2020 ; Landier et al, 2018 ).…”

Section: Impact and Consequences Of Population-level Drug-based Interventions: Smc Mdamentioning

confidence: 99%

Genetic surveillance for monitoring the impact of drug use on Plasmodium falciparum populations

Ndiaye

Hartl

McGregor

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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The use of antimalarial drugs is an effective strategy in the fight against malaria. However, selection of drug resistant parasites is a constant threat to the continued use of this approach. Antimalarial drugs are used not only to treat infections but also as part of population-level strategies to reduce malaria transmission toward elimination. While there is strong evidence that the ongoing use of antimalarial drugs increases the risk of the emergence and spread of drug-resistant parasites, it is less clear how population-level use of drug-based interventions like seasonal malaria chemoprevention (SMC) or mass drug administration (MDA) may contribute to drug resistance or loss of drug efficacy. Critical to sustained use of drug-based strategies for reducing the burden of malaria is the surveillance of population-level signals related to transmission reduction and resistance selection. Here we focus on Plasmodium falciparum and discuss the genetic signatures of a parasite population that are correlated with changes in transmission and related to drug pressure and resistance as a result of drug use. We review the evidence for MDA and SMC contributing to malaria burden reduction and drug resistance selection and examine the use and impact of these interventions in Senegal. Throughout we consider best strategies for ongoing surveillance of both population and resistance signals in the context of different parasite population parameters. Finally, we propose a roadmap for ongoing surveillance during population-level drug-based interventions to reduce the global malaria burden.

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“…High prevalence of multiple copies of the plasmepsin 2 ( Pfpm2 ) gene, a marker of piperaquine resistance [ 15 ], has been observed to be associated with DP treatment failure in Southeast Asian countries, where artemisinin resistance is frequent [ 16 – 18 ]. Studies on African isolates showed varying frequencies of multiple copies of Pfpm2 gene: < 5% in Mozambique [ 19 ], 30.5% and 33.9% in Burkina Faso and Uganda, respectively [ 20 ], and up to 50% in Burundi [ 3 ]. However, in high transmission areas like Africa, the detection of minor clones with amplified Pfpm2 in polyclonal infections (MOI > 1) are challenging.…”

Section: Introductionmentioning

confidence: 99%

Artesunate–amodiaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: in vivo efficacy and frequency of molecular markers

Koko¹,

Warsame

Vonhm

et al. 2022

Malar J

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Background Artesunate–amodiaquine (ASAQ) and Artemether–lumefantrine (AL) are the recommended treatment for uncomplicated Plasmodium falciparum malaria in Liberia. Intermittent preventive treatment with sulfadoxine/pyrimethamine is also recommended for pregnant women. The therapeutic efficacy of Artesunate–amodiaquine and Artemether–lumefantrine, and the frequency of molecular markers associated with anti-malarial drug resistance were investigated. Methods The therapeutic efficacy of ASAQ and AL was evaluated using the standard World Health Organization protocol (WHO. Methods for Surveillance of Antimalarial Drug Efficacy. Geneva: World Health Organization; 2009. https://www.who.int/malaria/publications/atoz/9789241597531/en/). Eligible children were recruited and monitored clinically and parasitologically for 28 days. Polymorphisms in the Pfkelch 13, chloroquine resistance transporter (Pfcrt), multidrug resistance 1 (Pfmdr-1), dihydrofolate reductase (Pfdhfr), and dihydropteroate synthase (Pfdhps) genes and copy number variations in the plasmepsin-2 (Pfpm2) gene were assessed in pretreatment samples. Results Of the 359 children enrolled, 180 were treated with ASAQ (89 in Saclepea and 91 in Bensonville) and 179 with AL (90 in Sinje and 89 in Kakata). Of the recruited children, 332 (92.5%) reached study endpoints. PCR-corrected per-protocol analysis showed ACPR of 90.2% (95% CI: 78.6–96.7%) in Bensonville and 92.7% (95% CI: 83.4.8–96.5%) in Saclepea for ASAQ, while ACPR of 100% was observed in Kakata and Sinje for AL. In both treatment groups, only two patients had parasites on day 3. No artemisinin resistance associated Pfkelch13 mutations or multiple copies of Pfpm2 were found. Most samples tested had the Pfcrt 76 T mutation (80/91, 87.9%), while the Pfmdr-1 86Y (40/91, 44%) and 184F (47/91, 51.6%) mutations were less frequent. The Pfdhfr triple mutant (51I/59R/108 N) was the predominant allele (49.2%). For the Pfdhps gene, it was the 540E mutant (16.0%), and the 436A mutant (14.3%). The quintuple allele (51I/59R/108 N-437G/540E) was detected in only one isolate (1/357). Conclusion This study reports a decline in the efficacy of ASAQ treatment, while AL remained highly effective, supporting the recent decision by NMCP to replace ASAQ with AL as first-line treatment for uncomplicated falciparum malaria. No association between the presence of the mutations in Pfcrt and Pfmdr-1 and the risk of parasite recrudescence in patients treated with ASAQ was observed. Parasites with signatures known to be associated with artemisinin and piperaquine resistance were not detected. The very low frequency of the quintuple Pfdhfr/Pfdhps mutant haplotype supports the continued use of SP for IPTp. Monitoring of efficacy and resistance markers of routinely used anti-malarials is necessary to inform malaria treatment policy. Trial registration ACTRN12617001064392.

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Effect of mass dihydroartemisinin–piperaquine administration in southern Mozambique on the carriage of molecular markers of antimalarial resistance

Cited by 17 publications

References 52 publications

Molecular surveillance of anti-malarial resistance pfcrt, pfmdr1, and pfk13 polymorphisms in African Plasmodium falciparum imported parasites to Wuhan, China

Molecular surveillance of anti-malarial resistance pfcrt, pfmdr1, and pfk13 polymorphisms in African Plasmodium falciparum imported parasites to Wuhan, China

Genetic surveillance for monitoring the impact of drug use on Plasmodium falciparum populations

Artesunate–amodiaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: in vivo efficacy and frequency of molecular markers

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